tag:blogger.com,1999:blog-14221584874201016972024-03-07T19:41:46.588-08:00Pharmaceutical Formulationpharmaceuticalformulationhttp://www.blogger.com/profile/15915251551551692435noreply@blogger.comBlogger1125tag:blogger.com,1999:blog-1422158487420101697.post-7161484875984075502008-04-14T05:44:00.000-07:002008-04-14T05:58:27.454-07:00WHO EXPERT COMMITTEE<br />ON SPECIFICATIONS FOR<br />PHARMACEUTICAL PREPARATIONS<br /><br /><br /><br /><br /><br />Contents<br />1. Introduction 1<br />2. Quality control — specifications and tests 2<br />2.1 The international pharmacopoeia — 50 years on 2<br />2.2 Monographs for The international pharmacopoeia 3<br />2.3 Dissolution test requirements for individual monographs 3<br />2.4 Basic tests for pharmaceutical substances and dosage forms 3<br />3. Quality control — reference materials 4<br />3.1 International Chemical Reference Substances 4<br />3.2 International Infrared Reference Spectra 4<br />3.3 Biological reference materials 5<br />3.4 Information on reference materials for pharmacopoeial analysis 5<br />4. Quality control — pharmaceutical control laboratories 5<br />4.1 Good practices for national pharmaceutical control laboratories 5<br />4.2 Equipment for drug control laboratories 6<br />4.3 Requests for analysis of drug samples 6<br />4.4 External quality assessment 6<br />5. Quality assurance — good manufacturing practices 6<br />5.1 Good manufacturing practices in pharmaceutical production 6<br />5.2 Good manufacturing practices for sterile pharmaceutical<br />products 7<br />5.3 Guidelines for good storage practices 7<br />5.4 Hazard analysis and critical control point system 7<br />6. Quality assurance — inspection 7<br />6.1 Pre-approval inspections 7<br />6.2 Quality systems for national GMP inspectorates 8<br />7. Quality assurance — packaging 8<br />7.1 General aspects of packaging 8<br />7.2 Glass containers for pharmaceutical use and rubber closures<br />for containers of pharmaceuticals 8<br />8. Quality assurance — general topics 8<br />8.1 Starting materials for pharmaceutical products: control and<br />safe trade 8<br />8.2 Model certificate of analysis for use in trade and procurement 9<br />8.3 Screening tests for antimalarials and antituberculosis drugs 9<br />8.4 Tuberculosis programme — fixed-dose combinations 9<br />8.5 Comparator products for equivalence assessment of<br />interchangeable multisource (generic) products 10<br />8.6 Measures to combat counterfeit drugs 10<br />8.7 Information on general publications 11<br />9. Nomenclature and computerized systems 11<br />9.1 International Nonproprietary Names for pharmaceutical<br />substances 11.iv<br />9.2 Regulatory information systems 12<br />9.3 Drug quality assurance terminology 12<br />10. Regulatory issues 12<br />10.1 Harmonization of regulatory requirements 12<br />Acknowledgements 13<br />References 15<br />Annex 1<br />List of available International Chemical Reference Substances 18<br />Annex 2<br />List of available International Infrared Reference Spectra 25<br />Annex 3<br />Good practices for national pharmaceutical control laboratories 27<br />Annex 4<br />Considerations for requesting analysis of drug samples 69<br />Annex 5<br />Basic elements of good manufacturing practices in pharmaceutical<br />production 73<br />Annex 6<br />Good manufacturing practices for sterile products 76<br />Annex 7<br />Guidelines on pre-approval inspections 94<br />Annex 8<br />Quality systems requirements for national good manufacturing practice<br />inspectorates 101<br />Annex 9<br />Guidelines on packaging for pharmaceutical products 119<br />Annex 10<br />Model certificate of analysis 157<br />Annex 11<br />Guidance on the selection of comparator pharmaceutical products for<br />equivalence assessment of interchangeable multisource (generic) products 161<br />Annex 12<br />Guidelines on the use of International Nonproprietary Names (INNs) for<br />pharmaceutical substances 181.v<br /><br />1. Introduction<br />The WHO Expert Committee on Specifications for Pharmaceutical<br />Preparations met in Geneva from 31 May to 4 June 1999. The meeting<br />was opened on behalf of the Director-General by Dr M. Scholtz,<br />Executive Director of Health Technology and Pharmaceuticals, who<br />stressed that it was of the utmost importance that WHO should vigor-ously<br />maintain and strengthen its constitutional responsibility for<br />setting clear and practical norms if it was to meet the needs and<br />expectations of its 191 Member States. Essential drugs were recog-nized<br />as a high priority, but WHO also needed to maintain all its<br />activities concerned with drugs, including innovative products. A cru-cial<br />part of the quality assurance programme was the network of 13<br />WHO collaborating centres, whose activities included the verifica-tion<br />of test methods, the establishment of reference materials, and<br />training. During the World Health Assembly in May 1999, concern<br />had been expressed about persistent problems in ensuring the quality<br />of medicines and their starting materials. Member States were urged<br />to establish and enforce regulations to ensure quality assurance of<br />pharmaceuticals, and WHO was called on to extend guidelines in-corporated<br />in the WHO Certification Scheme on the Quality of<br />Pharmaceutical Products Moving in International Commerce (1) to<br />cover pharmaceutical starting materials. WHO was also called on to<br />develop further training tools for inspectors to ensure compliance<br />with good manufacturing practices (GMP) published by WHO.<br />Dr Scholtz also emphasized the importance of the links between the<br />setting and the implementation of normative standards, and urged<br />the Expert Committee to keep those links in mind throughout its<br />discussions.<br />The Ninth International Conference of Drug Regulatory Authorities<br />(ICDRA), held in Berlin in April 1999, had reviewed progress made<br />in the international harmonization of regulatory requirements, and<br />the collaboration between WHO and the International Conference<br />on Harmonisation (ICH). WHO’s role was to ensure that the advan-tages<br />of harmonization were of benefit to all concerned (as endorsed<br />by the World Health Assembly in resolution WHA45.28; 2).<br />Dr J.D. Quick, Director, Essential Drugs and other Medicines,<br />briefed the Committee on the new headquarters structure of WHO,<br />and outlined new challenges for WHO in the area of pharmaceuticals<br />and biologicals. These included, inter alia, increased internationaliza-tion<br />of the trade in, and production of, starting materials, intermedi-ates<br />and finished products. A matter of serious concern was that drugs.2<br />of poor quality that were ineffective and harmful remained on sale.<br />Only one-sixth of the 191 WHO Member States had well-developed<br />capacities for drug regulation. WHO’s strategies to meet these chal-lenges<br />included the provision of global guidance by means of interna-tionally<br />applicable norms and standards, and the strengthening of<br />national drug regulation (through, for example, guidelines, manuals<br />and training on GMP, laboratory practices, inspection and registra-tion).<br />WHO facilitated communication and information exchange<br />through newsletters and bodies such as the Association of South-East<br />Asian Nations (ASEAN) and the African Drug Regulatory Authori-ties<br />Network (AFDRAN), and provided a forum for regulators.<br />Dr J. Idänpään-Heikkilä, Special Adviser on Quality Assurance and<br />Safety within Health Technology and Pharmaceuticals, informed the<br />Committee of the progress made in drug quality assurance since its<br />last meeting. Because of the concern that exists regarding the control<br />of starting materials, a meeting was held in 1998 at which proposals<br />were made for a model certificate of analysis, and for expansion of the<br />WHO Certification Scheme on the Quality of Pharmaceutical Prod-ucts<br />Moving in International Commerce to include starting materials,<br />as well as brokers and traders in such materials (3). Efforts to enhance<br />the implementation of GMP and to create an awareness of the need<br />to produce good quality products, as well as the preparation of train-ing<br />modules for GMP inspectors, were also proposed.<br />A list of international comparator products, together with guidance<br />on how best to choose such a product for the purpose of assessing<br />interchangeability, had been drafted in collaboration with drug regu-latory<br />authorities and the pharmaceutical industry. This list was pre-sented<br />to the Committee, which was asked to consider its adoption.<br />Collaboration with the World Intellectual Property Organization<br />(WIPO) for the protection of International Nonproprietary Names<br />(INNs) had also been strengthened. The Committee was further in-formed<br />that WHO retained its observer status in ICH and continued<br />its role in ICDRA.<br />2. Quality control — specifications and tests<br />2.1 The international pharmacopoeia — 50 years on<br />The Committee confirmed that publication of The international phar-macopoeia<br />(4) continued to fulfil a need in developing countries by<br />providing less technically advanced tests for specific substances and<br />preparations. The usefulness of monographs for finished products was<br />also confirmed..3<br />The Committee discussed the merits of introducing modern analytical<br />techniques. It was recognized that such new techniques could some-times<br />be more sensitive, rapid and robust, as well as potentially less<br />expensive. However, there was still a need for less advanced methods.<br />It was proposed that information on both types of methods might<br />be provided in parallel, with the newer techniques indicated as the<br />first choice and the less advanced methods as alternatives. Thus,<br />where resources permitted, the more technically advanced methods<br />should be used. However, the possibility of using the less advanced<br />alternative methods to check compliance with pharmacopoeial<br />specifications, where necessary, would increase the usefulness of The<br />international pharmacopoeia. In making these proposals, the Com-mittee<br />emphasized the importance of compliance with pharmacopoe-ial<br />requirements as part of the overall strategy for detecting<br />counterfeit and substandard products (5). The introduction of alter-native<br />methods would require careful presentation, and it was recom-mended<br />that a statement should be inserted in Volume 5 of The<br />international pharmacopoeia to introduce the concept, together with<br />the use of appropriate headings. This would reiterate that implemen-tation<br />of The international pharmacopoeia was the responsibility of<br />national drug authorities.<br />2.2 Monographs for The international pharmacopoeia<br />The Committee was pleased to note that a number of additional<br />monographs for drug substances, pharmaceutical preparations (e.g.<br />tablets) and excipients are nearing completion for inclusion in The<br />international pharmacopoeia. It approved the inclusion of mono-graphs<br />for antimalarials in Volume 5 of The international pharmaco-poeia,<br />which is currently in press.<br />2.3 Dissolution test requirements for individual monographs<br />The Committee was informed that the WHO collaborating centres<br />were assisting with proposals on work in establishing dissolution re-quirements,<br />test conditions and acceptance criteria (limits) for certain<br />monographs. The Committee supported the concept of cooperation<br />with the International Pharmaceutical Federation (FIP) in hands-on<br />courses on dissolution testing. It is envisaged that WHO collaborating<br />centres might provide a venue for such courses and that attendance<br />would be open to participants from national control laboratories and<br />the pharmaceutical industry.<br />2.4 Basic tests for pharmaceutical substances and dosage forms<br />The Committee was informed of progress in the development of basic<br />tests, and verification by the collaborating laboratories. So far, three.4<br />volumes (Basic tests for pharmaceutical substances, Basic tests for<br />pharmaceutical dosage forms and Basic tests for drugs: pharmaceutical<br />substances, medicinal plant materials and dosage forms (6–8)) have<br />been published. These volumes now include 345 basic tests for sub-stances,<br />208 for dosage forms and four for medicinal plant materials.<br />The next volume will be made available once a sufficient number of<br />tests have been developed and verified.<br />The need for four verifications of each test for dosage forms as<br />currently applied according to Annex 6 of the Committee’s twenty-ninth<br />report (9) was discussed. The possibility of accepting three<br />verifications was suggested, provided that there were no significant<br />differences between the results. The use of additional laboratories,<br />and encouraging feedback from those using the tests, was advocated.<br />3. Quality control — reference materials<br />3.1 International Chemical Reference Substances<br />The 1997 and 1998 reports of the WHO Collaborating Centre for<br />Chemical Reference Substances were presented to the Committee.<br />Nine new International Chemical Reference Substances (ICRS)<br />1<br />were adopted by the Committee according to the procedure de-scribed<br />in its thirty-second report (10). The recommendation to with-draw<br />the reference substance for tubocurarine hydrochloride was<br />endorsed since it is no longer required. The total collection now<br />comprises 205 chemical reference substances and 12 melting-point<br />reference substances (Annex 1).<br />The Committee adopted the reports and expressed its appreciation to<br />the WHO Collaborating Centre for Chemical Reference Substances<br />for its work, and to the National Corporation of Swedish Pharmacies<br />for its continued financial support to the WHO programme on ICRS.<br />3.2 International Infrared Reference Spectra<br />A total of 69 International Infrared Reference Spectra (IIRS) are<br />currently available from the WHO Collaborating Centre for Chemi-cal<br />Reference Substances, Kungens Kurva, Sweden (Annex 2). The<br />Committee acknowledged the contribution of the WHO Collaborat-ing<br />Centre for International Infrared Reference Spectra, Zurich,<br />1<br />Captopril, captopril disulfide, ciprofloxacin hydrochloride, cisplatin, kanamycin<br />monosulfate, piperazine adipate, piperazine citrate, sodium amidotrizoate and<br />streptomycin sulfate..5<br />Switzerland, which prepares the spectra. It was agreed that in future<br />the infrared reference spectra would be recorded on a Fourier trans-form<br />infrared spectroscopy instrument and that they should be pub-lished<br />in reduced size, either in The international pharmacopoeia or as<br />a separate publication.<br />3.3 Biological reference materials<br />The Committee noted that the WHO Expert Committee on Biologi-cal<br />Standardization was carrying out a review of biological reference<br />materials. Any such materials proposed for discontinuation as a<br />biological reference material would be assessed by the WHO Col-laborating<br />Centre for Chemical Reference Substances for its potential<br />suitability for use as an ICRS.<br />3.4 Information on reference materials for pharmacopoeial<br />analysis<br />The Committee noted that the comprehensive list of reference<br />substances and infrared reference spectra is regularly updated and<br />available on the Internet at http://www.who.int/medicines.<br />4. Quality control — pharmaceutical control<br />laboratories<br />4.1 Good practices for national pharmaceutical control<br />laboratories<br />The Committee adopted the revised guidelines (11) on good practices<br />for national pharmaceutical control laboratories (GPCL) (Annex 3).<br />The new title was chosen to emphasize that these guidelines were<br />intended primarily for national control laboratories. They take into<br />account other existing guidance on the subject, including that pro-vided<br />by the International Organization for Standardization (12),<br />the Organisation for Economic Co-operation and Development (13)<br />and the Swiss Association for Standardization (14), as well as the<br />recommendations on a quality system for official medicines control<br />laboratories, published by the Pharmaceutical Inspection Convention<br />(PIC) (15).<br />The importance of these guidelines should be drawn to the attention<br />of the national drug control authorities that would be responsible for<br />their implementation. It should be noted that a model test report for<br />active pharmaceutical ingredients, excipients and medicinal products<br />is appended to the guidelines..6<br />4.2 Equipment for drug control laboratories<br />The Committee adopted a revised list of equipment for pharmaceuti-cal<br />control laboratories to be appended to the GPCL (see Annex 3).<br />National control laboratories may contact the WHO Secretariat for<br />detailed information on costs.<br />4.3 Requests for analysis of drug samples<br />The Committee adopted recommendations to countries which need<br />to request the analysis of drug samples, e.g. where a national control<br />laboratory does not exist, or where it lacks competence in a particular<br />technique. These recommendations (Annex 4) are applicable to drug<br />regulatory authorities but may also be suitable for the independent<br />analysis of pharmaceuticals in trade.<br />4.4 External quality assessment<br />The Committee was informed that, since its previous meeting, 12<br />national quality control laboratories had been identified and had<br />agreed to participate in a pilot external quality assessment pro-gramme.<br />Progress would be reported at its next meeting.<br />5. Quality assurance — good manufacturing<br />practices<br />5.1 Good manufacturing practices in pharmaceutical production<br />The Committee acknowledged the importance of putting norms and<br />standards into practice. If GMP are to be implemented in countries,<br />decision-makers at all levels in the national public health sector must<br />be properly informed about them and convinced of their importance.<br />Information on the progress made with the project on the implemen-tation<br />of GMP in Member States was reported. Training material on<br />basic GMP principles had been prepared and training modules for<br />advanced GMP topics were planned. It was anticipated that the<br />project would include initial consultation, review and planning; the<br />preparation of training modules; country visits and training in<br />the performance of GMP inspections; the preparation of advanced<br />training modules in validation, water supply and sterile product<br />manufacture; and follow-up workshops. The possibility of establish-ing<br />training networks was considered, in order to establish a training<br />cascade, i.e. to train trainers, who in turn would train others.<br />The objective of the project was to improve the implementation of<br />GMP in countries. The selection criteria to be met by the countries.7<br />involved included their willingness and commitment to partici-pate,<br />and the presence of local and multinational pharmaceutical<br />manufacturers.<br />The Committee endorsed the project and encouraged the Secretariat<br />to continue work in this area.<br />Information on the basic elements of GMP in pharmaceutical produc-tion<br />is needed by interested parties and decision-makers at all levels,<br />and the provision of such information is encouraged. A brief sum-mary,<br />intended mainly for non-specialists, is given in Annex 5.<br />5.2 Good manufacturing practices for sterile pharmaceutical<br />products<br />A revised text for the section of the GMP guidelines dealing with<br />sterile products (16, section 17) was adopted (Annex 6). This took<br />account of the European and other guidelines (17, 18) and comments<br />received, which supported harmonization.<br />5.3 Guidelines for good storage practices<br />The Committee encouraged the Secretariat to collaborate with FIP<br />on guidelines for good storage practices. It was noted that a draft<br />prepared by FIP was already available.<br />5.4 Hazard analysis and critical control point system<br />A system known as the hazard analysis and critical control point<br />system (HACCP) was brought to the attention of the Committee.<br />While to date HACCP has been used primarily to assess hazards<br />associated with the production of food, it was recognized that the<br />identification of risks and critical processes is part of GMP. The<br />Secretariat was encouraged to explore and make use of appropriate<br />HACCP documentation that might be useful to illustrate the concepts<br />of GMP.<br />6. Quality assurance — inspection<br />6.1 Pre-approval inspections<br />The Committee adopted the guidelines on pre-approval inspections<br />(Annex 7) which extend the advice provided in the provisional guide-lines<br />on the inspection of pharmaceutical manufacturers in Annex 2<br />of its thirty-second report (19). Conducting inspections before grant-ing<br />marketing authorization could avoid problems at a later stage in<br />the evaluation process. This should assist both regulatory authorities<br />and manufacturers..8<br />6.2 Quality systems for national GMP inspectorates<br />The Committee adopted the guidelines given in Annex 8, which are<br />based on PIC recommendations for PIC Contracting States (20).<br />Recommendations and requirements for quality systems for the<br />operation of inspection services within a competent authority con-cerned<br />with GMP inspections are given, relating to administrative<br />structure, organization, personnel, records, inspection procedures,<br />confidentiality and internal audits. These guidelines are intended for<br />use by inspection services as the basis for developing their own quality<br />systems.<br />7. Quality assurance — packaging<br />7.1 General aspects of packaging<br />The Committee adopted a text relating to packaging material which is<br />addressed mainly to those involved in the supply of pharmaceuticals,<br />but also contains important information and references for their de-velopment,<br />manufacture and quality control (Annex 9). It focuses on<br />the role of packaging in relation to the stability of pharmaceuticals<br />and the potential for counterfeiting. The objective is to ensure that<br />medicines arrive safely in the hands of the patients for whom they are<br />intended.<br />7.2 Glass containers for pharmaceutical use and rubber closures<br />for containers of pharmaceuticals<br />The Committee approved two texts for inclusion in The international<br />pharmacopoeia. They provide information on the types and use of<br />glass containers and rubber closures for pharmaceutical purposes.<br />8. Quality assurance — general topics<br />8.1 Starting materials for pharmaceutical products: control and<br />safe trade<br />Further to the discussion during the thirty-fifth meeting of the Com-mittee<br />(21) on pharmaceuticals contaminated with diethylene glycol,<br />several activities aimed at ensuring the control of, and safe trade in,<br />starting materials for pharmaceutical products have been identified.<br />The Committee was informed of the report and recommendations of<br />a meeting on this subject that had been held in Geneva in May 1998<br />(3). The Committee noted that the World Health Assembly had<br />adopted the proposed resolution on the revised drug strategy.9<br />(WHA52.19) in May 1999 (22). Efforts were needed to promote<br />increased awareness of existing guidelines. The Committee noted that<br />several recommendations were made in the report for action by gov-ernments,<br />manufacturers, traders and brokers, as well as by WHO,<br />which would need to collaborate with all the parties involved. It was<br />suggested that the above-mentioned recommendations should be<br />consolidated and priorities assigned, and the resulting document cir-culated<br />widely among associations and representative bodies.<br />8.2 Model certificate of analysis for use in trade and procurement<br />A model certificate of analysis was adopted (Annex 10) for use in<br />trade in starting materials and for manufacturers of pharmaceutical<br />substances, excipients and medicinal products, as recommended by<br />World Health Assembly resolution WHA52.19 (22).<br />8.3 Screening tests for antimalarials and antituberculosis drugs<br />In view of the high priority of WHO’s Roll Back Malaria and Stop TB<br />programmes, the Committee emphasized the importance of the dif-ferent<br />projects being conducted in a number of Member States aimed<br />at developing methods for the rapid detection of counterfeit and<br />substandard drugs. These would be a useful supplement to the WHO<br />basic tests (6–8). In particular, it was agreed that thin-layer chroma-tography<br />(TLC) was a useful method for the rapid screening of<br />pharmaceuticals.<br />In line with established practice in The international pharmacopoeia<br />and the basic tests, the use of hazardous solvents such as chloroform<br />and ether should be avoided, and an effort should be made to mini-mize<br />the quantities of any solvents used. This is consistent with cur-rent<br />safety and environmental considerations.<br />For both the malaria and tuberculosis programmes, the Committee<br />encouraged the preparation of test manuals to incorporate all rel-evant<br />tests focused on the particular drug groups concerned. Such<br />manuals should reflect the stepwise approach of progressing first from<br />basic tests to screening methods and then to full pharmacopoeial<br />analysis.<br />8.4 Tuberculosis programme — fixed-dose combinations<br />The Committee was informed of WHO treatment policies for tuber-culosis<br />aimed at preventing acquired drug resistance and taking into<br />account the most efficient use of limited resources for combating<br />the disease. The key element is the development and promotion of.10<br />fixed-dose combination (FDC) tablets to replace single drug tablets<br />for the treatment of tuberculosis. FDC tablets simplify drug manage-ment,<br />treatment (increased patient and doctor compliance) and distri-bution.<br />Problems possibly associated with FDC tablets include the<br />management of side-effects, stability, the lack of standardization and<br />the poor bioavailability of rifampicin.<br />It was recommended that the Secretariat should take advantage of the<br />expertise of the Committee to provide advice on the quality assurance<br />aspects of FDC tablets. While appreciating the urgency with which an<br />adequate supply of FDC tablets is required, the Committee empha-sized<br />that quality assurance should not be compromised. Attention<br />should be paid to the pharmaceutical aspects of such tablets, particu-larly<br />their stability and in vitro dissolution. The development of<br />monographs on FDC tablets for The international pharmacopoeia was<br />recommended.<br />8.5 Comparator products for equivalence assessment of<br />interchangeable multisource (generic) products<br />In line with the recommendations made at its previous meeting (21),<br />the Committee adopted the document on “comparator products”<br />(Annex 11). This contains a list of international comparator phar-maceutical<br />products for the equivalence testing and assessment of<br />interchangeable multisource (generic) products and includes a<br />decision-tree for use in identifying comparator pharmaceutical pro-ducts.<br />It was emphasized that the list was intended to serve as an<br />information tool for drug regulatory authorities and pharmaceutical<br />manufacturers. The suggested use of comparator products is not in<br />any way intended to be binding on those responsible for choosing a<br />reference product. The final decision must be made at the national<br />level. The list and the guidance provided will need to be updated<br />periodically.<br />8.6 Measures to combat counterfeit drugs<br />The Committee noted that the guidelines for the development of<br />measures to combat counterfeit and substandard products are ap-proaching<br />finalization. It emphasized the importance of communica-tion<br />among all the bodies involved.<br />Vigilance and the reporting of counterfeit drugs were necessary at all<br />times, rather than only in response to isolated incidents or when<br />special requests for information were made. The Committee encour-aged<br />the sharing of information by national regulatory authorities<br />through the network of liaison officers established to combat counter-feit<br />pharmaceuticals..11<br />8.7 Information on general publications<br />The Committee noted that the Secretariat maintains a number of<br />useful information resources and databases, including WHO drug<br />quality control data, an index of pharmacopoeias, a list of GMP,<br />monographs of national and regional pharmacopoeias, and official<br />compendia. It was suggested that the Secretariat should explore the<br />feasibility of making these more widely available, possibly in elec-tronic<br />form.<br />Publications (in English, French and Spanish) are available, inter alia,<br />on basic tests for pharmaceutical substances, dosage forms and me-dicinal<br />plant materials (6–8). It was noted that the texts on some basic<br />tests have also been translated into Chinese.<br />The Committee noted that Volume 1 of a compilation of various<br />guidelines from previous WHO technical reports has been published<br />under the title Quality assurance of pharmaceuticals: a compendium<br />of guidelines and related materials (23), and that Volume 2, which<br />contains GMP reports and inspection guidelines, is expected to be<br />published shortly.<br />1<br />However, Volume 3 has not yet been planned as<br />compilation will depend on the approval and adoption of reports.<br />Continuation of this work is encouraged to ensure that any changes<br />and additional information will be widely available.<br />The Committee also noted that the tenth cumulative list of INNs for<br />pharmaceutical substances, which includes all INNs published to date,<br />is being prepared.<br />9. Nomenclature and computerized systems<br />9.1 International Nonproprietary Names for pharmaceutical<br />substances<br />The Committee endorsed the guidelines on the use of INNs for phar-maceutical<br />substances (Annex 12).<br />The Committee was informed of the current activities of the<br />programme on INNs for pharmaceutical substances. Since it last met,<br />245 new names have been published as proposed INNs, and 275<br />names have reached recommended INN status. The Committee was<br />1<br />Quality assurance of pharmaceuticals: a compendium of guidelines and related<br />materials. Vol. 2. Good manufacturing practices and inspection. Geneva, World Health<br />Organization, 1999..12<br />pleased with the progress made with regard to the use of INNs in<br />Chinese and Russian.<br />The revision of the procedure for the selection of INNs will attempt to<br />cover aspects such as objections raised to a proposed INN and the<br />replacement of a recommended INN. New developments in naming<br />biotechnology-derived products are also receiving attention. The<br />Committee endorsed the close collaboration with the WHO Expert<br />Committee on Biological Standardization.<br />Closer collaboration with WIPO in the field of protection of INNs has<br />been initiated. WIPO’s Standing Committee on the Law of Trade-marks,<br />Industrial Designs and Geographic Indications has discussed<br />the issue of trademarks and INNs and agreed to conduct a survey to<br />enquire to what extent national patent offices examine trademarks for<br />potential conflict with INNs. Another area of collaboration is with the<br />Internet Corporation for Assigned Names and Numbers (ICANN) in<br />the protection of INNs against misuse in Internet domain names.<br />9.2 Regulatory information systems<br />The Committee supported the investigation undertaken to assess the<br />feasibility of establishing information systems linking drug regulatory<br />authorities with WHO, and considered that such systems would be a<br />useful asset. National drug regulatory authorities should be alerted to<br />the possibility that a global information system may be established by<br />WHO in order to avoid problems of duplication or incompatibility.<br />9.3 Drug quality assurance terminology<br />As a first step towards greater harmonization, the establishment of a<br />glossary of existing terminology was suggested. While maintaining an<br />awareness of other harmonization initiatives is necessary, the first<br />priority should be to ensure consistency within WHO documents.<br />Many of the basic terms and concepts used in quality assurance are<br />the same for biologicals and pharmaceuticals.<br />10. Regulatory issues<br />10.1 Harmonization of regulatory requirements<br />The Committee noted the accelerating pace of regional and interre-gional<br />harmonization activities, particularly those under the auspices<br />of ICH. Recognizing WHO’s international normative responsibilities,<br />the Committee strongly supported WHO’s active participation in<br />such activities. This would facilitate the wider dissemination of.13<br />harmonization proposals and consideration of their applicability to<br />the regulatory situations in Member States at different stages of de-velopment.<br />While WHO was encouraged to take account of interre-gional<br />guidelines, the Committee emphasized the need to use these<br />flexibly when formulating WHO recommendations. The latter should<br />be appropriate for use in the context of the broader constituency of<br />WHO’s 191 Member States.<br />The Committee endorsed the recent ICDRA recommendation of<br />April 1999 that WHO should focus, in particular, on the quality and<br />regulation of multisource (generic) medicinal products. It urged the<br />Secretariat to take measures to make its international normative<br />function more widely known and understood, and to provide informa-tion<br />on its participation in other harmonization activities.<br />Acknowledgements<br />Special acknowledgement was made by the Committee to the following WHO staff<br />members, who assisted in the preparation and proceedings of the meeting: Mrs K.<br />Bremer, Quality Assurance and Safety: Medicines, Essential Drugs and other<br />Medicines; Dr M. Demesmaeker, Quality Assurance and Safety: Medicines,<br />Essential Drugs and other Medicines; Mr P. Graaff, Essential Drugs Programme,<br />WHO Regional Office for the Eastern Mediterranean, Alexandria, Egypt; Dr<br />E. Griffiths, Quality Assurance and Safety: Biologicals, Vaccines and other<br />Biologicals; Dr C.-C. Heuck, Blood Safety and Technology; Dr K. Kimura, Quality<br />Assurance and Safety: Medicines, Essential Drugs and other Medicines; Dr<br />Y. Motarjemi, Protection of the Human Environment; Dr M. Sesay, Policy, Access<br />and Rational Use, Essential Drugs and other Medicines; Dr S. Spinaci, Country<br />Support, Communicable Disease Prevention and Control; Dr G. Szalay, Informatics<br />and Infrastructure Services; Dr M. ten Ham, Drug Safety, Drug Management and<br />Policies; Dr P. Trigg, Communicable Disease Prevention and Control; Mr E.<br />Wondemagegnehu, Quality Assurance and Safety: Medicines, Essential Drugs<br />and other Medicines; Mr T. Yoshida, Quality Assurance and Safety: Medicines,<br />Essential Drugs and other Medicines.<br />The Committee also acknowledged with thanks the valuable contributions made to<br />its work by the following institutions and individuals: WHO Collaborating Centre<br />for Drug Quality Control, Woden, Australian Capital Territory, Australia; WHO<br />Collaborating Centre for Drug Quality Assurance, Beijing, China; WHO<br />Collaborating Centre for Biopharmaceutical Aspects of Drug Quality Control,<br />Clermont-Ferrand, France; WHO Collaborating Centre for Stability Studies of<br />Drugs, Nantes, France; WHO Collaborating Centre for Drug Information and<br />Quality Control, Budapest, Hungary; WHO Collaborating Centre for Drug<br />Information and Quality Assurance of Essential Drugs, Calcutta, India; WHO<br />Collaborating Centre for Quality Assurance of Essential Drugs, Jakarta, Indonesia;<br />WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, Petaling<br />Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Singapore;<br />WHO Collaborating Centre for the Quality Assurance of Drugs, Potchefstroom,<br />South Africa; WHO Collaborating Centre for Chemical Reference Substances,<br />Kungens Kurva, Sweden; WHO Collaborating Centre for International Infrared<br />Reference Spectra, Zurich, Switzerland; WHO Collaborating Centre for Quality<br />Assurance of Essential Drugs, Nonthaburi, Thailand..14<br />Professor R.I. Akubue, University of Nigeria, Nsukka, Nigeria; Mr O. Andriollo,<br />Pharmaciens sans Frontières, Clermont-Ferrand, France; Dr H.E. Bale, Jr,<br />International Federation of Pharmaceutical Manufacturers Associations (IFPMA),<br />Geneva, Switzerland; Professor F. Ballereau, Faculty of Pharmacy, Epidemiology<br />and Public Health, Nantes, France; Dr D. Beck, Basel, Switzerland; Professor R.<br />Boudet-Dalbin, René Descartes University, Paris, France; Mr D.R. Buckley,<br />Therapeutic Goods Administration, Woden, Australian Capital Territory, Australia;<br />Dr Y. Chiu, Office of New Drug Chemistry, Center for Drug Evaluation and<br />Research, Food and Drug Administration, Rockville, MD, USA; Miss M. Cone,<br />IFPMA, Geneva, Switzerland; Mr T. Corquaye, Food and Drugs Board, Accra,<br />Ghana; Mrs E.M. Cortes Montejano, Ministry of Health and Consumer Affairs,<br />Madrid, Spain; Dr R. Dabbah, The United States pharmacopeia, Rockville, MD,<br />USA; Mrs E.F. Damas, Direction de Pharmacie, Ministry of Health, Port-au-Prince,<br />Haiti; Dr G. Détári, National Institute of Pharmacy, Budapest, Hungary; Dr D.<br />Doelcher, West Pharmaceutical Services Deutschland GmbH, Eschweiler,<br />Germany; Mr P. Duneton, Drugs Agency, Saint-Denis, France; Dr R. Freimanis,<br />United States Adopted Names Council, American Medical Association, Chicago,<br />IL, USA; Dr H. Fukuda, Society of Japanese Pharmacopoeia, Tokyo, Japan; Mrs E.<br />Fuller, Geneva, Switzerland; Dr G. Gernez, Villemoisson-sur-Orge, France; Ms E.<br />Gómez, Baxter Laboratories, Cali, Colombia; Dr T. Godschan, Intercantonal Office<br />for the Control of Medicines, Berne, Switzerland; Mr J. Gouws, Medicines Control<br />Council, Cape Town, South Africa; Professor A. Haggag, Alexandria, Egypt; Mr H.<br />Ikäläinen, National Agency for Medicines, Helsinki, Finland; Dr H.J. de Jong,<br />International Regulatory Affairs, Leiden University, Leiden, Netherlands; Dr K.<br />Kawamura, Otsuka Pharmaceutical Co., Tokyo, Japan; Dr M. Keller, Intercantonal<br />Office for the Control of Medicines, Berne, Switzerland; Professor Kil-Soo Kim,<br />Ewha Women’s University, Seoul, Republic of Korea; Mr R. Kuwana, Medicines<br />Control Authority, Harare, Zimbabwe; Mr J. Lanet, Qualassur, Paris, France; Ms K.<br />Lang, Shell Chemicals Ltd, London, England; Dr H. Leblanc, European Chemical<br />Industry Council, Brussels, Belgium; Dr H. Letterman, New Providence, NJ, USA;<br />Mrs V. Li-Frankenstein, UNICEF Supply Division, Copenhagen, Denmark; Dr R.<br />Lindauer, The United States pharmacopeia, Rockville, MD, USA; Professor J.<br />Lipták, National Public Health Service, Budapest, Hungary; Mr J.A. Lisman,<br />Ministry of Health, Welfare and Sport, Rijswijk, Netherlands; Dr K.L. Loening,<br />Topterm, North American Division, Columbus, OH, USA; Dr M.K. Majumdar,<br />Calcutta, India; Mr R.F. Mantik, Bogor, Indonesia; Mrs J. Maritoux, Réseau<br />Médicaments et Développement, Paris, France; Professor L. Martinec, State<br />Institute for the Control of Drugs, Bratislava, Slovakia; Dr N. Miyata, National<br />Institute of Health Sciences, Tokyo, Japan; Mr M.G. Moester, Ministry of Health,<br />Welfare and Sport, Rijswijk, Netherlands; Mrs D. Monk, Australian Pharmaceutical<br />Manufacturers Association, North Sydney, New South Wales, Australia; Mrs Z.J.<br />Montbrun de Reinfeld, National Institute of Hygiene, Caracas, Venezuela; Dr A.B.<br />Moraes da Silva, National Health Institute of Quality Control, Rio de Janeiro, Brazil;<br />Professor R.C. Moreau, Paris, France; Dr M. Negwer, FIZ Chemie, Berlin, Germany;<br />Dr E. Njau, Arusha, United Republic of Tanzania; Professor T.L. Paál, National<br />Institute of Pharmacy, Budapest, Hungary; Dr P.R. Pabrai, Ranbaxy Laboratories<br />Ltd, New Delhi, India; Mrs E. Pelkonen, National Agency for Medicines, Helsinki,<br />Finland; Mr G. Pierce, Division of Emergency and Investigational Operations, Food<br />and Drug Administration, Rockville, MD, USA; Dr S. Raicu, State Institute for Drug<br />Control and Pharmaceutical Research, Bucharest, Romania; Dr M. Raijmakers,<br />Wemos Foundation, Amsterdam, Netherlands; Dr J. Reinstein, World Self-Medication<br />Industry, London, England; Mrs N. Ridolphi, Réseau Médicaments<br />et Développement, Strasbourg, France; Mr N. Sasidharan, World Customs<br />Organization, Brussels, Belgium; Dr K. Satiadarma, Bandung, Indonesia; Mr A.<br />Schijveschuurder, Avrachem AG, Zurich, Switzerland; Dr D. Schnädelbach,<br />Federal Institute for Drugs and Medical Devices, Berlin, Germany; Dr J. Schrank,<br />Interpharma, Basel, Switzerland; Dr M.A. Siewert, Hoechst Marion Roussel,.15<br />Frankfurt am Main, Germany; Dr E. Spingler-Kloess, Schönenbuch, Switzerland;<br />Mrs L. Stefanini-Oresic, Croatian Institute for Medicines Control, Zagreb, Croatia;<br />Dr S. Sur, Central Laboratory for Quality Control of Medicines, Kiev, Ukraine; Dr R.<br />Szyszkowsky, Latin American Pharmaceutical Industries Association, Buenos<br />Aires, Argentina; Mrs Tan Shook Fong, Ministry of Health, Singapore; Dr R. Tengler,<br />Intercantonal Office for the Control of Medicines, Berne, Switzerland; Dr A. Thépot,<br />Roche, Paris, France; Dr S. Throm, German Association of Research-based<br />Pharmaceutical Companies (VFA) e.V., Bonn, Germany; Mr P. Thummel,<br />Interpharma, Basel, Switzerland; Mr R.B. Trigg, British Pharmacopoeia<br />Commission, London, England; Professor Tu Guoshi, National Institute for the<br />Control of Pharmaceutical and Biological Products, Ministry of Public Health,<br />Beijing, China; Mrs E. Uramis, BioCen National Centre for Bio-Preparations,<br />Havana, Cuba; Dr W. van de Poel, Helvoet S.A., Alken, Belgium; Dr T. van Quy,<br />National Institute of Drug Quality Control, Hanoi, Viet Nam; Mr J.-Y. Videau,<br />Pharmaciens sans Frontières, Clermont-Ferrand, France; Mr P.H. Vree, Ministry of<br />Health, Welfare and Sport, Rijswijk, Netherlands; Mrs M.C. de Vries, Ministry of<br />Health, Welfare and Sport, Rijswijk, Netherlands; Mrs M. Westermark, Apoteket AB,<br />Central Laboratory, Kungens Kurva, Sweden; Professor W. Wieniawski, Polish<br />Pharmacopoeia Commission, Warsaw, Poland; Dr H. Woerder, Bünder Glass<br />GmbH, Bünde, Germany; Dr Woo Soo On, Department of Scientific Services,<br />Institute of Science and Forensic Medicine, Singapore; Mr D.R. Work, North<br />Carolina Board of Pharmacy, Carrboro, NC, USA; Mrs C. Yzer, VFA e.V., Bonn,<br />Germany.<br />References<br />1. Guidelines for implementation of the WHO Certification Scheme on the<br />Quality of Pharmaceutical Products Moving in International Commerce. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 10<br />(WHO Technical Report Series, No. 863).<br />2. Handbook of resolutions and decisions of the World Health Assembly and<br />the Executive Board, Volume III, 1985–1992, 3rd ed. Geneva, World Health<br />Organization, 1993:94.<br />3. Starting materials for pharmaceutical products: control and safe trade.<br />Geneva, World Health Organization, 1998 (unpublished document WHO/<br />PHARM/98.605; available from Essential Drugs and Medicines Policy, World<br />Health Organization, 1211 Geneva 27, Switzerland).<br />4. The international pharmacopoeia, 3rd ed. Vol. 1. General methods of<br />analysis; Vol. 2. Quality specifications; Vol. 3. Quality specifications; Vol. 4.<br />Tests, methods, and general requirements. Quality specifications for<br />pharmaceutical substances, excipients, and dosage forms. Geneva, World<br />Health Organization, 1979–1994.<br />5. Counterfeit drugs. Guidelines for the development of measures to combat<br />counterfeit drugs. Geneva, World Health Organization, 1999 (unpublished<br />document WHO/EDM/QSM/99.1; available from Essential Drugs and<br />Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />6. Basic tests for pharmaceutical substances. Geneva, World Health<br />Organization, 1986..16<br />7. Basic tests for pharmaceutical dosage forms. Geneva, World Health<br />Organization, 1991.<br />8. Basic tests for drugs: pharmaceutical substances, medicinal plant materials<br />and dosage forms. Geneva, World Health Organization, 1998.<br />9. Collaboration within the basic test programme. In: WHO Expert Committee<br />on Specifications for Pharmaceutical Preparations. Twenty-ninth report.<br />Geneva, World Health Organization, 1984, Annex 6 (WHO Technical Report<br />Series, No. 704).<br />10. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-second report. Geneva, World Health Organization, 1992 (WHO<br />Technical Report Series, No. 823).<br />11. National laboratories for drug quality surveillance and control. In: WHO<br />Expert Committee on Specifications for Pharmaceutical Preparations.<br />Twenty-ninth report. Geneva, World Health Organization, 1984, Annex 1<br />(WHO Technical Report Series, No. 704).<br />12. General requirements for the competence of testing and calibration<br />laboratories. International Standard ISO/IEC 17025. Geneva, International<br />Organization for Standardization, 1999.<br />13. OECD series on principles of good laboratory practice and compliance<br />monitoring. No. 1. OECD principles of good laboratory practice. Paris,<br />Organisation for Economic Co-operation and Development, 1997 (available<br />from Head of Publications Service, OECD, 2 rue André-Pascal, 75775 Paris<br />Cédex 16, France).<br />14. General criteria for the operation of testing laboratories. SN EN 45001.<br />1<br />Zurich, Swiss Association for Standardization, 1989 (available from the<br />Swiss Association for Standardization, Kirchweg 4, Postfach, 8032 Zurich,<br />Switzerland).<br />15. Recommendations on a quality system for official medicines control<br />laboratories. Geneva, Pharmaceutical Inspection Convention, 1995<br />(unpublished document PH 2/95; available from EFTA Secretariat, 9–11 rue<br />de Varembé, 1211 Geneva 20, Switzerland).<br />16. Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second<br />report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823).<br />17. Manufacture of sterile medicinal products. Brussels, European Commission,<br />1997 (available from Directorate-General for Internal Market and Industrial<br />Affairs, 200 rue de la Loi, B-1049 Brussels, Belgium).<br />18. Clean rooms and associated controlled environments. International standard<br />ISO/TC 209. Geneva, International Organization for Standardization, 1999.<br />1<br />Superseded by General requirements for the competence of testing and calibration<br />laboratories. SN EN 17025. Zurich, Swiss Association for Standardization, 2000<br />(available from the Swiss Association for Standardization, Kirchweg 4, Postfach, 8032<br />Zurich, Switzerland)..17<br />19. Provisional guidelines on the inspection of pharmaceutical manufacturers.<br />In: WHO Expert Committee on Specifications for Pharmaceutical<br />Preparations. Thirty-second report. Geneva, World Health Organization,<br />1992, Annex 2 (WHO Technical Report Series, No. 823).<br />20. Quality system requirements for GMP inspectorates. Geneva, Pharma-ceutical<br />Inspection Convention, 1995 (unpublished document PH 7/94;<br />available from EFTA Secretariat, 9–11 rue de Varembé, 1211 Geneva 20,<br />Switzerland).<br />21. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fifth report. Geneva, World Health Organization, 1999 (WHO Technical<br />Report Series, No. 885).<br />22. The revised drug strategy. In: Fifty-second World Health Assembly, Geneva,<br />17–25 May 1999. Volume 1. Resolutions and decisions, and list of<br />participants. Geneva, World Health Organization, 1999 (unpublished<br />document WHA52/1999/REC/1).<br />23. Quality assurance of pharmaceuticals: a compendium of guidelines and<br />related materials. Vol. 1. Geneva, World Health Organization, 1997..18<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 1<br />List of available International Chemical Reference<br />Substances<br />1<br />International Chemical Reference Substances (ICRS) are established<br />on the advice of the WHO Expert Committee on Specifications for<br />Pharmaceutical Preparations. They are supplied primarily for use in<br />physical and chemical tests and assays described in the specifica-tions<br />for quality control of drugs published in The international phar-macopoeia<br />or proposed in draft monographs. The ICRS are mainly<br />intended to be used as primary standards to calibrate secondary<br />standards.<br />Directions for use, and the analytical data required for the use de-scribed<br />in the relevant specifications of The international pharmaco-poeia,<br />are given in the certificates enclosed with the substances when<br />distributed. More detailed analytical reports on the substances may<br />be obtained from the WHO Collaborating Centre for Chemical<br />Reference Substances.<br />ICRS may also be used in tests and assays not described in The<br />international pharmacopoeia. However, the responsibility for assess-ing<br />the suitability of the substances then rests with the user or with the<br />pharmacopoeia commission or other authority that has prescribed<br />this use.<br />It is generally recommended that the substances should be stored<br />protected from light and moisture and preferably at a temperature of<br />about 5°C. When special storage conditions are required, this is<br />stated on the label or in the accompanying leaflet. It is recommended<br />that the user purchase only an amount sufficient for immediate use.<br />The stability of the ICRS kept at the Collaborating Centre is moni-tored<br />by regular re-examination, and any material that has deterio-rated<br />is replaced by new batches as necessary. Lists giving control<br />numbers for the current batches are issued in the annual reports from<br />the Centre and new yearly lists may be obtained on request.<br />1<br />As updated at the thirty-sixth meeting of the WHO Expert Committee on Specifications<br />for Pharmaceutical Preparations, 31 May–4 June 1999..19<br />Orders for the ICRS should be sent to:<br />WHO Collaborating Centre for Chemical Reference Substances<br />Apoteket AB<br />Produktion & Laboratorier Centrallaboratoriet, ACL<br />Prismavägen 2<br />S-141 75 Kungens Kurva<br />Sweden<br />Tel.: +46 8 466 1000<br />Fax: +46 8 740 6040<br />Email: who.apl@apoteket.se<br />The ICRS are supplied only in the standard packages indicated in<br />Table 1.<br />Table 1<br />Available International Chemical Reference Substances<br />Reference substance Package size Control number<br />aceclidine salicylate 100mg 172048<br />p-acetamidobenzalazine 25mg 290042<br />acetazolamide 100mg 186128<br />allopurinol 100mg 287049<br />amidotrizoic acid 100mg 196205<br />2-amino-5-nitrothiazole 25mg 186131<br />3-aminopyrazole-4-carboxamide hemisulfate 100mg 172050<br />3-amino-2,4,6-triiodobenzoic acid 100mg 196206<br />amitriptyline hydrochloride 100mg 181101<br />amodiaquine hydrochloride 200mg 192160<br />amphotericin B 400mg 191153<br />ampicillin (anhydrous) 200mg 390001<br />ampicillin sodium 200mg 388002<br />ampicillin trihydrate 200mg 274003<br />anhydrotetracycline hydrochloride 25mg 180096<br />atropine sulfate 100mg 183111<br />azathioprine 100mg 172060<br />bacitracin zinc 200mg 192174<br />beclometasone dipropionate 200mg 192175<br />bendazol hydrochloride 100mg 173066<br />benzobarbital 100mg 172051<br />benzylamine sulfate 100mg 172052<br />benzylpenicillin potassium 200mg 180099<br />benzylpenicillin sodium 200mg 280047<br />bephenium hydroxynaphthoate 100mg 183112<br />betamethasone 100mg 183113<br />betamethasone sodium phosphate 100mg 196203<br />betamethasone valerate 100mg 190145<br />betanidine sulfate 100mg 172053<br />bupivacaine hydrochloride 100mg 289054.20<br />Table 1 ( continued)<br />Reference substance Package size Control number<br />caffeine 100mg 181102<br />calcium folinate (leucovorin calcium) 100mg 194188<br />captopril 100mg 197214<br />captopril disulfide 25mg 198216<br />carbamazepine 100mg 189143<br />carbenicillin monosodium 200mg 383043<br />chloramphenicol 200mg 486004<br />chloramphenicol palmitate 1g 286072<br />chloramphenicol palmitate (polymorph A) 200mg 175073<br />5-chloro-2-methylaminobenzophenone 100mg 172061<br />chloroquine sulfate 200mg 195201<br />2-(4-chloro-3-sulfamoylbenzoyl)benzoic acid 50mg 181106<br />chlorphenamine hydrogen maleate 100mg 182109<br />chlorpromazine hydrochloride 100mg 178080<br />chlortalidone 100mg 183114<br />chlortetracycline hydrochloride 200mg 187138<br />cimetidine 100mg 190150<br />ciprofloxacin hydrochloride 400mg 197210<br />ciprofloxacin by-compound A 20mg 198220<br />ciprofloxacin desfluoro-compound 20mg 198219<br />ciprofloxacin ethylenediamine-compound 20mg 198218<br />ciprofloxacin fluoroquinolonic acid 20mg 198217<br />cisplatin 100mg 197207<br />clomifene citrate 100mg 187136<br />clomifene citrate Z-isomer see zuclomifene<br />cloxacillin sodium 200mg 274005<br />colecalciferol (vitamin D3 ) 500mg 190146<br />cortisone acetate 100mg 167006<br />dapsone 100mg 183115<br />desoxycortone acetate 100mg 167007<br />dexamethasone 100mg 388008<br />dexamethasone acetate 100mg 288009<br />dexamethasone phosphoric acid 100mg 192161<br />dexamethasone sodium phosphate 100mg 192158<br />diazepam 100mg 172062<br />diazoxide 100mg 181103<br />dicloxacillin sodium 200mg 174071<br />dicolinium iodide 100mg 172055<br />dicoumarol 100mg 178077<br />diethylcarbamazine dihydrogen citrate 100mg 181100<br />digitoxin 100mg 277010<br />digoxin 100mg 587011<br />N, N¼ñêô-di-(2,3-xylyl)anthranilamide 50mg 173067<br />dopamine hydrochloride 100mg 192159<br />doxorubicin hydrochloride 100mg 196202<br />emetine hydrochloride 100mg 187134<br />4-epianhydrotetracycline hydrochloride 25mg 288097.21<br />Table 1 ( continued)<br />Reference substance Package size Control number<br />4-epitetracycline hydrochloride 25mg 293098<br />ergocalciferol (vitamin D2 ) 500mg 190147<br />ergometrine hydrogen maleate 50mg 277012<br />ergotamine tartrate 50mg 385013<br />erythromycin 250mg 191154<br />erythromycin B 150mg 194186<br />erythromycin C 25mg 194187<br />estradiol benzoate 100mg 167014<br />estrone 100mg 279015<br />etacrynic acid 100mg 281056<br />ethambutol hydrochloride 100mg 179081<br />ethinylestradiol 100mg 291016<br />ethisterone 100mg 167017<br />ethosuximide 100mg 179088<br />etocarlide 100mg 172057<br />flucloxacillin sodium 200mg 195194<br />flucytosine 100mg 184121<br />fludrocortisone acetate 200mg 195199<br />fluorouracil 100mg 184122<br />fluphenazine decanoate dihydrochloride 100mg 182107<br />fluphenazine enantate dihydrochloride 100mg 182108<br />fluphenazine hydrochloride 100mg 176076<br />folic acid 100mg 388019<br />3-formylrifamycin 200mg 190149<br />framycetin sulfate (neomycin B sulfate) 200mg 193178<br />furosemide 100mg 171044<br />gentamicin sulfate 100mg 194183<br />griseofulvin 200mg 280040<br />haloperidol 100mg 172063<br />hydrochlorothiazide 100mg 179087<br />hydrocortisone 100mg 283020<br />hydrocortisone acetate 100mg 280021<br />hydrocortisone sodium succinate 200mg 194184<br />()-3-(4-hydroxy-3-methoxyphenyl)-2-hydrazino-2-<br />methylalanine (3- O-methylcarbidopa) 25mg 193180<br />()-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine<br />(3- O-methylmethyldopa) 25mg 179085<br />ibuprofen 100mg 183117<br />imipramine hydrochloride 100mg 172064<br />indometacin 100mg 178078<br />o-iodohippuric acid 100mg 171045<br />isoniazid 100mg 185124<br />kanamycin monosulfate 12mg 197211<br />lanatoside C 100mg 281022<br />levodopa 100mg 295065.22<br />Table 1 ( continued)<br />Reference substance Package size Control number<br />levonorgestrel 200mg 194182<br />levothyroxine sodium 100mg 189144<br />lidocaine 100mg 181104<br />lidocaine hydrochloride 100mg 181105<br />liothyronine sodium 50mg 193179<br />loperamide hydrochloride 100mg 194185<br />mebendazole 200mg 195195<br />mefenamic acid 100mg 173068<br />melting-point reference substances<br />azobenzene (69°C) 4g 192168<br />vanillin (83 °C) 4g 192169<br />benzil (96 °C) 4g 294170<br />acetanilide (116 °C) 4g 297171<br />phenacetin (136°C) 4g 297172<br />benzanilide (165 °C) 4g 192173<br />sulfanilamide (166 °C) 4g 192162<br />sulfapyridine (193 °C) 4g 192163<br />dicyanodiamide (210°C) 4g 192164<br />saccharin (229 °C) 4g 192165<br />caffeine (237 °C) 4g 192166<br />phenolphthalein (263 °C) 4g 192167<br />metazide 100mg 172058<br />methaqualone 100mg 173069<br />methotrexate 100mg 194193<br />methyldopa 100mg 179084<br />methyltestosterone 100mg 167023<br />meticillin sodium 200mg 274024<br />metronidazole 100mg 183118<br />nafcillin sodium 200mg 272025<br />neamine hydrochloride (neomycin A hydrochloride) 0.5 mg 193177<br />neomycin B sulfate see framycetin sulfate<br />neostigmine metilsulfate 100mg 187135<br />nicotinamide 100mg 179090<br />nicotinic acid 100mg 179091<br />nifurtimox 100mg 194189<br />niridazole 200mg 186129<br />niridazole-chlorethylcarboxamide 25mg 186130<br />norethisterone 100mg 186132<br />norethisterone acetate 100mg 185123<br />nystatin 200mg 191152<br />oubain 100mg 283026<br />oxacillin sodium 200mg 382027<br />oxytetracycline dihydrate 200mg 189142<br />oxytetracycline hydrochloride 200mg 189141<br />papaverine hydrochloride 100mg 185127<br />paracetamol 100mg 195198.23<br />Table 1 ( continued)<br />Reference substance Package size Control number<br />paromomycin sulfate 75mg 195197<br />pheneticillin potassium 200mg 167028<br />phenoxymethylpenicillin 200mg 179082<br />phenoxymethylpenicillin calcium 200mg 179083<br />phenoxymethylpenicillin potassium 200mg 176075<br />phenytoin 100mg 179089<br />piperazine adipate 100mg 197212<br />piperazine citrate 100mg 197213<br />praziquantel 100mg 194191<br />prednisolone 100mg 389029<br />prednisolone acetate 100mg 289030<br />prednisolone hemisuccinate 200mg 195196<br />prednisolone sodium phosphate 200mg 194190<br />prednisone 100mg 167031<br />prednisone acetate 100mg 169032<br />probenecid 100mg 192156<br />procaine hydrochloride 100mg 183119<br />procarbazine hydrochloride 100mg 184120<br />progesterone 100mg 167033<br />propicillin potassium 200mg 274034<br />propranolol hydrochloride 100mg 187139<br />propylthiouracil 100mg 185126<br />pyrantel embonate (pyrantel pamoate) 500mg 192157<br />pyridostigmine bromide 100mg 182110<br />reserpine 100mg 186133<br />retinol acetate (solution) 5 capsules<br />a<br />898038<br />riboflavin 250mg 382035<br />rifampicin 200mg 191151<br />rifampicin quinone 200mg 190148<br />sodium amidotrizoate 100mg 198221<br />sodium cromoglicate 100mg 188140<br />spectinomycin hydrochloride 200mg 193176<br />streptomycin sulfate 100mg 197215<br />sulfacetamide 100mg 196200<br />sulfamethoxazole 100mg 179092<br />sulfamethoxypyridazine 100mg 178079<br />sulfanilamide 100mg 179094<br />sulfasalazine 100mg 191155<br />tamoxifen citrate 100mg 196208<br />tamoxifen citrate E-isomer 10mg 196209<br />testosterone enantate 200mg 194192<br />testosterone propionate 100mg 167036<br />tetracycline hydrochloride 200mg 180095<br />thioacetazone 100mg 171046<br />4,4¼ñêô-thiodianiline 50mg 183116.24<br />Table 1 ( continued)<br />Reference substance Package size Control number<br />thyroxine sodium see levothyroxine sodium<br />tolbutamide 100mg 179086<br />tolnaftate 100mg 176074<br />toluene-2-sulfonamide 100mg 196204<br />trimethadione 200mg 185125<br />trimethoprim 100mg 179093<br />trimethylguanidine sulfate 100mg 172059<br />vincristine sulfate 9.7 mg/vial 193181<br />vitamine A acetate (solution) see retinol acetate<br />(solution)<br />warfarin 100mg 168041<br />zuclomifene 50mg 187137<br />a<br />Each containing about 8 mg in 230 mg of oil..25<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 2<br />List of available International Infrared Reference<br />Spectra<br />International Infrared Reference Spectra are established on the<br />advice of the WHO Expert Committee on Specifications for Pharma-ceutical<br />Preparations. Full-scale reproductions of spectra produced<br />from authenticated material on a suitable instrument are supplied for<br />use in identification tests described in the specifications for quality<br />control of drugs, published in The international pharmacopoeia or<br />proposed in draft monographs.<br />Precise instructions for the preparation of spectra are given on the<br />label of each reference spectrum. All International Infrared<br />Reference Spectra are distributed together with a document giving<br />further details on the use of such spectra, entitled “General recom-mendations<br />for the preparation and use of infrared spectra in<br />pharmaceutical analysis”.<br />1<br />Orders for International Infrared Reference Spectra should be sent<br />to:<br />WHO Collaborating Centre for Chemical Reference Substances<br />Apoteket AB<br />Produktion & Laboratorier Centrallaboratoriet, ACL<br />Prismavägen 2<br />S-141 75 Kungens Kurva<br />Sweden<br />Tel.: +46 8 466 1000<br />Fax: +46 8 740 6040<br />Email: who.apl@apoteket.se<br />The following International Infrared Reference Spectra are currently<br />available from the Centre:<br />1<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth<br />report. Geneva, World Health Organization, 1996, Annex 4 (WHO Technical Report<br />Series, No. 863).<br />amiloride hydrochloride<br />amitriptyline hydrochloride<br />ampicillin trihydrate<br />aceclidine salicylate<br />acetazolamide<br />allopurinol.26<br />beclometasone dipropionate<br />benzylpenicillin potassium<br />biperiden<br />biperiden hydrochloride<br />bupivacaine hydrochloride<br />caffeine (anhydrous)<br />calcium folinate<br />carbidopa<br />chlorphenamine hydrogen<br />maleate<br />clofazimine<br />cloxacillin sodium<br />colchicine<br />cytarabine<br />dexamethasone<br />dexamethasone acetate,<br />monohydrate<br />dextromethorphan<br />hydrobromide<br />diazepam<br />dicolinium iodide<br />dicoumarol<br />diethylcarbamazine dihydrogen<br />citrate<br />diphenoxylate hydrochloride<br />erythromycin ethylsuccinate<br />erythromycin stearate<br />etacrynic acid<br />ethionamide<br />ethosuximide<br />furosemide<br />gallamine triethiodide<br />glibenclamide<br />haloperidol<br />hydrochlorothiazide<br />ibuprofen<br />imipramine hydrochloride<br />indometacin<br />isoniazid<br />lidocaine<br />lidocaine hydrochloride<br />lindane<br />metronidazole<br />miconazole nitrate<br />niclosamide<br />nicotinamide<br />noscapine<br />oxamniquine<br />papaverine hydrochloride<br />phenobarbital<br />phenoxymethylpenicillin<br />calcium<br />phenytoin<br />primaquine phosphate<br />propylthiouracil<br />protionamide<br />pyrimethamine<br />salbutamol<br />salbutamol sulfate<br />sulfadimidine<br />sulfadoxine<br />sulfamethoxazole<br />sulfamethoxypyridazine<br />tiabendazole<br />trihexyphenidyl hydrochloride<br />trimethoprim<br />valproic acid<br />verapamil hydrochloride.27<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 3<br />Good practices for national pharmaceutical<br />control laboratories<br />General considerations 28<br />Glossary 29<br />Part One. Management and infrastructure 33<br />1. Organization and management 33<br />2. Quality system 34<br />3. Control of documentation 35<br />4. Records 36<br />5. Data-processing equipment 37<br />6. Personnel 37<br />7. Premises 40<br />8. Equipment, instruments and other devices 41<br />Part Two. Materials and setting-up of equipment, instruments and<br />other devices 42<br />9. Specifications archive 42<br />10. Reagents 43<br />11. Reference materials 45<br />12. Calibration, validation and verification of equipment, instruments<br />and other devices 46<br />13. Traceability 49<br />Part Three. Working procedures 52<br />14. Incoming samples 52<br />15. Analytical worksheet 54<br />16. Testing 57<br />17. Evaluation of test results 57<br />18. Retained samples 58<br />Part Four. Safety 59<br />19. General rules 59<br />References 60<br />Appendix 1<br />Model analytical test report for active pharmaceutical ingredients,<br />excipients and pharmaceutical products 62<br />Appendix 2<br />Equipment for a first-stage and medium-size pharmaceutical control<br />laboratory 64.28<br />General considerations<br />The government, normally through the drug regulatory authority,<br />establishes and maintains a pharmaceutical control laboratory to<br />carry out the required tests and assays to ensure that active pharma-ceutical<br />ingredients, excipients and pharmaceutical products meet<br />quality specifications. Throughout the process of marketing authori-zation,<br />the laboratory works closely with the national drug regulatory<br />authority. The review of test methods for newly registered drugs plays<br />an important role in ensuring their suitability for the control of quality<br />and safety, and requires a major effort, especially since routine drug<br />testing must also be carried out. Some countries maintain larger<br />establishments called “drug control centres” or “drug control<br />institutes”.<br />The importance of a pharmaceutical control laboratory to a national<br />drug control system has already been outlined in three guidelines on<br />quality assessment (1–3).<br />In most countries the laboratory is responsible for analytical services<br />only, and not for the inspection of pharmaceuticals. However, some<br />aspects of inspection are included in these guidelines.<br />A governmental pharmaceutical control laboratory provides effective<br />support for a drug regulatory authority acting together with its inspec-tion<br />services. The analytical results obtained should accurately<br />describe the properties of the samples assessed, permitting correct<br />conclusions to be drawn about the quality of each drug, and also<br />serving as an adequate basis for any subsequent administrative regu-lations<br />and legal action.<br />To ensure patient safety, the role of the control laboratory must be<br />defined in the general drug legislation of the country in such a way<br />that the results provided by it can, if necessary, lead to enforcement of<br />the law and legal action.<br />For the quality of a drug sample to be correctly assessed:<br />— the submission of a sample to the laboratory, selected in accor-dance<br />with national requirements, must be accompanied by a<br />statement of the reason why the analysis has been requested;<br />— the analysis must be correctly planned and meticulously executed;<br />— the results must be competently evaluated to determine whether<br />the sample complies with the quality specifications or other<br />relevant criteria.<br />Precise documentation is required to make each operation simple and<br />unambiguous as far as possible (see also Part One, section 2.1)..29<br />These guidelines provide advice on the analysis of active pharmaceu-tical<br />ingredients, excipients and pharmaceutical products. Particular<br />consideration is given to countries with limited resources wishing to<br />establish a governmental pharmaceutical control laboratory, having<br />recently done so, or planning to modernize the existing laboratory.<br />Many of the recommendations are also relevant to drug quality con-trol<br />testing by the pharmaceutical manufacturer. This is usually a<br />matter of repetitive testing of samples of active pharmaceutical ingre-dients<br />or of a limited number of pharmaceutical products, whereas,<br />theoretically, governmental control laboratories have to deal with all<br />the drugs on the market and therefore have to use a wider variety of<br />test methods.<br />Special attention must be given to ensuring the correct and efficient<br />functioning of the laboratory. Planning and future budgets must<br />ensure that the necessary resources are available, inter alia, for the<br />maintenance of the laboratory, as well as for an adequate infrastruc-ture<br />and energy supply. Means and procedures must be in place (in<br />case of anticipated supply problems) to ensure that the laboratory can<br />continue its activities.<br />The laboratory should be appropriately equipped to respond to all<br />reasonable demands.<br />Glossary<br />The definitions given below apply to the terms as used in these guide-lines.<br />They may have different meanings in other contexts.<br />active pharmaceutical ingredient<br />A substance or compound that is intended to be used in the manufac-ture<br />of a pharmaceutical product as a pharmacologically active com-pound<br />(ingredient) (4).<br />analytical worksheet<br />A printed form for recording information about the sample, test<br />procedure and results of testing (see Part Three, section 15).<br />batch (or lot)<br />A defined quantity of starting material, packaging material, or product<br />processed in a single process or series of processes so that it could be<br />expected to be homogeneous. In the case of continuous manufacture,<br />the batch must correspond to a defined fraction of the production,<br />characterized by its intended homogeneity. It may sometimes be nec-essary<br />to divide a batch into a number of sub-batches, which are later<br />brought together to form a final homogeneous batch (4)..30<br />batch number (or lot number)<br />A distinctive combination of numbers and/or letters which specifically<br />identifies a batch on the labels, the batch records, the certificate of<br />analysis, etc. (4).<br />calibration<br />The set of operations that establish, under specified conditions, the<br />relationship between values indicated by an instrument or system for<br />measuring (especially weighing), recording and controlling, or the<br />values represented by a material measure, and the corresponding<br />known values of a reference standard. Limits for acceptance of the<br />results of measuring should be established (4).<br />calibration of equipment<br />The documented act of proving that the equipment is performing to<br />predefined tolerances or criteria.<br />certificate of analysis<br />Report of the results obtained, including the final conclusion of the<br />examination of a sample issued by the manufacturer and repacker/<br />trader (see Annex 10).<br />drug<br />An active pharmaceutical ingredient or a pharmaceutical product<br />(see also pharmaceutical excipient and pharmaceutical product).<br />good manufacturing practice(s) (GMP)<br />That part of quality assurance which ensures that pharmaceutical<br />products are consistently produced and controlled to the quality<br />standards appropriate to their intended use and as required by the<br />marketing authorization (4).<br />manufacturer<br />A company that carries out at least one step of manufacture (4).<br />marketing authorization (product licence, registration certificate)<br />A legal document issued by the competent drug regulatory authority<br />that establishes the detailed composition and formulation of the<br />pharmaceutical product and the pharmacopoeial or other recognized<br />specifications of its ingredients and of the final product itself, and<br />includes details of packaging, labelling and shelf-life.<br />pharmaceutical excipient<br />A substance, other than the active pharmaceutical ingredient, which<br />has been appropriately evaluated for safety and is included in a drug<br />delivery system to:.31<br />— aid in the processing of the drug delivery system during its<br />manufacture;<br />— protect, support or enhance stability, bioavailability or patient<br />acceptability;<br />— assist in pharmaceutical product identification; or<br />— enhance any other attribute of the overall safety and effectiveness<br />of the drug during its storage or use (5, 6).<br />pharmaceutical product<br />Any medicine intended for human or veterinary use, presented in its<br />finished dosage form, that is subject to control by pharmaceutical<br />legislation in both the exporting state and the importing state.<br />qualification of equipment<br />The act of planning, carrying out and recording the results of the<br />tests on equipment to demonstrate that it will perform as intended.<br />Measuring instruments and systems must be calibrated (see Part Two,<br />section 12).<br />quality assurance<br />A wide-ranging concept covering all matters that individually or col-lectively<br />influence the quality of a product. It is the totality of the<br />arrangements made with the object of ensuring that pharmaceutical<br />products are of the quality required for their intended use (4).<br />quality control<br />All measures taken, including the setting of specifications, sampling,<br />testing and analytical clearance, to ensure that raw materials, inter-mediates,<br />packaging materials and finished pharmaceutical products<br />conform with established specifications for identity, strength, purity<br />and other characteristics (4).<br />quality manual<br />A handbook that describes the various elements of the system for<br />assuring the quality of the test results generated by a laboratory (see<br />Part One, section 2.1).<br />quality specification<br />Explicit written test procedures and requirements that must be met.<br />quality system<br />An appropriate infrastructure, encompassing the organizational<br />structure, procedures, processes and resources, and systematic actions<br />necessary to ensure adequate confidence that a product (or services).32<br />will satisfy given requirements for quality (see Part One, sections 2.1<br />and 3.1).<br />specification<br />A document describing in detail the requirements with which the<br />pharmaceutical products or materials used or obtained during manu-facture<br />have to conform. Specifications serve as a basis for quality<br />evaluation.<br />specifications archive<br />An up-to-date collection of all quality specifications and related docu-ments<br />(see Part Two, section 9).<br />standard operating procedure (SOP)<br />An authorized written procedure giving instructions for performing<br />operations not necessarily specific to a given product or material<br />but of a more general nature (e.g. equipment operation, maintenance<br />and cleaning; validation; cleaning of premises and environmental con-trol;<br />sampling and inspection). Certain SOPs may be used to supple-ment<br />product-specific master and batch production documentation<br />(4).<br />test report<br />The report of the results, including the final conclusion of the analysis<br />of a sample which has been submitted by a laboratory in another<br />country or in the field not having appropriate facilities to perform<br />certain tests, and issued by the official pharmaceutical control labora-tory<br />that performed the test. This is often in the same style as a<br />certificate of analysis (see Part Three, section 17.3).<br />traceability<br />Traceability aims at ensuring that the results of laboratory measure-ments<br />using procedures of lower metrological order are reproducible<br />and scientifically acceptable by referring to an internationally agreed<br />denominator by means of a reference procedure of highest metrologi-cal<br />order and/or a primary reference material (see Part Two, section<br />13).<br />validation of analytical procedures/methods<br />The documented evidence that analytical procedures or methods are<br />suitable for their intended purpose (7).<br />verification of methods<br />Verification is conducted where the methods are compendial to con-firm<br />whether the pharmaceutical product as compounded can be<br />analysed satisfactorily by the official method..33<br />Part One. Management and infrastructure<br />1. Organization and management<br />1.1 The laboratory, or the organization of which it is part, must be an<br />entity that is legally authorized to function and can be held legally<br />responsible.<br />1.2 The laboratory must be organized and operate so as to meet the<br />requirements laid down in these guidelines.<br />1.3 The laboratory must:<br />(a) have managerial and technical personnel with the authority and<br />resources needed to carry out their duties and to identify the<br />occurrence of departures from the quality system or the proce-dures<br />for performing tests and/or calibrations, validation and<br />verification, and to initiate actions to prevent or minimize such<br />departures;<br />(b) have arrangements to ensure that its management and personnel<br />are not subject to commercial, political, financial and other pres-sures<br />or conflicts of interest that may adversely affect the quality<br />of their work;<br />(c) define, with the aid of organizational charts, the organization and<br />management structure of the laboratory, its place in any parent<br />organization, such as the ministry or the drug regulatory author-ity,<br />and the relationships between management, technical opera-tions,<br />support services and the quality system;<br />(d) specify the responsibility, authority and interrelationships of all<br />personnel who manage, perform or verify work which affects<br />the quality of the tests and/or calibrations, validations and<br />verifications;<br />(e) provide adequate supervision of staff, including trainees, by<br />persons familiar with the test and/or calibration, validation and<br />verification methods and procedures, as well as their purpose and<br />the assessment of the results;<br />(f) have a technical manager who has overall responsibility for the<br />technical operations and the provision of resources needed to<br />ensure the required quality of laboratory operations; and<br />(g) have appropriate safety procedures (see Part Four).<br />1.4 The laboratory, regardless of whether it is small (without sub-units)<br />or large (and possibly divided into subunits), must have a<br />central registry with the following functions:.34<br />(a) receiving, distributing and supervising the consignment of the<br />samples to the specific units;<br />(b) keeping records on all incoming samples and accompanying<br />documents;<br />(c) ensuring the precise allocation of responsibilities, particularly<br />in the designation of specific units for particular types of drugs;<br />and<br />(d) maintaining a specifications archive (see Part Two, section 9)<br />containing an up-to-date collection of all quality specifications<br />and related documents.<br />1.5 In a large laboratory, communication and coordination must be<br />guaranteed between the staff involved in the testing of the same<br />sample in different units.<br />2. Quality system<br />2.1 The laboratory management establishes, implements and main-tains<br />a quality system appropriate to the scope of its activities,<br />including the type, range and volume of testing and/or calibration,<br />validation and verification activities it undertakes. The laboratory<br />management must describe its policies, systems, programmes, proce-dures<br />and instructions to the extent necessary to enable the labora-tory<br />to assure the quality of the test results that it generates. The<br />documentation used in this quality system must be communicated and<br />available to, and understood and implemented by, the appropriate<br />personnel. The elements of this system must be documented in a<br />quality manual, available to the laboratory personnel, which must<br />be maintained and updated by a nominated responsible member<br />of the laboratory personnel. The quality manual must contain as a<br />minimum:<br />(a) the structure of the laboratory (organizational chart);<br />(b) the operational and functional activities pertaining to quality, so<br />that each person concerned will know the extent and the limits of<br />his or her responsibilities;<br />(c) the general internal quality assurance procedures;<br />(d) references to specific quality assurance procedures for each test;<br />(e) information on participation in appropriate proficiency testing<br />schemes, use of reference materials, etc.;<br />(f) details of satisfactory arrangements for feedback and corrective<br />action when testing discrepancies are detected;.35<br />(g) a procedure for dealing with complaints;<br />(h) a flow-chart for samples;<br />(i) details of audit and quality system review;<br />(j) information on the appropriate qualifications that personnel are<br />required to possess;<br />(k) information on initial and in-service training of staff;<br />(l) a quality policy statement, including at least the following:<br />(i) a statement of the laboratory management’s intentions with<br />respect to the standard of service it will provide;<br />(ii) the purpose of the quality system;<br />(iii) the laboratory management’s commitment to good profes-sional<br />practice and quality of testing, calibration, validation<br />and verification, as a service to its clients;<br />(iv) the laboratory management’s commitment to compliance<br />with the content of these guidelines;<br />(v) a requirement that all personnel concerned with testing<br />and calibration activities within the laboratory familiarize<br />themselves with the documentation concerning quality and<br />the implementation of the policies and procedures in their<br />work.<br />2.2 The quality system must be reviewed systematically and periodi-cally<br />(internal and external audits) by, or on behalf of, the manage-ment<br />to ensure the continued effectiveness of the arrangements and<br />apply any necessary corrective measures. Such reviews must be re-corded,<br />together with details of any corrective action taken.<br />2.3 The laboratory management must appoint a member of the staff<br />as quality manager, who, irrespective of other duties and responsi-bilities,<br />should have defined responsibilities and authority for ensur-ing<br />that the quality system is implemented and followed at all times.<br />The quality manager must have direct access to the highest level of<br />management at which decisions are taken on laboratory policies or<br />resources.<br />3. Control of documentation<br />3.1 Documentation is an essential part of the quality system. The<br />laboratory must establish and maintain procedures to control and<br />review all documents (both internally generated and from external<br />sources) that form part of the quality documentation..36<br />4. Records<br />4.1 The laboratory must establish and maintain procedures for the<br />identification, collection, indexing, retrieval, storage, maintenance<br />and disposal of, and access to, all quality documentation and technical<br />records.<br />4.2 All original observations, calculations and derived data, calibra-tion,<br />validation and verification records, etc., and final results must be<br />retained on record for an appropriate period of time in accordance<br />with national regulations. Ideally, they should be kept for the whole<br />length of time that the drug concerned is on the market. The records<br />for each test must contain sufficient information to permit the tests to<br />be repeated. The records must include the identity of the personnel<br />involved in the sampling, preparation and testing of the samples. The<br />records of samples to be used in legal proceedings should be kept<br />according to the legal requirements applicable to them.<br />4.3 All records must be legible, readily retrievable, stored and<br />retained, using facilities that provide a suitable environment that will<br />prevent modification, damage or deterioration and/or loss. The condi-tions<br />under which all original records are stored must be such as to<br />ensure their security and confidentiality. Quality records must include<br />reports from internal (and external, if performed) audits and manage-ment<br />reviews, including records of possible corrective and preventive<br />actions.<br />4.4 Authorized written standardized operating procedures (SOPs)<br />are required, including, but not limited to, instructions for administra-tive<br />and technical operations, such as:<br />(a) the purchase and receipt of consignments of materials (e.g.<br />samples, reference materials, reagents);<br />(b) the internal labelling, quarantine and storage of materials;<br />(c) the appropriate installation of each instrument and item of<br />equipment;<br />(d) sampling and inspection;<br />(e) the testing of materials, with descriptions of the methods and<br />equipment used;<br />(f) the qualification of equipment;<br />(g) the calibration of analytical apparatus;<br />(h) maintenance, cleaning and sanitation;<br />(i) safety measures;.37<br />( j) actions relating to personnel matters, including qualifications,<br />training, clothing and hygiene;<br />(k) environmental monitoring;<br />(l) the preparation and control of reference materials.<br />5. Data-processing equipment<br />5.1 For computers, automated tests or calibration equipment, and the<br />collection, processing, recording, reporting, storage or retrieval of test<br />and/or calibration data, the laboratory must ensure that:<br />(a) calculations and data transfers are systematically subject to<br />appropriate verifications;<br />(b) computer software developed by the user is documented in<br />sufficient detail and appropriately validated or verified as being<br />adequate for use;<br />(c) procedures are established and implemented for protecting the<br />integrity of data. Such procedures must include, but are not<br />limited to, measures to ensure the integrity and confidentiality of<br />data entry or collection, and the storage, transmission and pro-cessing<br />of data;<br />(d) computers and automated equipment are maintained so as to<br />function properly, and are provided with the environmental and<br />operating conditions necessary to ensure the integrity of test and<br />calibration data;<br />(e) procedures are established and implemented for making, docu-menting<br />and controlling for changes to information maintained in<br />computerized systems; and<br />(f) procedures exist to protect and keep back-up data on computers<br />or other means (e.g. magnetic tapes, diskettes and CD-ROMs) at<br />all times, and to prevent unauthorized access or amendments to<br />the data.<br />6. Personnel<br />6.1 The laboratory must have sufficient personnel with the necessary<br />education, training, technical knowledge and experience for their<br />assigned functions. They should be free from any conflict of interest<br />and not subject to any pressure that would interfere with the quality<br />of the results.<br />6.2 The laboratory management must ensure the competence of all<br />persons operating specific equipment, instruments or other devices,.38<br />who are performing tests and/or calibrations, validations or veri-fications.<br />Their duties also involve the evaluation of results as well as<br />signing test reports (see Appendix 1) and calibration certificates.<br />6.3 Staff undergoing training must be appropriately supervised, and<br />a formal assessment after training is recommended. Personnel per-forming<br />specific tasks must be appropriately qualified in terms of<br />their education, training, experience and/or demonstrated skills, as<br />required.<br />6.4 The laboratory personnel must be permanently employed or<br />under contract. The laboratory must ensure that additional technical<br />and key support personnel who are under contract are supervised<br />and sufficiently competent and motivated, and that their work is in<br />accordance with the good practice of the laboratory.<br />6.5 The laboratory must maintain current job descriptions for mana-gerial,<br />technical and key support personnel involved in tests and/or<br />calibrations, validations and verifications. The laboratory must also<br />maintain records of all technical personnel, including those under<br />contract, describing their areas of competence, educational and pro-fessional<br />qualifications, training, skills and experience. This informa-tion<br />must be readily available and must include the date on which<br />authorization and/or competence was confirmed. The criteria on<br />which the authorization is based must also be given, together with the<br />name of the confirming authority.<br />6.6 The laboratory must have the following managerial and technical<br />personnel:<br />(a) a head of laboratory (supervisor), who must be of high profes-sional<br />standing with extensive experience in drug analysis and<br />laboratory management in a pharmaceutical control laboratory in<br />the regulatory sector or in industry. The head of laboratory also<br />takes final responsibility for recommending any regulatory action<br />in the event of non-compliance of a tested sample. The person’s<br />function is to ensure that:<br />(i) all key members of the laboratory staff have the requisite<br />competence and are given grades matching their<br />responsibilities;<br />(ii) standard samples are analysed periodically;<br />(iii) the adequacy of existing staffing, management and training<br />procedures is reviewed periodically;<br />(iv) “self-checking” procedures for instrument operators are<br />devised;.39<br />(v) regular in-service training programmes to update and extend<br />the skills of both professionals and technicians are arranged;<br />(vi) the safe keeping of any narcotics (see Part One, sections<br />7.10–7.12) kept in the workplace is under the supervision of<br />an authorized person;<br />(b) a head of central registry, who must have wide experience in drug<br />analysis and be responsible for:<br />(i) receiving and keeping records of all incoming samples and<br />accompanying documents;<br />(ii) supervising their consignment to the specific units con-cerned;<br />(iii) monitoring the progress of analyses and the dispatch of<br />completed reports (see also Part One, section 1.4);<br />(iv) if required, collating and evaluating the test results for each<br />analysis;<br />(c) analysts, who must be graduates in pharmacy, analytical chemis-try,<br />microbiology or other relevant subjects with the requisite<br />knowledge, skills and ability to adequately perform the tasks<br />assigned to them by management and to supervise technical staff;<br />(d) technical staff, who should hold diplomas in their subjects<br />awarded by technical or vocational schools;<br />(e) a storekeeper (see Part Two, section 10.13), who is responsible<br />for keeping the central store and must have appropriate compe-tence<br />and be trained to handle reagents and materials with the<br />necessary care and safety;<br />(f) a quality manager (see Part One, section 2.3).<br />6.7 In large laboratories with subunits, the following additional per-sonnel<br />are necessary:<br />(a) heads of various subunits;<br />(b) a reference material coordinator (see Part Two, section 11.8).<br />6.8 The more routine analyses performed, the greater the propor-tion<br />of technicians required. Non-routine work, and particularly the<br />review of test methods for newly registered drugs, requires a higher<br />proportion of fully qualified specialists. In general, the ratio of techni-cians<br />to analysts in a routine testing environment has been shown to<br />be 3: 1 in a chemical or physicochemical unit, and 5 : 2 in a biological<br />or microbiological laboratory..40<br />7. Premises<br />7.1 The laboratory should be of a suitable size, construction and<br />location. Safety requirements should be taken into consideration in<br />the design (see Part Four).<br />7.2 The design of the laboratory should be such as to provide an<br />adequate degree of separation of any activity which may interfere<br />with the proper conduct of each study.<br />7.3 The laboratory should have a sufficient number of rooms or areas<br />to ensure that test systems are isolated from one another.<br />7.4 The premises must have suitable testing and safety equipment.<br />The necessary energy sources should be available; if the line voltage<br />is variable, suitable voltage stabilizers should be installed.<br />7.5 Storage rooms or areas should be available, as needed, for sup-plies<br />and materials, and should be conveniently located. These rooms<br />should be separated from those areas housing the test systems and<br />should provide adequate protection against infestation, contamina-tion<br />and/or deterioration.<br />7.6 To prevent contamination or mix-ups, separate rooms or areas<br />for the receipt and storage of test and reference items should be<br />available, as well as for the mixing of test items with a vehicle.<br />7.7 Storage rooms or areas for test items should be separate from<br />those containing the test systems. They should be constructed in such<br />a way as to preserve the identity, concentration, purity and stability of<br />the test item, and ensure safe storage of hazardous substances. All<br />storage areas must be located and equipped in accordance with fire<br />regulations. For safety reasons, and to reduce contamination of the<br />laboratory environment, flammable reagents, fuming and concen-trated<br />acids and bases, volatile amines, etc., must never be kept in the<br />laboratory without good reason.<br />Central store<br />7.8 Separate central storage facilities must be maintained for the<br />secure storage of samples, retained samples (see Part Three, section<br />18), and reagents, laboratory accessories (see Part Two, sections<br />10.12–10.14) and reference materials (see Part Two, section 11).<br />Storage facilities must be equipped to store material, if necessary,<br />under refrigeration and securely locked. Access must be restricted to<br />designated personnel.<br />7.9 The central store should be organized in such a way so as to<br />accommodate incoming and outgoing samples, reagents, equipment,<br />instruments and other devices..41<br />7.10 Appropriate safety regulations must be drawn up and rigorously<br />implemented wherever toxic or flammable reagents are stored or<br />used.<br />7.11 Reagents subject to poison regulations or to the controls applied<br />to narcotic and psychotropic substances must be clearly marked as<br />“Poison”. They must be kept separately from other reagents in locked<br />cabinets.<br />7.12 The designated responsible member of staff must maintain a<br />register of these substances. The head of each unit must accept per-sonal<br />responsibility for the safe keeping of any of these reagents kept<br />in the workplace (see Part One, section 6.6).<br />7.13 Archive facilities should be provided to ensure the secure<br />storage and retrieval of all documents (internally generated or from<br />external sources), samples of test items and specimens. The design<br />and condition of the archives should be such as to protect the<br />contents from untimely deterioration. Access to the archives must be<br />restricted to designated personnel.<br />7.14 The handling and disposal of wastes should be carried out in<br />such a way as not to jeopardize the integrity of studies and the<br />environment. Appropriate facilities for the collection, storage and<br />disposal of wastes should be available, as well as a means of decon-tamination,<br />where applicable, and transportation.<br />7.15 The environment in which the tests are undertaken must not be<br />such as to invalidate the test results or adversely affect the required<br />accuracy of measurements. This applies particularly to sites other<br />than permanent laboratory premises. Testing premises must be pro-tected,<br />as required, from conditions such as heat, cold, dust, moisture,<br />steam, noise, vibration and electromagnetic disturbance or interfer-ence.<br />Devices to monitor the environmental conditions must be in-stalled,<br />if required by the nature of the testing. Access to, and use of,<br />all test areas must be controlled and limited to the minimum neces-sary<br />for their designated purpose. Persons external to the laboratory<br />must satisfy the specified conditions of entry. Adequate measures<br />must be taken to ensure good housekeeping in the test laboratory.<br />8. Equipment, instruments and other devices<br />8.1 Equipment, instruments and other devices must be designed, con-structed,<br />adapted, located, calibrated, qualified, verified and main-tained<br />as required by the operations to be carried out in the local<br />environment. The user should purchase the equipment from an<br />agent capable of providing full technical support and maintenance.42<br />when necessary. Documentation should be written in the language<br />employed in the laboratory.<br />8.2 To ensure proper sampling and measurement, the laboratory<br />must have the required test equipment, instruments and other devices<br />for the correct performance of the tests and/or calibrations, valida-tions<br />and verifications (including the preparation of test and/or<br />calibration items, and the processing and analysis of test and/or<br />calibration data). As a guide, a list of basic equipment, instruments<br />and other devices is given in Appendix 2.<br />8.3 Equipment, instruments and other devices, including those used<br />for sampling, must meet the laboratory’s requirements, and comply<br />with the relevant standard specifications, as well as be verified and/or<br />calibrated (see Part Two, section 12).<br />Part Two. Materials and setting-up of equipment,<br />instruments and other devices<br />9. Specifications archive<br />9.1 It is recommended that every pharmaceutical control labora-tory<br />should have a specifications archive. Current versions of all<br />necessary specifications should be kept in accordance with the<br />national legislation, as described in pharmacopoeial compendia or in<br />manufacturers’ registration documents. All updates and corrections<br />must be noted in the principal volumes of pharmacopoeias to prevent<br />the use of obsolete sections. Additional or replacement pages for<br />loose-leaf publications must be inserted immediately upon receipt,<br />and pages no longer valid must be removed. Adequate numbers of<br />supplements and addenda must be available.<br />Content<br />9.2 The specifications archive must contain:<br />(a) a list of all the pharmacopoeias in the laboratory;<br />(b) a file of non-pharmacopoeial quality specifications for drugs<br />tested to specifications established either by the manufacturer or<br />by the laboratory itself and approved by the authority responsible<br />for drug control. In this file, each entry must be numbered and<br />dated so that the latest version can easily be recognized. In ad-dition,<br />the version in the archive file (master copy) must bear<br />the date of approval by the national registration authority or the<br />specific unit and contain any other information relevant to the<br />status of the quality specifications. All subsequent corrections or.43<br />changes must be entered in the master copy and endorsed with<br />the name and signature of the person responsible and the date. A<br />revised document should be produced as soon as possible.<br />9.3 Master copies of documents should not be released from the<br />archive; photocopies must be accounted for and controlled for labora-tory<br />use.<br />9.4 Manufacturers’ specifications are the property of the company<br />concerned. They are often made available to governments strictly for<br />the purpose of assessing applications for marketing authorization.<br />The pharmaceutical control laboratory may need to negotiate their<br />release with manufacturers or even, in some cases, to develop inde-pendent<br />specifications. National laboratories may be asked routinely<br />to give their opinion on the specifications for each newly introduced<br />pharmaceutical product before it is authorized for marketing by the<br />drug regulatory authority.<br />9.5 In a large laboratory the specifications archive supervisor will<br />provide a documentation service and will be responsible for:<br />(a) updating all pharmacopoeias, including the insertion of supple-ments,<br />addenda and descriptions of corrective measures used in<br />the laboratory;<br />(b) maintaining a specifications file for all drugs authorized for mar-keting<br />within the country concerned.<br />10. Reagents<br />10.1 All reagents and chemicals, including solvents and materials<br />used in tests and assays, must be of appropriate quality.<br />10.2 Reagents must be purchased from reputable manufacturers or<br />dealers, and be accompanied by the certificate of analysis. In some<br />cases, a list of pre-qualified suppliers will have to be established.<br />10.3 In the preparation of reagents in the laboratory:<br />(a) responsibility for this task must be clearly specified in the job<br />description of the person assigned to carry it out;<br />(b) prescribed procedures must be used which are in accordance with<br />published pharmacopoeial or other standards, where available.<br />Records should be kept of the preparation and standardization of<br />volumetric solutions.<br />10.4 The labels of all reagents must clearly specify:<br />(a) the contents, the manufacturer, the date received and, as appro-priate,<br />the concentration, standardization factor, shelf-life and.44<br />storage conditions. Labels for reagents prepared in the laboratory<br />must state the date of preparation, and give the name and initials<br />of the responsible technician;<br />(b) for volumetric solutions prepared by dilution, the name of the<br />manufacturer of the original reagent, the date of preparation,<br />the date of standardization, the dilution factor, and the name of<br />the responsible technician.<br />10.5 In the transportation and subdivision of reagents:<br />(a) they must not be moved unnecessarily from unit to unit;<br />(b) whenever possible, they must be transported in the original<br />containers;<br />(c) when subdivision is necessary, scrupulously clean, fully labelled<br />containers must always be used.<br />Inspection<br />10.6 All reagent containers must be inspected to ensure that the seals<br />are intact both when they are delivered to the central store and when<br />they are distributed to the units.<br />10.7 These inspections must be recorded on the label, together with<br />the date, and the name and initials of the person responsible.<br />10.8 Reagents appearing to have been tampered with should be<br />rejected; however, this requirement may exceptionally be waived if<br />the identity and purity of the reagent concerned can be confirmed<br />by testing.<br />Distilled water and deionized water<br />10.9 Water should be considered as a reagent.<br />10.10 Precautions must be taken to avoid contamination during its<br />supply, storage and distribution.<br />10.11 Stocks must be verified regularly to ensure that pharmaco-poeial<br />and other official quality requirements are met.<br />Storage<br />10.12 Stocks of reagents must be maintained in a central store under<br />the appropriate storage conditions. The store must contain a supply<br />of clean bottles, vials, spoons, funnels and labels, as required, for<br />dispensing reagents from larger to smaller containers. Special equip-ment<br />may be needed for the transfer of larger volumes of corrosive<br />liquids..45<br />10.13 The storekeeper is responsible for looking after the central<br />store and its inventory, and for noting the expiry date of chemicals<br />and reagents. Training may be needed in handling chemicals with the<br />necessary care and safety.<br />10.14 The laboratory must provide separate rooms or areas for stor-ing<br />flammable substances, fuming and concentrated acids and bases,<br />volatile amines and other reagents, such as hydrochloric acid, nitric<br />acid, ammonia and bromine. Self-igniting materials, such as metallic<br />sodium and potassium, must also be stored separately.<br />11. Reference materials<br />11.1 Reference materials (8, 9) (e.g. official reference substances<br />and reference preparations, secondary reference materials and non-official<br />materials prepared in the laboratory as working standards) are<br />necessary for the testing and/or calibration, validation or verification<br />of a sample or of equipment, instruments or other devices.<br />Registration and labelling<br />11.2 An identification number must be assigned to all reference<br />materials, whether newly delivered or prepared in the laboratory.<br />11.3 A new identification number must be assigned to each new<br />batch.<br />11.4 This number must be marked on each vial of the material.<br />11.5 The identification number must be quoted on the analytical<br />worksheet every time the material is used (see Part Three, section<br />15.5).<br />Central register<br />11.6 Details concerning all reference materials required are compiled<br />in a central register, which may be a record book, a card file, or data-processing<br />equipment.<br />11.7 The central register must provide the following information:<br />(a) the identification number of the material;<br />(b) a precise description of the material;<br />(c) the source;<br />(d) the date of receipt;<br />(e) the batch designation or other identification code;.46<br />(f) the intended use of the material (e.g. as an infrared reference<br />material, as an impurity reference material for thin-layer chroma-tography,<br />etc.);<br />(g) the location of storage in the laboratory, and any special storage<br />conditions;<br />(h) any further necessary information (e.g. the results of inspections).<br />11.8 The functions of a person serving as a reference material co-ordinator<br />in a large laboratory (see Part One, section 6.7) must be<br />specified. This person is responsible for keeping the central register<br />for reference materials.<br />11.9 If a national drug laboratory is required to establish reference<br />materials for use by other institutions or by drug manufacturers, a<br />separate reference materials unit, which would perform all the duties<br />of the reference material coordinator, may be required.<br />Information file<br />11.10 In addition to the central register, a file must be kept in which<br />all information on the properties of each reference material is<br />entered.<br />11.11 For working standards prepared in the laboratory, the file must<br />include the results of all tests and verifications used to establish the<br />standard; these must be initialled by the responsible analyst.<br />Inspection<br />11.12 All reference materials must be inspected at regular intervals to<br />ensure that deterioration has not occurred and that the storage condi-tions<br />are appropriate for the materials concerned.<br />11.13 The results of these inspections must be recorded in the central<br />register and/or the information file, and initialled by the responsible<br />analyst.<br />11.14 Further details on the handling and storage of reference mate-rials<br />are given in the general guidelines on the establishment, mainte-nance<br />and distribution of reference materials (8). A compilation of<br />national, regional and international reference substances, which is<br />kept up to date, is available from the Secretariat (9).<br />12. Calibration, validation and verification of equipment,<br />instruments and other devices<br />12.1 All equipment, instruments and other devices used to measure<br />the physical properties of substances must be regularly calibrated,<br />validated and verified..47<br />12.2 Specific procedures must be established for each type of equip-ment,<br />instrument and other device, having regard to the extent to<br />which they are used, verified and calibrated at regular intervals ac-cording<br />to the SOP.<br />For example:<br />(a) pH meters are verified with standard certified buffer solutions at<br />least once a day;<br />(b) infrared spectrophotometers require verification at least once a<br />day and calibration at regular intervals.<br />12.3 Only authorized personnel should operate equipment, instru-ments<br />and devices. Up-to-date instructions on the use, maintenance,<br />verification and calibration of equipment, instruments and devices<br />(including any relevant manuals provided by the manufacturer) must<br />be readily available for use by the appropriate laboratory personnel<br />(e.g. a copy of these instructions should be placed beside each appa-ratus,<br />together with a schedule of the dates on which it is due for<br />verification and/or calibration). The results of the verification must<br />be recorded on a control chart, forming the basis for the timing of<br />calibration.<br />12.4 Each item of equipment, instrument or other device used for<br />testing, verification and calibration must, when practicable, be uni-quely<br />identified.<br />12.5 Records must be kept of each item of equipment, instrument or<br />other device used to perform testing, verification and/or calibration.<br />The records must include at least the following:<br />(a) the identity of the equipment, instrument or other device;<br />(b) the manufacturer’s name, the type identification, serial number<br />or other unique identification;<br />(c) the verification and/or calibration required to comply with the<br />specifications;<br />(d) the current location, where appropriate;<br />(e) the manufacturer’s instructions, if available, or an indication of<br />their location;<br />(f) the dates, results and copies of reports, verifications and certifi-cates<br />of all calibrations, adjustments, acceptance criteria, and the<br />due date of the next verification and/or calibration;<br />(g) the maintenance carried out to date and the maintenance plan;<br />(h) a history of any damage, malfunction, modification or repair..48<br />It is also recommended that records should be kept and additional<br />observations made of the time for which the equipment, instruments<br />or devices were used.<br />12.6 To prevent contamination or deterioration, the laboratory must<br />perform systematic verifications, specify procedures and have an es-tablished<br />plan for the safe handling, transport, storage, use and main-tenance<br />of measuring equipment so as to ensure that it functions<br />properly.<br />12.7 Maintenance procedures must be established (regular servicing<br />must be performed by a team of maintenance specialists, whether<br />internal or external, whenever possible).<br />12.8 Equipment, instruments and other devices, either subjected<br />to overloading or mishandling, giving suspect results, shown to be<br />defective or outside specified limits, must be taken out of service<br />and clearly labelled or marked. Wherever possible, they must not be<br />used until they have been repaired and shown by calibration or testing<br />to perform correctly.<br />12.9 All equipment, instruments and other devices under the control<br />of the laboratory and requiring calibration must be labelled, coded or<br />otherwise identified to indicate the status of calibration and the date<br />when recalibration is due.<br />12.10 When the equipment, instruments and other devices are out-side<br />the direct control of the laboratory for a certain period of time,<br />the laboratory must ensure that their function and calibration status<br />are verified and shown to be satisfactory before they are returned to<br />service.<br />12.11 Depending on the types of analytical equipment, instruments<br />and other devices used, their fragility, the extent to which they are<br />used, and the skills required to operate them, they can be:<br />(a) grouped together;<br />(b) dispersed between the various units;<br />(c) protected from extreme states of humidity or temperature in a<br />specially designed area;<br />(d) adequately protected so as to be resistant to corrosion;<br />(e) protected against mould and fungal growth.<br />12.12 Further guidance:<br />(a) Procedures for verifying and calibrating refractometers, ther-mometers<br />used in determinations of melting temperatures, and.49<br />potentiometers for pH determinations are given in The inter-national<br />pharmacopoeia (10), together with methods for verifying<br />the reliability of scales for ultraviolet and infrared spectropho-tometers<br />and spectrofluorometers.<br />(b) Guidelines for the validation of analytical procedures used in the<br />examination of chemical and physicochemical attributes of phar-maceutical<br />materials are provided in Annex 5 of the thirty-second<br />report of the WHO Expert Committee on Specifications for Phar-maceutical<br />Preparations (11). Other guidelines are also available<br />(12).<br />13. Traceability<br />13.1 Traceability aims at ensuring that the results of laboratory mea-surements<br />using procedures of lower metrological order are repro-ducible<br />and scientifically acceptable by referring to an internationally<br />agreed denominator by means of a reference procedure of highest<br />metrological order and/or a primary reference material. The analyti-cal<br />specificities of each measurement procedure and reference mate-rial<br />that is used to ascertain traceability must therefore be known.<br />A transfer protocol, together with a detailed description of the trace-ability<br />chain, including measurement procedures and reference<br />materials at all levels, must be prepared. The protocol must be<br />meticulously followed to ensure the reproducibility of results.<br />13.2 Traceability takes into account the fact that the validity of labo-ratory<br />investigations is limited by uncertainties. It applies to measure-ment<br />procedures as well as to reference materials used for the<br />calibration of such procedures.<br />13.3 For the majority of quantities, a variety of measurement proce-dures<br />have been developed to meet the requirements of the intended<br />purpose of analysis.<br />13.4 Both quantitative and qualitative measurement procedures are<br />available (8).<br />13.5 Quantitative measurement procedures provide numerical re-sults<br />that vary in terms of their precision, accuracy, and the analytical<br />sensitivity and selectivity of measurement. A hierarchy of procedures<br />can be established on the basis of the accuracy of measurement, as<br />follows:<br />(a) Measurement procedures of the highest metrological order (pri-mary<br />reference measurement procedures). These are used to<br />quantitatively measure a quantity of known physicochemical<br />structure with a negligible measurement error (bias). The re-sult<br />obtained by the use of such a procedure, which some experts.50<br />refer to as a definitive method, is nearest to the “true value”.<br />(Examples include weighing, gas chromatography–mass spectro-metry<br />and isotope dilution techniques.)<br />(b) Reference measurement procedures (secondary reference<br />measurement procedures). The accuracy of such procedures is<br />assessed by:<br />(i) comparing the results of measurement by such a procedure<br />with those of a measurement procedure of highest metro-logical<br />order;<br />(ii) calibration with an international reference material with an<br />assigned value in arbitrary units;<br />(iii) calibration with a primary reference material (e.g. an<br />International Chemical Reference Substance). (Examples<br />include flame photometry, atomic absorption spectroscopy<br />and assay methods.)<br />(c) A routine measurement procedure (selected measurement pro-cedure).<br />This measures with sufficient reliability and practicality<br />for its intended purpose. The extent of any systematic deviation<br />of the results from their true value, as determined by a routine<br />measurement method, should be known.<br />13.6 “Semi-quantitative” measurement procedures provide results<br />that are less accurate and less precise than those obtained by quanti-tative<br />measurement. Such procedures measure a quantity in discrete<br />concentration intervals. In pharmacopoeias, these tests are referred<br />to as “limit tests”; they compare the response of the test substance<br />with that of the reference substance at the limiting level. The intervals<br />are expressed as rough estimates on an ordinal scale. In laboratory<br />observations made after geometrical dilution of the specimen, the<br />results are expressed in terms of titres. Typically, no linear relation<br />exists between the signal of observation and the concentration of the<br />quantity.<br />13.7 Qualitative measurement procedures are descriptive, and may<br />distinguish between the absence and presence of a quantity in<br />samples. The results are expressed in terms of a nominal scale. The<br />distinction between the presence and absence of the quantity in a<br />sample is related to the ability of the measurement procedure to<br />detect that quantity at a minimal concentration. The minimal concen-tration<br />of a quantity that will be positively indicated by the test system<br />(limit of detection), or the ability to quantify the analyte in the pres-ence<br />of other components of the specimen (limit of quantification),<br />may vary from one test system to another. A different approach is.51<br />used for pharmacopoeial standards and for substances that are estab-lished<br />and distributed by pharmacopoeial authorities, which give the<br />information provided by certificates of analysis together with expiry<br />dates.<br />13.8 Reference materials are used for the calibration of measurement<br />procedures, and have assigned values of a quantity. These values<br />should be established, whenever possible, by means of a method of<br />highest metrological order. The assigned values may also be estab-lished<br />by means of more than one measurement procedure, provided<br />that the results are not significantly different. A hierarchy of refer-ence<br />materials also exists, as follows:<br />(a) A designated primary chemical substance is one that is widely<br />acknowledged to possess the appropriate qualities within a speci-fied<br />context, and whose value is accepted without comparison<br />with another chemical substance being required (8).<br />(b) A secondary chemical reference substance is a substance whose<br />characteristics are assigned and/or calibrated by comparison with<br />a primary chemical reference substance. The extent of characteri-zation<br />and testing of a secondary chemical reference substance<br />may be less than that required for a primary chemical reference<br />substance. This definition may apply, inter alia, to working stan-dards<br />(see below).<br />(c) International biological standards are biological reference mate-rials<br />which have been exhaustively studied and which meet inter-national<br />requirements for accuracy, consistency and stability.<br />They are established by the WHO Expert Committee on Biologi-cal<br />Standardization. Such standards are generally assigned po-tency<br />values expressed in terms of International Units (IU) of<br />biological activity, on the basis of an extensive international col-laborative<br />study.<br />(d) A working standard (working calibrator) has an assigned value of<br />a quantity using one or more selected measurement procedures.<br />This calibrator is sometimes called a “manufacturer’s master cali-brator”<br />or an “in-house calibrator”. The working standard should<br />be compatible with the manufacturer’s selected measurement<br />procedure and with the procedure to be calibrated.<br />(e) A manufacturer’s product calibrator is used for the calibration of<br />a routine measurement procedure of an end user.<br />(f) A control material is used for testing the precision and accuracy<br />of the results. Such a material should have a matrix similar to that.52<br />of the samples to be measured. Assigned values, together with the<br />uncertainty of measurement appropriate to the intended use,<br />should be given.<br />Part Three. Working procedures<br />14. Incoming samples<br />14.1 Guidelines on sampling procedures for industrially manufac-tured<br />pharmaceuticals were adopted by the WHO Expert Committee<br />on Specifications for Pharmaceutical Preparations at its thirty-first<br />meeting (13). A compendium of guidelines is also available (14).<br />14.2 Samples received by the laboratory may be routine samples for<br />control, samples suspected of not complying with the specifications,<br />or samples submitted in connection with a marketing authorization<br />process. Close collaboration with those providing the samples is im-portant.<br />In particular, pharmaceutical inspectors who frequently sub-mit<br />samples should note that the sample must be large enough to<br />enable, if required, a number of replicate tests to be carried out (see<br />Part Three, section 16.3) and for part of the sample to be retained (see<br />Part Three, section 18).<br />14.3 It is common for three samples to be taken; these must be sealed<br />and documented. Where non-compliance is suspected, two samples<br />are retained in the laboratory and the third is retained by the manu-facturer.<br />The first sample is tested in accordance with the specifica-tion.<br />If it is non-compliant and the manufacturer objects to the results,<br />the third sample is analysed in the presence of the manufacturer’s<br />specialist. The second sample is analysed in case of dispute.<br />14.4 The laboratory must have a sampling plan and an internal proce-dure<br />for sampling, available to all analysts and technicians within the<br />laboratory.<br />Test request<br />14.5 A standard test request form must be filled out during sampling<br />and must accompany each sample submitted to the laboratory.<br />14.6 The test request form must provide or leave space for the follow-ing<br />information:<br />(a) the name of the institution or inspector that supplied the sample;<br />(b) the source of the material;<br />(c) a full description of the drug, including its composition, Interna-tional<br />Nonproprietary Name (INN) (if available), brand name(s),.53<br />dosage form and concentration or strength, the manufacturer, the<br />batch number (if available) and the marketing authorization<br />number;<br />(d) the size of the sample;<br />(e) the reason for requesting the analysis;<br />(f) the date on which the sample was collected;<br />(g) the size of the consignment from which it was taken, when<br />appropriate;<br />(h) the expiry date (for pharmaceutical products) or the retest date<br />(for starting materials or pharmaceutical excipients);<br />(i) the pharmacopoeial specifications or other official specifications<br />to be used for testing;<br />(j) a record of any further comments (e.g. discrepancies found);<br />(k) the required storage conditions.<br />Registration and labelling<br />14.7 All newly delivered samples and the accompanying documents<br />(e.g. the test request) must be assigned a registration number. Sepa-rate<br />registration numbers must be assigned to requests referring to<br />two or more drugs, different dosage forms, or different batches of the<br />same drug. If applicable (see Part Three, section 18), a registration<br />number must also be assigned to any incoming retained sample.<br />14.8 A label bearing the registration number must be affixed to each<br />container of the sample. Care must be taken to avoid obliterating any<br />other markings or inscriptions.<br />Central register<br />14.9 A central register must be kept, which may be a record book, a<br />card file, or data-processing equipment, where the following informa-tion<br />is recorded:<br />(a) the registration number of the sample;<br />(b) the date of receipt;<br />(c) the specific unit to which the sample was forwarded.<br />Inspection of the submitted sample<br />14.10 The sample received must immediately be inspected by labora-tory<br />staff to ensure that the labelling is in conformity with the infor-mation<br />contained in the test request. The findings must be recorded,.54<br />dated and initialled. If discrepancies are found, or if the sample is<br />obviously damaged, the fact must be recorded without delay on the<br />test request form. Any queries must be immediately referred back to<br />the provider of the sample.<br />Storage<br />14.11 The sample prior to testing (see Part Three, section 16.1), the<br />retained sample (see Part Three, section 18) and any portions of the<br />sample remaining after performance of all the required tests must be<br />stored safely taking into account, if necessary, the storage conditions<br />(15, 16) specified for the sample.<br />Forwarding to testing<br />14.12 The specific unit to which the sample is sent to for testing is<br />determined by the head of central registry.<br />14.13 The examination of a sample must not be started before the<br />relevant test request has been received.<br />14.14 The sample must be properly stored until all relevant documen-tation<br />has been received.<br />14.15 A request for analysis may be accepted verbally only in case of<br />emergencies. All details must immediately be placed on record, pend-ing<br />the receipt of written confirmation.<br />14.16 Data must be recorded on the analytical worksheet (see Part<br />Three, section 15).<br />14.17 Copies or duplicates of all documentation must accompany<br />each numbered sample when sent to the specific unit.<br />14.18 Testing must be performed as described under Part Three,<br />section 16.<br />15. Analytical worksheet<br />15.1 The analytical worksheet is an internal document in printed<br />form for recording information about the sample, the test procedure<br />and the results of testing. It may be complemented by the raw data<br />obtained in the analysis.<br />Purpose<br />15.2 The analytical worksheet contains:<br />(a) confirmation that the sample being examined is in accordance<br />with the requirements;<br />(b) documentary evidence to support regulatory action, if necessary..55<br />Use<br />15.3 A separate analytical worksheet must be used for each num-bered<br />sample.<br />15.4 If necessary, a further set of analytical worksheets in duplicate<br />can be used for a collaborating unit (after testing, all the results<br />should be assembled in a single analytical worksheet, using the data<br />from all collaborating units).<br />Content<br />15.5 The analytical worksheet must provide or leave space for the<br />following information:<br />(a) the registration number of the sample (see Part Three, section<br />14.7);<br />(b) page numbering, including the total number of pages (including<br />annexes);<br />(c) the date of the test request;<br />(d) the date on which the analysis was performed;<br />(e) the name and signature of the analyst;<br />(f) a description of the sample received;<br />(g) references to the specifications to which the sample was tested,<br />including the limits (adding any special methods employed) (see<br />Part Three, section 14.6), and the reference number of the speci-fications,<br />if available (e.g. pharmacopoeial monograph);<br />(h) the results obtained with the tested sample (see Part Three, sec-tion<br />16.4);<br />(i) the interpretation of the results and the final conclusions<br />(whether or not the sample was found to comply with the<br />specifications), signed by each of the analysts involved and ini-tialled<br />by the supervisor;<br />(j) the identity of the test equipment used (see Part Two, section 12);<br />(k) any further comments, for example, for internal information (see<br />Part Three, section 16.1). The above information may be comple-mented<br />by:<br />(i) detailed notes on the specifications selected and the methods<br />of assessment used (see Part Three, section 15.7);<br />(ii) whether and when portions of the sample were forwarded to<br />other units for special tests (for example, mass spectrometry,.56<br />X-ray diffraction), and the date when the results were<br />received;<br />(iii) the identification number of any reference material (see Part<br />Two, section 11.5);<br />(iv) if applicable, the results of an instrument verification;<br />(v) if applicable, the results of a reagent verification.<br />15.6 The completed analytical worksheet must be signed by the re-sponsible<br />analyst(s) and initialled by the supervisor.<br />Selection of the specifications to be used<br />15.7 The specifications necessary to assess the sample may be those<br />given in the test request; these are usually an existing particular<br />pharmacopoeial monograph, or the manufacturer’s specifications. If<br />no precise instruction is given, the specifications in the officially rec-ognized<br />national pharmacopoeia may be used or, failing this, the<br />manufacturer’s officially approved or other nationally recognized<br />specifications. If no suitable method is available:<br />(a) the specifications contained in the product licence may be re-quested<br />from the manufacturer and validated, if the general<br />policy of the laboratory permits this action (see Part Two, section<br />9.4); or<br />(b) the requirements are drafted in the laboratory itself on the basis<br />of published information and any other relevant documentation<br />and should be validated by the testing laboratory before they are<br />adopted as a SOP (1–3).<br />15.8 For official specifications, the current version must be available<br />(see Part Two, section 9.1).<br />Filing<br />15.9 The analytical worksheet must be placed on file for safe keeping,<br />together with any attachments, including calculations and tracings of<br />instrumental analyses.<br />15.10 If the analytical worksheet is stored in a central archive, a copy<br />should be retained in the specific unit concerned for easy reference.<br />15.11 The analytical test report (see Part Three, sections 17.3 and<br />17.4) must be prepared on the basis of the worksheet (see Appendix<br />1 and Annex 10).<br />15.12 When mistakes are made in analytical worksheets or when data<br />or text need to be amended, the old information should be deleted by.57<br />means of a single line (not erased nor made illegible) and the new<br />information added alongside. All such alterations should be initialled<br />or signed by the person making the correction and the date of the<br />change inserted. The reason for the change should also be given on<br />the worksheet.<br />16. Testing<br />16.1 The sample must be tested in accordance with the workplan of<br />the laboratory after completion of the preliminary procedures. If this<br />is not feasible, the reasons must be noted, for example in the analyti-cal<br />worksheet (see Part Three, section 15), and the sample must be<br />stored in a special place which is kept locked (see Part Three, section<br />14.11).<br />16.2 Specific tests required, such as mass spectrometry or X-ray dif-fraction,<br />may need to be carried out by another unit or by a special-ized<br />external laboratory. The responsible person should prepare the<br />request and arrange for the transfer of the required number of units<br />(bottles, vials, tablets) from the sample. Each of these units must bear<br />the correct registration number.<br />Guidance for performing test methods<br />16.3 Detailed guidance on official pharmacopoeial requirements is<br />usually given in the general notices and specific monographs of the<br />pharmacopoeia concerned. Where system suitability criteria are<br />defined in the method, they should be fulfilled.<br />16.4 All values obtained from each test, including blank results, must<br />immediately be entered on the analytical worksheet, and all graphical<br />data, whether obtained from recording instruments or plotted by<br />hand, must be attached (see Part Three, section 15).<br />17. Evaluation of test results<br />17.1 Test results must be reviewed and, where appropriate, evaluated<br />statistically after completion of all the tests to determine whether they<br />are mutually consistent and if they meet the specifications used. The<br />evaluation should take into consideration the results of all the tests.<br />Whenever doubtful results are obtained, they should be investigated.<br />The complete testing procedure needs to be checked according to the<br />internal quality system (see also Part One, section 2). Doubtful results<br />can be rejected only if they are clearly due to error, which has been<br />identified.<br />17.2 All conclusions must be entered on the analytical worksheet (see<br />Part Three, section 15) by the analyst and initialled by the supervisor..58<br />Analytical test report<br />17.3 The analytical test report (see Appendix 1) is a compilation of<br />the results and states the conclusions of the examination of a sample.<br />It must be:<br />(a) issued by the laboratory;<br />(b) based on the analytical worksheet (see Part Three, section 15).<br />Content of the analytical test report<br />17.4 The analytical test report must provide the following informa-tion<br />(see Appendix 1):<br />(a) the registration number of the sample;<br />(b) the name and address of the laboratory testing the sample;<br />(c) the name and address of the originator of the request for<br />analysis;<br />(d) the name and description and batch number of the sample,<br />where appropriate;<br />(e) a reference to the specifications used for testing the sample,<br />including the limits;<br />(f) the results of all the tests performed, or the numerical results of<br />all the tests performed (if applicable);<br />(g) a conclusion whether or not the sample was found to be within<br />the limits of the specifications used;<br />(h) the date on which the test was performed;<br />(i) the signature of the head of the laboratory or authorized person;<br />(j) the name and address of the repacker and/or trader, if<br />applicable;<br />(k) the name and address of the original manufacturer;<br />(l) whether or not the sample complies with the requirements;<br />(m) the date on which the sample was received;<br />(n) the expiry date.<br />18. Retained samples<br />18.1 Samples are retained for at least 6 months if they are found to<br />comply with the requirements and for at least 12 months or until their<br />expiry date (whichever is longer) in the case of non-compliance (for<br />storage, see Part Three, section 14.11)..59<br />Part Four. Safety<br />19. General rules<br />19.1 General and specific safety instructions must be made available<br />to each staff member and supplemented regularly as appropriate (e.g.<br />with written material, poster displays, audiovisual material and occa-sional<br />seminars).<br />19.2 General rules for safe working in accordance with national regu-lations<br />and SOPs normally include the following requirements:<br />(a) safety data sheets must be available to staff before testing is<br />carried out;<br />(b) smoking, eating and drinking in the laboratory must be<br />prohibited;<br />(c) staff must be familiar with the use of fire-fighting equipment,<br />including fire extinguishers, fire blankets and gas masks;<br />(d) staff must wear laboratory coats or other protective clothing,<br />including eye protection;<br />(e) special care must be taken, as appropriate, in handling, for ex-ample,<br />highly potent, infectious or volatile substances;<br />(f) all containers of chemicals must be fully labelled and include<br />prominent warnings (e.g. “Poison”, “Flammable”, “Radiation”,<br />etc.) whenever appropriate;<br />(g) adequate insulation and spark-proofing must be provided for<br />electrical wiring and equipment, including refrigerators;<br />(h) safety rules in handling cylinders of compressed gases must be<br />observed, and staff must be familiar with the relevant colour<br />identification codes;<br />(i) staff must be aware of the need to avoid working alone in the<br />laboratory;<br />(j) first-aid materials must be provided, and staff instructed in first-aid<br />techniques, emergency care and the use of antidotes.<br />19.3 Protective clothing must be available, including eye protection,<br />masks and gloves. Water showers should be installed. Rubber suction<br />bulbs must be used on manual pipettes and siphons. Staff must be<br />instructed in the safe handling of glassware, corrosive reagents and<br />solvents, and particularly in the use of safety containers or baskets<br />to avoid spillage from containers. Warnings, precautions and<br />instructions must be given for work with violent, uncontrollable or.60<br />dangerous reactions when handling specific reagents (e.g. mixing<br />water and acids, or acetone–chloroform and ammonia), flammable<br />products, oxidizing or radioactive agents, and especially biologicals<br />such as infectious agents. Peroxide-free solvents should be used. Staff<br />must be aware of methods for the safe disposal of unwanted corrosive<br />or dangerous products by neutralization or deactivation and of the<br />need for safe and complete disposal of mercury and its salts (see also<br />Part One, section 7.14).<br />19.4 Poisonous or hazardous products must be singled out and la-belled<br />appropriately, but it must not be taken for granted that all<br />other chemicals and biologicals are safe. Unnecessary contact with<br />reagents, especially solvents and their vapours, must be avoided. The<br />use of known carcinogens and mutagens must be limited or totally<br />excluded if required by local regulations. Replacement of toxic<br />solvents and reagents by less toxic materials or reduction of their<br />use must always be the aim, particularly when new techniques are<br />developed.<br />References<br />1. Quality assurance in pharmaceutical supply systems. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations.<br />Twenty-seventh report. Geneva, World Health Organization, 1980, Annex 1 (WHO<br />Technical Report Series, No. 645).<br />2. Distribution. In: Quality assurance of pharmaceuticals. A compendium of<br />guidelines and related materials. Vol. 1. Geneva, World Health Organization,<br />1997:105–115.<br />3. Analytical criteria for drug quality assessment. In: WHO Expert Committee<br />on Specifications for Pharmaceutical Preparations. Twenty-sixth report.<br />Geneva, World Health Organization, 1977, Annex 1 (WHO Technical Report<br />Series, No. 614).<br />4. Quality assurance of pharmaceuticals. A compendium of guidelines and<br />related materials. Vol. 2. Good manufacturing practices and inspection.<br />Geneva, World Health Organization, 1999.<br />5. Guidelines for inspection of drug distribution channels. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-fifth<br />report. Geneva, World Health Organization, 1999, Annex 6 (WHO Technical<br />Report Series, No. 885).<br />6. Good manufacturing practices: supplementary guidelines for the<br />manufacture of pharmaceutical excipients. In: WHO Expert Committee on<br />Specifications for Pharmaceutical Preparations. Thirty-fifth report. Geneva,<br />World Health Organization, 1999, Annex 5 (WHO Technical Report Series,<br />No. 885).<br />7. Department of Health and Human Services, Food and Drug Administration.<br />International Conference on Harmonisation; guidelines on validation of.61<br />analytical procedures: definitions and terminology; availability. Federal<br />Register, 1995, 60(40):11260–11262.<br />8. General guidelines for the establishment, maintenance and distribution<br />of chemical reference substances. In: WHO Expert Committee on<br />Specifications for Pharmaceutical Preparations. Thirty-fifth report. Geneva,<br />World Health Organization, 1999, Annex 3 (WHO Technical Report Series,<br />No. 885).<br />9. Reference substances and infrared reference spectra for pharmacopoeial<br />analysis. Geneva, World Health Organization, 1998 (unpublished document<br />WHO/EDM/QSM/99.5; available from Quality Assurance and Safety: Medi-cines,<br />Essential Drugs and Medicines Policy, World Health Organization,<br />1211 Geneva 27, Switzerland).<br />10. The international pharmacopoeia, 3rd ed. Vol. 1. General methods of<br />analysis. Geneva, World Health Organization, 1979.<br />11. Validation of analytical procedures used in the examination of pharma-ceutical<br />materials. In: WHO Expert Committee on Specifications for<br />Pharma-ceutical Preparations. Thirty-second report. Geneva, World Health Organiza-tion,<br />1992, Annex 5 (WHO Technical Report Series, No. 823).<br />12. The international pharmacopoeia and related activities. In: Quality<br />assurance of pharmaceuticals. A compendium of guidelines and related<br />materials. Vol. 1. Geneva, World Health Organization, 1997:116–149.<br />13. Sampling procedures for industrially manufactured pharmaceuticals. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-first report. Geneva, World Health Organization, 1990, Annex 2 (WHO<br />Technical Report Series, No. 790).<br />14. Laboratory services. In: Quality assurance of pharmaceuticals. A<br />com-pendium of guidelines and related materials. Vol. 1. Geneva, World Health<br />Organization, 1997:154–186.<br />15. Guidelines for stability testing of pharmaceutical products containing well<br />established drug substances in conventional dosage forms. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth<br />report. Geneva, World Health Organization, 1996, Annex 5 (WHO Technical<br />Report Series, No. 863).<br />16. Product assessment and registration. In: Quality assurance of<br />pharmaceu-ticals. A compendium of guidelines and related materials. Vol. 1. Geneva,<br />World Health Organization, 1997:31–104..62<br />Appendix 1<br />Model analytical test report for active<br />pharmaceutical ingredients, excipients and<br />pharmaceutical products<br />Registration no.:<br />1<br />Name and address of laboratory testing the sample:<br />Name and address of originator requesting analysis (if applicable):<br />Sample information<br />Name of product (INN,<br />2<br />brand name(s), etc.):<br />Dosage form (if applicable):<br />Concentration or strength (if applicable):<br />Marketing authorization number (if applicable):<br />Description (appearance of container and contents):<br />Batch number(s):<br />Required storage conditions (if applicable):<br />Date received:<br />Date of manufacture (if known):<br />Expiry date (for pharmaceutical products) or retest date (for starting<br />materials or pharmaceutical excipients):.63<br />Name and address of original manufacturer:<br />Telephone: Fax:<br />Name and address of repacker/trader (if applicable):<br />Telephone: Fax:<br />Test procedure Result Acceptance criteria<br />(reference) (numerical) (limits)<br />(if applicable) (if applicable)<br />Conclusions<br />Compliance with acceptance criteria: yes _ no _<br />Date test performed/finalized:<br />Name and address of head of laboratory/authorized person:<br />Telephone: Fax:<br />Signature:<br />Explanatory notes<br />1<br />Of sample or analytical test report.<br />2<br />The International Nonproprietary Name should be used whenever possible..64<br />Appendix 2<br />Equipment for a first-stage and medium-size<br />pharmaceutical control laboratory<br />A list of equipment considered by the Committee to be adequate<br />either for a first-stage or medium-size pharmaceutical control labora-tory<br />is given below.<br />National drug regulatory authorities or laboratories wishing to per-form<br />pharmaceutical analyses should consider the following list in the<br />establishment or upgrading of their testing facilities. For budgetary<br />reasons, it is necessary, besides the cost of equipment, to take into<br />consideration the cost of reference materials, reagents, solvents,<br />glassware, other laboratory commodities and personnel charges. Ex-perience<br />has shown that for sustainability, a laboratory should allow<br />a margin of 10–15% per year of the purchasing expenditure on equip-ment<br />to cover the cost of maintenance.<br />Guidance and information on the cost of equipment can be obtained<br />from the Secretariat.<br />First-stage laboratory<br />Equipment and major instruments Quantity<br />Top-loading balance 1<br />Analytical balance, semi-micro (4 digits) 1<br />Melting-point apparatus 1<br />pH meter (with assorted electrodes) 1<br />Microscope (binocular) 1<br />Polarimeter (manual) 1<br />High-performance liquid chromatograph with ultraviolet<br />detector 1<br />Ultraviolet/visible spectrophotometer 1<br />Infrared spectrophotometer with pellet press 1<br />Agate mortar with pestle 1<br />Equipment for thin-layer chromatography (TLC),<br />including spreader 1<br />TLC spotter 1<br />Developing chambers 6<br />Atomizers 6<br />Ultraviolet viewing lamp 1.65<br />Disintegration test equipment (1 basket for 6 tablets) 1<br />Soxhlet extraction apparatus (60 ml) 1<br />Micrometer callipers 1<br />Pycnometers 2<br />Burettes 5<br />Desiccator 1<br />Centrifuge (table-top model, 4-place swing rotor) 1<br />Water-bath (20 litres) 1<br />Hot plates with magnetic stirrers 3<br />Vacuum pump (rotary, oil) 1<br />Drying oven (60 litres) 1<br />Vacuum oven (17 litres) 1<br />Muffle furnace 1<br />Refrigerator (explosion-proof) 1<br />Water distilling apparatus (8 litres/hour) 1<br />Water deionizer (10 litres/hour) 1<br />Dehumidifier (where needed) 1<br />Fume hood 1<br />Optional items<br />Analytical balance, micro (5 digits) 1<br />Flame photometer (including air compressor) 1<br />Refractometer 1<br />Viscometer 1<br />Vortex mixer 1<br />Shaker (wrist-action) 1<br />Pipette rinser 1<br />Constant temperature water-bath 1<br />Ultrasonic cleaner (5 litres) 1<br />Medium-size laboratory<br />General laboratory equipment Quantity<br />Top-loading balance 1 or 2<br />Analytical balance, semi-micro (4 digits) 2<br />Analytical balance, micro (5 digits) 1.66<br />Microscope (binocular) 1 or 2<br />Equipment for TLC, including spreader 1<br />TLC multispotter 1<br />Developing chambers 6<br />Atomizers 6<br />Ultraviolet viewing lamp 1<br />Potentiometric titrimeter 1<br />Micro-Kjeldahl equipment (including fume flasks) 1<br />Burettes 6<br />Micrometer callipers 1<br />Heating mantles for flasks (assorted sizes: 50, 200 and<br />2000ml) 6<br />Sieves (assorted sizes) 2 sets<br />Centrifuge (floor model) 1<br />Shaker (wrist-action) 1<br />Vortex mixers 2<br />Water-bath (electrical, 20 litres) 2 or 3<br />Hot plates with magnetic stirrers 3 or 4<br />Vacuum pump (rotary, oil) 2<br />Vacuum rotary evaporator 1 or 2<br />Drying oven (60 litres) 2 or 3<br />Muffle furnace (23 litres) 1<br />Vacuum oven (17 litres) 1<br />Desiccators 2<br />Refrigerator (explosion-proof) 1<br />Freezer 1<br />Ultrasonic cleaners (5 litres) 2<br />Ultrasonic pipette cleaner 1<br />Water distilling apparatus (8 litres/hour) 1<br />Water deionizing equipment (10 litres/hour) 1<br />Fume hoods 2<br />Major instruments<br />Melting-point apparatus 1<br />Polarimeter 1<br />pH meters (with assorted electrodes) 2<br />High-performance liquid chromatograph with variable<br />wavelength ultraviolet/visible detector 1.67<br />Ultraviolet/visible spectrophotometer, double-beam 1<br />Infrared spectrophotometer with pellet press 1<br />Agate mortar with pestle 1<br />Gas chromatograph (flame ionization, direct head space) 1<br />Refractometer 1<br />Karl Fischer titrator 1<br />Potentiograph 1<br />Oxygen flask combustion apparatus 1<br />Disintegration test equipment (1 basket for 6 tablets) 1<br />Dissolution test equipment (for 6 tablets/capsules) 1<br />Optional items<br />Atomic absorption spectrophotometer 1<br />Spectrofluorometer 1<br />High-performance liquid chromatograph: 1<br />— with fluorescence detector 1<br />— with diode-array detector 1<br />— with refractive index detector 1<br />— with conductivity detector 1<br />TLC scanner 1<br />Crushing strength tester 1<br />Friability tester 1<br />Viscometer 1<br />Ice machine 1<br />Solvent-recovery apparatus 1<br />Equipment for microbiology unit<br />pH meter 1<br />Ultraviolet/visible spectrophotometer, single-beam 1<br />Microscopes (for bacteriology) 2<br />Membrane filter assembly for sterility tests 1<br />Colony counter with magnifier 1<br />Laminar air flow unit 1<br />Hot-air sterilizer 1<br />Incubators, 60 litres 2 or 3<br />Anaerobic jar 1<br />Zone reader 1<br />Centrifuge 1.68<br />Water-bath (thermostatically controlled) 2<br />Autoclaves (100 litres, top-loading) 2<br />Refrigerators (340 litres) 2<br />Deep freezer 1<br />Cleaning device for glassware, including pipettes 2.69<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 4<br />Considerations for requesting analysis of drug<br />samples<br />1<br />Many WHO Member States do not have adequate drug quality con-trol<br />facilities of their own. For drugs imported into such countries,<br />manufacturers’ batch certificates issued in accordance with the WHO<br />Certification Scheme (1) will normally provide sufficient information<br />on the quality and origin of a product. This assumes that an official<br />inspection of the manufacturing site has been performed and that the<br />manufacturer complies with good manufacturing practices (2). For<br />domestically manufactured pharmaceuticals, manufacturers’ batch<br />certificates may be relied upon to indicate the quality of a product.<br />This implies that the results of an inspection by the competent<br />national authority have shown that the manufacturer is capable of<br />reliably producing a product of the required quality.<br />However, in certain situations a need may arise for national authori-ties<br />to test drug samples when testing facilities are not available. For<br />this purpose, laboratories in other countries or contract laboratories<br />in the same or in another country may be contacted (for a model<br />certificate of analysis, see Annex 10). General considerations before<br />approaching them are set out below.<br />Important note: Any laboratory contacted has the right to decline<br />a request for analysis without furnishing any explanation or<br />remark.<br />Reason for analysis<br />Full-scale pharmacopoeial testing is expensive. The national author-ity<br />may prefer to limit analysis to those products which:<br />— show physical signs of instability or deterioration (3);<br />— are of unidentifiable origin;<br />— emanate from a supplier suspected of dealing in substandard<br />products;<br />— have given rise to disputed analytical results;<br />— are suspected of causing adverse reactions;<br />1<br />These considerations are applicable to national drug regulatory authorities, but may also<br />apply to the independent analysis of pharmaceuticals in trade..70<br />— will be used as evidence in litigation;<br />— are provided through drug donations.<br />Where the information on the quality of a product is important and<br />needs to be communicated rapidly (such as the presence of products<br />of deterioration or a new impurity profile), selected purity tests may<br />be performed instead of full-scale pharmacopoeial testing. These tests<br />should include a potency test, and any tests additional to those in the<br />pharmacopoeial monograph that might be required. Since the se-lected<br />tests may not always be capable of detecting all the impurities<br />of unknown source, a combination of analytical methods, such as<br />several different chromatographic methods or differential scanning<br />calorimetry together with gas or liquid chromatography, could be<br />used. The suitability of the pharmacopoeial monograph from the<br />point of view of the detection of impurities should be evaluated,<br />especially if the drug is from a new source, which may cause it to have<br />a different impurity profile. If necessary, the advice of an experienced<br />laboratory should be sought.<br />Communication before samples are submitted<br />Before a sample of a product is sent to a laboratory in another country<br />or a contract laboratory and its analysis is requested, the laboratory<br />concerned must be asked whether it is willing to carry out the analysis.<br />The request should be accompanied, as a minimum, by the following<br />information, which should be given in writing:<br />— the reason(s) for the request;<br />— the name and address of the manufacturer and/or distributor;<br />— the marketing authorization and its number or reference;<br />— the pharmaceutical dosage form;<br />— the composition of the product (using International Non-proprietary<br />Names (INNs), where possible);<br />— the concentration or strength;<br />— the date of manufacture;<br />— details of the storage conditions and the expiry date;<br />— any background information about the route of synthesis of the<br />ingredients, if available;<br />— a reference to pharmacopoeial or other specifications, including<br />details of the analytical methods that should be used;<br />— the purpose of the analyses;<br />— the number of separate samples to be analysed and their batch<br />(lot) number(s);<br />— the proposed mode of payment for the analysis;<br />— the preferred language and format of the report containing the<br />results (see below)..71<br />It is recommended that a contract between the requesting party and<br />the laboratory that will perform the tests should be drawn up to settle<br />issues such as liability, and the mode of payment for the expenses<br />involved. The responsibilities of the two parties should be defined.<br />The laboratory that has been contacted should indicate, at the earliest<br />possible opportunity, its decision whether or not to undertake the<br />analyses.<br />If the laboratory agrees to undertake the analysis, the following<br />should be communicated to the requesting party:<br />— the nature and size of the sample required;<br />— any additional non-pharmacopoeial tests which may be required;<br />— the cost and the mode of payment;<br />— a tentative estimate of the time that the analysis will take;<br />— the method to be used to transmit the results.<br />Submission of samples<br />Upon agreement with a laboratory, the sample should be dispatched<br />by the national drug regulatory authority or the requesting party.<br />The sample must be suitably packaged and labelled (4). It should be<br />divided into two portions, each of which must be properly packed and<br />sealed. The laboratory should analyse one sealed portion only, and<br />retain the other for presenting during litigation or investigation. In<br />the case of products that are subject to legal controls on exportation,<br />appropriate arrangements must be made by the national drug regula-tory<br />authority to ensure due compliance with customs requirements.<br />Analytical results<br />All analyses undertaken by a laboratory should be in accordance with<br />the specified pharmacopoeial or other specifications mentioned in<br />the request for analysis, or as subsequently agreed (see Annex 3). If<br />requested, results of the analyses can be transmitted by facsimile or<br />other means (e.g. electronic mail), and confirmed with a detailed<br />signed report. The report should be in the working language of the<br />laboratory, or as agreed between the parties (see Annex 3).<br />References<br />1. Guidelines for implementation of the WHO Certification Scheme on the<br />Quality of Pharmaceutical Products Moving in International Commerce. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 10<br />(WHO Technical Report Series, No. 863).<br />2. Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second.72<br />report. Geneva, World Health Organization, 1992, Annex 2 (WHO Technical<br />Report Series, No. 823).<br />3. The international pharmacopoeia, 3rd ed. Vol. 4. Tests, methods, and general<br />requirements. Quality specifications for pharmaceutical substances,<br />excipients, and dosage forms. Geneva, World Health Organization, 1994.<br />4. Sampling procedure for industrially manufactured pharmaceuticals. In: WHO<br />Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-first report. Geneva, World Health Organization, 1990, Annex 2 (WHO<br />Technical Report Series, No. 790)..73<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 5<br />Basic elements of good manufacturing practices in<br />pharmaceutical production<br />Poor-quality medicines are not only a health hazard, but a waste of<br />money for both governments and individual consumers, since they<br />may contain toxic substances that have been unintentionally added.<br />For example, in Haiti in 1996, more than 80 children died after receiv-ing<br />a syrup for cough and colds containing glycerol contaminated with<br />diethylene glycol (1). If the manufacturer had followed good manufac-turing<br />practices (GMP), these deaths could have been prevented.<br />In addition, a medicine that contains little or none of the claimed<br />active ingredient will not have the intended therapeutic effect. An<br />antibiotic with some — but not enough — of the active ingredient will<br />not cure infections. Even worse, bacteria exposed to low levels of the<br />antibiotic may not be killed and may become resistant to the drug,<br />even at the correct dosage, putting more lives at risk.<br />Good manufacturing practices help boost pharmaceutical export<br />opportunities<br />Most countries will accept the import and sale of medicines only if<br />they have been manufactured according to internationally recognized<br />GMP. For this reason, governments seeking to promote their coun-try’s<br />export of pharmaceuticals can do so by making GMP mandatory<br />for all pharmaceutical production and by training their inspectors in<br />GMP requirements.<br />What are good manufacturing practices?<br />GMP are that part of quality assurance which ensures that products<br />are consistently produced and controlled according to quality stan-dards.<br />They are designed to minimize the main risks involved in<br />pharmaceutical production that cannot be eliminated through testing<br />of the final product. These risks are:<br />— the unexpected contamination of products, causing damage to<br />health or even death;<br />— incorrect labels on containers, which could mean that patients<br />receive the wrong medicine;<br />— insufficient or too much active ingredient, resulting in ineffective<br />treatment or adverse effects..74<br />GMP cover all aspects of production, from the starting materials,<br />premises and equipment to the training and personal hygiene of staff.<br />Detailed, written procedures are essential for each process that could<br />affect the quality of the finished product. Systems must be established<br />to provide documented proof that correct procedures are consistently<br />followed at each step in the manufacturing process — every time a<br />product is made.<br />WHO has established detailed guidelines for GMP (2), and many<br />countries have formulated their own GMP requirements based on<br />those of WHO. Others have harmonized their requirements, e.g. in<br />the Association of South-East Asian Nations (ASEAN), in the Euro-pean<br />Union and through the Pharmaceutical Inspection Convention.<br />Are good manufacturing practices necessary if there is a quality<br />control laboratory?<br />Good quality must be built in during the manufacturing process;<br />testing products after they have been manufactured is not enough.<br />GMP prevent errors that cannot be eliminated through quality con-trol<br />of the finished product. Without GMP it is impossible to be sure<br />that every unit of medicine is of the same quality as those tested in the<br />laboratory.<br />In the early 1970s, a manufacturer in the United Kingdom produced an<br />infusion fluid which caused the death of five patients because it was<br />heavily contaminated with bacteria ( 3). Before distributing the fluid, the<br />manufacturer had tested several bottles and found them to be sterile.<br />Eventually a technical fault was found in the sterilizer: the bottles at the<br />bottom had not been properly sterilized. The bottles that the manufac-turer<br />had tested were from the upper part, giving the false impression that<br />all the bottles were sterile.<br />Can manufacturers afford to implement good manufacturing<br />practices?<br />Making poor-quality products does not save money. In the long run,<br />it is more expensive finding mistakes after they have been made than<br />preventing them in the first place. GMP are designed to ensure that<br />mistakes do not occur.<br />Implementation of GMP is an investment in good-quality medicines,<br />and will improve the health of both the individual patient and the<br />community, as well as benefiting the pharmaceutical industry and<br />health professionals..75<br />Making and distributing poor-quality medicines leads to loss of<br />credibility for everyone, including public and private health care ser-vices<br />and pharmaceutical manufacturers.<br />References<br />1. Fatalities associated with ingestion of diethylene glycol — contaminated<br />glycerol used to manufacture acetaminophen syrup — Haiti, November<br />1995–June 1996. Morbidity and Mortality Weekly Report, 1996, 45(30):649–<br />650.<br />2. Quality assurance of pharmaceuticals. A compendium of guidelines and<br />related materials. Vol. 2. Good manufacturing practices and inspection.<br />Geneva, World Health Organization, 1999.<br />3. Meers PD et al. Intravenous infusion of contaminated dextrose solution: the<br />Devonport incident. Lancet, 1973, ii(7839):1189–1192..76<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 6<br />Good manufacturing practices for sterile<br />pharmaceutical products<br />Introductory note 76<br />1. General considerations 76<br />2. Quality control 77<br />3. Sanitation 77<br />4. Manufacture of sterile preparations 78<br />5. Sterilization 83<br />6. Terminal sterilization 85<br />7. Aseptic processing and sterilization by filtration 88<br />8. Personnel 89<br />9. Premises 90<br />10. Equipment 92<br />11. Finishing of sterile products 93<br />References 93<br />Introductory note<br />This document is a revision of section 17 of Part Three of “Good<br />manufacturing practices [GMP] for pharmaceutical products” (1),<br />which emphasizes specific points for the manufacture of sterile prepa-rations<br />to minimize the risks of microbiological, particulate and pyro-gen<br />contamination. It is not exhaustive in character, and some<br />technical requirements may change in line with developments in the<br />field of GMP or advances in engineering design.<br />1. General considerations<br />1.1 The production of sterile preparations should be carried out in<br />clean areas, entry to which should be through airlocks for personnel<br />and/or for equipment and materials. Clean areas should be main-tained<br />to an appropriate standard of cleanliness and supplied with air<br />that has passed through filters of the required efficiency.<br />1.2 The various operations of component preparation (such as those<br />involving containers and closures), product preparation, filling and.77<br />sterilization should be carried out in separate areas within a clean<br />area. These areas are classified into four grades (see section 4.1).<br />1.3 Manufacturing operations are divided here into two categories:<br />first, those where the product is terminally sterilized, and second,<br />those which are conducted aseptically at some or all stages.<br />2. Quality control<br />2.1 Samples taken for sterility testing should be representative of the<br />whole of the batch, but should, in particular, include samples taken<br />from parts of the batch considered to be most at risk of contamina-tion,<br />for example:<br />(a) for products that have been filled aseptically, samples should<br />include containers filled at the beginning and end of the batch and<br />after any significant interruption of work;<br />(b) for products that have been heat sterilized in their final con-tainers,<br />consideration should be given to taking samples from<br />that part of the load that is potentially the coolest.<br />2.2 The sterility of the finished product is ensured by validation of the<br />sterilization cycle in the case of terminally sterilized products, and by<br />“media-fills” runs for aseptically processed products. Batch process-ing<br />records and, in the case of aseptic processing, environmental<br />quality records, should be examined in conjunction with the results of<br />the sterility tests. The sterility test procedure should be validated for<br />a given product. Pharmacopoeial methods must be used for the vali-dation<br />and performance of the sterility test.<br />2.3 For injectable products, the water for injection and the intermedi-ate<br />and finished products should be monitored for endotoxins, using<br />an established pharmacopoeial method that has been validated for<br />each type of product. For large-volume infusion solutions, such<br />monitoring of water or intermediates should always be done, in addi-tion<br />to any tests required by an approved monograph for the finished<br />product. When a sample fails a test, the cause of such failure should be<br />investigated and remedial action taken where necessary.<br />3. Sanitation<br />3.1 The sanitation of clean areas is particularly important. They<br />should be cleaned frequently and thoroughly in accordance with an<br />approved written programme. Monitoring should be regularly under-taken<br />in order to detect the emergence of resistant strains of micro-organisms.<br />In view of its limited effectiveness, ultraviolet light should<br />not be used as a substitute for chemical disinfection..78<br />3.2 Disinfectants and detergents should be monitored for microbio-logical<br />contamination; dilutions should be kept in previously cleaned<br />containers and should only be stored for defined periods unless steri-lized.<br />Disinfectants and detergents used in grade A and B areas (see<br />section 4.1) should be sterilized before use.<br />3.3 In order to control the microbiological cleanliness of the various<br />grades in operation, the clean areas should be monitored. Where<br />aseptic operations are performed, monitoring should be frequent and<br />methods such as settle plates, and volumetric air and surface sampling<br />(e.g. swabs and contact plates) should be used. The zones should not<br />be contaminated through the sampling methods used in the opera-tions.<br />The results of monitoring should be considered when batch<br />documentation for release of the finished product is reviewed. Both<br />surfaces and personnel should be monitored after critical operations.<br />3.4 Levels (limits) of detection of microbiological contamination<br />should be established for alert and action purposes, and for monitor-ing<br />the trends in air quality in the facility. Limits expressed in colony-forming<br />units (CFU) for the microbiological monitoring of clean<br />areas in operation are given in Table 1. The sampling methods and<br />numerical values included in the table are not intended to represent<br />specifications, but are for information only.<br />4. Manufacture of sterile preparations<br />4.1 Clean areas for the manufacture of sterile products are classified<br />according to the required characteristics of the environment. Each<br />manufacturing operation requires an appropriate environmental<br />cleanliness level in the operational state in order to minimize the risks<br />of particulate or microbiological contamination of the product or<br />materials being handled.<br />Table 1<br />Limits for microbiological contamination<br />a<br />Grade<br />b<br />Air sample Settle plates Contact plates Glove print<br />(CFU/m<br />3<br />) (diameter 90 mm) (diameter 55 mm) (5 fingers)<br />(CFU/4 hours)<br />c<br />(CFU/plate) (CFU/glove)<br />A <3 <3 <3 <3<br />B 105 55<br />C 100 50 25 —<br />D 200 100 50 —<br />a<br />These are average values. The grades are defined in section 4.1.<br />b<br />The airborne particulate classification for the four grades is given in Table 2.<br />c<br />Individual settle plates may be exposed for less than 4 hours..79<br />In order to meet “in operation” conditions, these areas should be<br />designed to reach certain specified air-cleanliness levels in the “at<br />rest” occupancy state. This latter state is the condition where the<br />installation is complete, and production equipment has been installed<br />and is operating, but no operating personnel are present. The “in<br />operation” state is the condition where the installation is functioning<br />in the defined operating mode and the specified number of personnel<br />are present.<br />For the manufacture of sterile pharmaceutical preparations, four<br />grades are distinguished here, as follows:<br />• Grade A: The local zone for high-risk operations, e.g. filling and<br />making aseptic connections. Normally such conditions are provided<br />by a laminar-airflow workstation. Laminar-airflow systems should<br />provide a homogeneous air speed of approximately 0.45m/s ± 20%<br />(guidance value) at the working position.<br />• Grade B: In aseptic preparation and filling, the background envi-ronment<br />for the grade A zone.<br />• Grades C and D: Clean areas for carrying out less critical stages in<br />the manufacture of sterile products.<br />The airborne particulate classification for the four grades is given in<br />Table 2.<br />To obtain air of the required characteristics, methods specified by<br />national authorities should be used. It should be noted that:<br />• In order to reach the B, C and D air grades, the number of air<br />changes should be appropriate for the size of the room and the<br />equipment and personnel present in it. At least 20 air changes per<br />hour are usually required for a room with a good airflow pattern<br />and appropriate high-efficiency particulate air (HEPA) filters.<br />Table 2<br />Airborne particulate classification for manufacture of sterile pharmaceutical<br />preparations<br />Grade At rest In operation<br />Maximum number Maximum number<br />of particles permitted/m<br />3<br />of particles permitted/m<br />3<br />0.5–5.0 m m >5.0 m m 0.5–5.0 m m >5.0 m m<br />A 3500 0 3500 0<br />B 3500 0 350000 2000<br />C 350000 2000 3500000 20000<br />D 3500000 20000 Not defined Not defined.80<br />• Detailed information on methods for determining the microbio-logical<br />and particulate cleanliness of air, surfaces, etc. is not given<br />here. Reference should be made to other guidelines published<br />in compendia such as the European, Japanese or United States<br />pharmacopoeias, or in documents issued by the European Commit-tee<br />for Standardization and the International Organization for<br />Standardization (ISO).<br />The different airborne particulate classification systems for clean<br />areas are shown in Table 3.<br />4.2 The particulate conditions given in Table 2 for the “at rest” state<br />should be achieved in the absence of the operating personnel after a<br />short “clean-up” period of about 15–20 minutes (guidance value),<br />after completion of the operations. The particulate conditions given<br />in Table 2 for grade A “in operation” should be maintained in the<br />zone immediately surrounding the product whenever the product or<br />open container is exposed to the environment. It is accepted that it<br />may not always be possible to demonstrate conformity with particu-late<br />standards at the point of fill when filling is in progress, owing to<br />the generation of particles or droplets from the product itself.<br />4.3 In order to control the particulate cleanliness of the various clean<br />areas during operation, they should be monitored.<br />4.4 Appropriate alert and action limits should be set for the results<br />of particulate and microbiological monitoring. If these limits are<br />exceeded, the appropriate corrective actions should be taken, as<br />prescribed in the operating procedures.<br />4.5 The area grades as specified in sections 4.6–4.14 must be selected<br />by the manufacturer on the basis of the nature of the process opera-tions<br />being performed and validation runs (e.g. sterile media fills).<br />The determination of an appropriate process area environment and<br />Table 3<br />Comparison of different airborne particulate classification systems for clean<br />areas<br />a<br />WHO United States United States ISO/TC EEC<br />(GMP) (209E) (customary) (209) (GMP)<br />Grade A M 3.5 Class 100 ISO 5 Grade A<br />Grade B M 3.5 Class 100 ISO 5 Grade B<br />Grade C M 5.5 Class 10000 ISO 7 Grade C<br />Grade D M 6.5 Class 100000 ISO 8 Grade D<br />EEC: European Commission; ISO/TC: International Organization for Standardization Technical<br />Committee.<br />a<br />Source: references 1–4..81<br />a time limit should be based on the microbiological contamination<br />(bioburden) found.<br />Terminally sterilized products<br />4.6 Components and most products should be prepared in at least a<br />grade D environment in order to give low microbial and particulate<br />counts, suitable for filtration and sterilization. Where the product is at<br />unusual risk of microbial contamination (e.g. because it actively sup-ports<br />microbial growth, must be held for a long period before steril-ization,<br />or is necessarily not processed mainly in closed vessels), the<br />preparation should generally be done in a grade C environment.<br />4.7 The filling of products for terminal sterilization should generally<br />be done in at least a grade C environment.<br />4.8 Where the product is at unusual risk of contamination from the<br />environment (e.g. because the filling operation is slow or the contain-ers<br />are wide-necked or are necessarily exposed for more than a few<br />seconds before sealing), the filling should be done in a grade A zone<br />with at least a grade C background.<br />4.9 The preparation and filling of ointments, creams, suspensions and<br />emulsions should generally be done in a grade C environment before<br />terminal sterilization.<br />Aseptic preparation<br />4.10 Components after washing should be handled in at least<br />a grade D environment. The handling of sterile starting materials and<br />components, unless subjected to sterilization or filtration through a<br />microorganism-retaining filter later in the process, should be done in<br />a grade A environment with a grade B background.<br />4.11 The preparation of solutions which are to be sterile filtered<br />during the process should be done in a grade C environment; if not<br />sterile filtered, the preparation of materials and products should be<br />done in a grade A environment with a grade B background.<br />4.12 The handling and filling of aseptically prepared products, as<br />well as the handling of exposed sterile equipment, should be done in<br />a grade A environment with a grade B background.<br />4.13 The transfer of partially closed containers, as used in freeze–<br />drying, should, before stoppering is completed, be done either in a<br />grade A environment with a grade B background or in sealed transfer<br />trays in a grade B environment.<br />4.14 The preparation and filling of sterile ointments, creams, suspen-sions<br />and emulsions should be done in a grade A environment with a.82<br />grade B background when the product is exposed and is subsequently<br />filtered.<br />Processing<br />4.15 Precautions to minimize contamination should be taken during<br />all processing stages, including the stages before sterilization.<br />4.16 Preparations containing live microorganisms should not be<br />made or containers filled in areas used for the processing of other<br />pharmaceutical products; however, vaccines consisting of dead organ-isms<br />or of bacterial extracts may be dispensed into containers, after<br />validated inactivation and validated cleaning procedures, in the same<br />premises as other sterile pharmaceutical products.<br />4.17 The validation of aseptic processing should include simulating<br />the process using a nutrient medium. The form of the nutrient me-dium<br />used should generally be equivalent to the dosage form of the<br />product. The process-simulation test should imitate as closely as pos-sible<br />the routine aseptic manufacturing process and include all<br />the critical subsequent manufacturing steps. Consideration should be<br />given to simulation of the worst expected condition. The process-simulation<br />test should be repeated at defined intervals and after any<br />significant modification to the equipment and process. The number of<br />containers used for a medium fill should be sufficient to ensure a valid<br />evaluation. For small batches, the number of containers for the me-dium<br />fill should be at least equal to the size of the product batch.<br />4.18 Care should be taken to ensure that any validation does not<br />compromise the processes.<br />4.19 Water sources, water-treatment equipment and treated water<br />should be monitored regularly for chemicals, biological contamina-tion<br />and contamination with endotoxins to ensure that the water<br />complies with the specifications appropriate to its use. Records should<br />be maintained of the results of the monitoring and of any action<br />taken.<br />4.20 Activities in clean areas, especially when aseptic operations<br />are in progress, should be kept to a minimum, and the movement of<br />personnel should be controlled and methodical, so as to avoid exces-sive<br />shedding of particles and organisms due to over-vigorous activity.<br />The ambient temperature and humidity should not be uncomfortably<br />high because of the nature of the garments worn.<br />4.21 The presence of containers and materials liable to generate<br />fibres should be minimized in clean areas and avoided completely<br />when aseptic work is in progress..83<br />4.22 Components, bulk-product containers and equipment should<br />be handled after the final cleaning process in such a way that they are<br />not recontaminated. The stage of processing of components, bulk-product <br />containers and equipment should be properly identified.<br />4.23 The interval between the washing and drying and the steriliza-tion<br />of components, bulk-product containers and equipment, as<br />well as between sterilization and use, should be as short as possible<br />and subject to a time-limit appropriate to the validated storage<br />conditions.<br />4.24 The time between the start of the preparation of a solution and<br />its sterilization or filtration through a bacteria-retaining filter should<br />be as short as possible. A maximum permissible time should be set<br />for each product that takes into account its composition and the<br />prescribed method of storage.<br />4.25 Any gas that is used to purge a solution or blanket a product<br />should be passed through a sterilizing filter.<br />4.26 The bioburden of products should be monitored before steriliza-tion.<br />There should be a working limit on the contamination of prod-ucts<br />immediately before sterilization that is related to the efficiency<br />of the method to be used and the risk of pyrogens. All solutions, in<br />particular large-volume parenterals, should be passed through a<br />microorganism-retaining filter, if possible immediately before the<br />filling process. Where aqueous solutions are held in sealed vessels,<br />any pressure-release outlets should be protected, e.g. by hydrophobic<br />microbiological air filters.<br />4.27 Components, bulk-product containers, equipment and any other<br />articles required in a clean area where aseptic work is in progress<br />should be sterilized and, wherever possible, passed into the area<br />through double-ended sterilizers sealed into the wall. Other proce-dures<br />that prevent the introduction of contamination (e.g. triple<br />wrapping) may be acceptable in some circumstances.<br />4.28 The efficacy of any new processing procedure should be vali-dated,<br />and the validation should be repeated at regular intervals<br />thereafter or when any significant change is made in the process or<br />equipment.<br />5. Sterilization<br />5.1 Whenever possible, products intended to be sterile should prefer-ably<br />be terminally sterilized by heat in their final container. Where<br />it is not possible to carry out terminal sterilization by heating due to<br />the instability of a formulation, a decision should be taken to use an.84<br />alternative method of terminal sterilization following filtration and/or<br />aseptic processing.<br />5.2 Sterilization can be achieved by the use of moist or dry heat, by<br />irradiation with ionizing radiation (but not with ultraviolet radiation<br />unless the process is thoroughly validated), by ethylene oxide (or<br />other suitable gaseous sterilizing agents) or by filtration with subse-quent<br />aseptic filling of sterile final containers. Each method has its<br />particular advantages and disadvantages. Where possible and practi-cable,<br />heat sterilization is the method of choice.<br />5.3 The microbiological contamination of starting materials should<br />be minimal, and their bioburden should be monitored before steriliza-tion.<br />Specifications should include requirements for microbiological<br />quality when the need for this has been indicated by monitoring.<br />5.4 All sterilization processes must be validated. Particular attention<br />should be given when the adopted sterilization method is not in<br />accordance with pharmacopoeial or other national standards or when<br />it is used for a preparation that is not a simple aqueous or oily<br />solution.<br />5.5 Before any sterilization process is adopted, its suitability for the<br />product and its efficacy in achieving the desired sterilizing conditions<br />in all parts of each type of load to be processed should be demon-strated<br />by physical measurements and by biological indicators, where<br />appropriate. The validity of the process should be verified at sched-uled<br />intervals, at least annually, and whenever significant modifica-tions<br />have been made to the equipment. Records should be kept of<br />the results.<br />5.6 For effective sterilization, the whole of the material should be<br />subjected to the required treatment and the process should be<br />designed to ensure that this is achieved.<br />5.7 Biological indicators should be considered only as an additional<br />method of monitoring the sterilization process. They should be stored<br />and used according to the manufacturer’s instructions, and their qual-ity<br />checked by positive controls. If they are used, strict precautions<br />should be taken to avoid any transfer of microbiological contamina-tion<br />from them.<br />5.8 There should be a clear means of differentiating products that<br />have not been sterilized from those that have. Each basket, tray, or<br />other carrier of products or components should be clearly labelled<br />with the name of the material, its batch number, and an indication of<br />whether or not it has been sterilized. Indicators such as autoclave tape<br />may be used, where appropriate, to indicate whether or not a batch.85<br />(or sub-batch) has passed through a sterilization process, but they do<br />not give a reliable indication that the batch is, in fact, sterile.<br />5.9 Sterilization records should be available for each sterilization run.<br />They should be approved as part of the batch-release procedure.<br />6. Terminal sterilization<br />Sterilization by heat<br />6.1 Each heat-sterilization cycle should be recorded by means of<br />appropriate equipment of suitable accuracy and precision, e.g. on a<br />time/temperature chart with a suitably large scale. The temperature<br />should be recorded by a probe at the coolest part of the load or loaded<br />chamber, this point having been determined during the validation; the<br />temperature should preferably be checked against a second indepen-dent<br />temperature probe located at the same position. The chart, or a<br />photocopy of it, should form part of the batch record. Chemical or<br />biological indicators may also be used but should not take the place of<br />physical controls.<br />6.2 Sufficient time must be allowed for the whole of the load to reach<br />the required temperature before measurement of the sterilizing time<br />is started. This time must be determined for each type of load to be<br />processed.<br />6.3 After the high-temperature phase of a heat sterilization cycle,<br />precautions should be taken against contamination of a sterilized load<br />during cooling. Any cooling fluid or gas in contact with the product<br />should be sterilized.<br />Sterilization by moist heat<br />6.4 Sterilization by moist heat (heating in an autoclave) is suitable<br />only for water-wettable materials and aqueous formulations. Both<br />temperature and pressure should be used to monitor the process. The<br />temperature recorder should normally be independent of the control-ler,<br />and there should be an independent temperature indicator, the<br />reading from which should be routinely checked against the chart<br />recorder during the sterilization period. For sterilizers fitted with a<br />drain at the bottom of the chamber, it may also be necessary to record<br />the temperature at this position throughout the sterilization period.<br />There should be regular leak tests on the chamber when a vacuum<br />phase is part of the cycle.<br />6.5 The items to be sterilized, other than products in sealed con-tainers,<br />should be wrapped in a material that allows the removal of<br />air and the penetration of steam but prevents recontamination after.86<br />sterilization. All parts of the load should be in contact with water or<br />saturated steam at the required temperature for the required time.<br />6.6 Care should be taken to ensure that the steam used for steriliza-tion<br />is of suitable quality and does not contain additives at a level that<br />could cause contamination of the product or equipment.<br />Sterilization by dry heat<br />6.7 Sterilization by dry heat may be suitable for non-aqueous liquids<br />or dry powder products. The process used should include air circula-tion<br />within the chamber and the maintenance of a positive pressure to<br />prevent the entry of non-sterile air. If air is supplied, it should be<br />passed through a microorganism-retaining filter (e.g. an HEPA filter).<br />Where sterilization by dry heat is also intended to remove pyrogens,<br />challenge tests using endotoxins will be required as part of the<br />validation.<br />Sterilization by radiation<br />6.8 Sterilization by radiation is used mainly for the sterilization of<br />heat-sensitive materials and products. Many pharmaceutical products<br />and some packaging materials are radiation-sensitive, so this method<br />is permissible only when the absence of deleterious effects on the<br />product has been confirmed experimentally. Ultraviolet irradiation is<br />not an acceptable method for terminal sterilization.<br />6.9 If sterilization by radiation is carried out by an outside contractor,<br />the manufacturer is responsible for ensuring that the requirements of<br />section 6.8 are met, and that the sterilization process is validated. The<br />responsibilities of the radiation plant operator (e.g. for using the<br />correct dose) should also be specified.<br />6.10 During the sterilization procedure, the radiation dose should be<br />measured. For this purpose, the dosimeters used must be independent<br />of the dose rate and must provide a quantitative measurement of the<br />dose received by the product itself. Dosimeters should be inserted in<br />the load in sufficient number, and close enough together to ensure<br />that there is always a dosimeter in the chamber. Where plastic dosim-eters<br />are employed, they should be used within the time-limit of their<br />calibration. Dosimeter absorbances should be read shortly after expo-sure<br />to radiation. Biological indicators may be used only as an addi-tional<br />control. Radiation-sensitive colour discs may be used to<br />differentiate between packages that have been subjected to irradia-tion<br />and those that have not; they are not indicators of successful<br />sterilization. The information obtained should constitute part of the<br />batch record..87<br />6.11 Validation procedures should ensure that consideration is given<br />to the effects of variations in the density of the packages.<br />6.12 Handling procedures should prevent any misidentification of<br />irradiated and non-irradiated materials. Each package should carry a<br />radiation-sensitive indicator to show whether or not it has been sub-jected<br />to radiation treatment.<br />6.13 The total radiation dose should be administered within a prede-termined<br />period of time.<br />Sterilization by gases and fumigants<br />6.14 This method of sterilization should only be used for products<br />where there is no suitable alternative.<br />6.15 Various gases and fumigants may be used for sterilization (e.g.<br />ethylene oxide, hydrogen peroxide vapour). Ethylene oxide should be<br />used only when no other method is practicable. During process vali-dation<br />it should be shown that the gas has no damaging effect on the<br />product and that the conditions and time allowed for degassing are<br />such as to reduce any residual gas and reaction products to defined<br />acceptable limits for the type of product or material concerned. These<br />limits should be incorporated in the specifications.<br />6.16 Direct contact between gas and microorganisms is essential; pre-cautions<br />should therefore be taken to avoid the presence of organisms<br />likely to be enclosed in materials such as crystals or dried protein. The<br />nature and quantity of packaging materials can significantly affect the<br />process.<br />6.17 Before exposure to the gas, materials should be brought into<br />equilibrium with the humidity and temperature required by the pro-cess.<br />This requirement should be balanced against the need to mini-mize<br />the waiting time before sterilization.<br />6.18 Each sterilization cycle should be monitored with suitable bio-logical<br />indicators, using the appropriate number of test pieces distrib-uted<br />throughout the load. The information so obtained should form<br />part of the batch record.<br />6.19 Biological indicators should be stored and used according to the<br />manufacturer’s instructions, and their performance checked by<br />positive controls.<br />6.20 For each sterilization cycle, records should be made of the time<br />taken to complete the cycle, of the pressure, temperature and humidity<br />within the chamber during the process, and of the gas concentration.<br />The pressure and temperature should be recorded on a chart through-out<br />the cycle. The records should form part of the batch record..88<br />6.21 After sterilization, the load should be stored in a controlled<br />manner under ventilated conditions to allow concentrations of re-sidual<br />gas and reaction products to fall to their prescribed levels. This<br />process should be validated.<br />7. Aseptic processing and sterilization by filtration<br />7.1 The objective of aseptic processing is to maintain the sterility<br />of a product that is assembled from components, each of which<br />has been sterilized by one of the above methods (see sections 5<br />and 6).<br />7.2 The operating conditions should be such as to prevent microbial<br />contamination.<br />7.3 In order to maintain the sterility of the components and the<br />product during aseptic processing, careful attention needs to be given<br />to: (a) the environment; (b) the personnel; (c) the critical surfaces;<br />(d) the container/closure sterilization and transfer procedures; (e) the<br />maximum holding period of the product before filling into the final<br />container; and (f) the sterilizing filter.<br />7.4 Certain solutions and liquids that cannot be sterilized in the final<br />container can be filtered through a sterile filter of nominal pore size<br />0.22 m m (or less), or with at least equivalent microorganism-retaining<br />properties, into a previously sterilized container. Such filters can<br />remove bacteria and moulds, but not all viruses or mycoplasmas.<br />Consideration should be given to complementing the filtration<br />process with some degree of heat treatment.<br />7.5 Owing to the potential additional risks of the filtration method as<br />compared with other sterilization processes, a double filter layer or<br />second filtration via a further sterilized microorganism-retaining<br />filter immediately prior to filling may be advisable. The final sterile<br />filtration should be carried out as close as possible to the filling point.<br />7.6 The fibre-shedding characteristics of filters should be minimal<br />(virtually zero). Asbestos-containing filters must not be used under<br />any circumstances.<br />7.7 The integrity of the filter should be checked by an appropriate<br />method such as a bubble-point, diffusive-flow or pressure-hold test,<br />immediately after use (it may also be useful to test the filter in this<br />way before use). The time taken to filter a known volume of bulk<br />solution and the pressure difference to be used across the filter should<br />be determined during validation, and any significant differences from<br />these values should be noted and investigated. The results of these<br />checks should be recorded in the batch record. The integrity of critical.89<br />gas and air vent filters should be confirmed after use. The integrity of<br />other filters should be confirmed at appropriate intervals. Consider-ation<br />should be given to increased monitoring of filter integrity in<br />processes that involve harsh conditions, e.g. the circulation of high-temperature<br />air.<br />7.8 The same filter should not be used for more than 1 working day<br />unless such use has been validated.<br />7.9 The filter should not affect the product either by removing ingre-dients<br />from it or by releasing substances into it.<br />8. Personnel<br />8.1 Only the minimum number of personnel required should be<br />present in clean areas; this is particularly important during aseptic<br />processes. Inspections and controls should be conducted from outside<br />such areas as far as possible.<br />8.2 All personnel (including those concerned with cleaning and main-tenance)<br />employed in such areas should receive initial and regular<br />training in disciplines relevant to the correct manufacture of sterile<br />products, including hygiene and the basic elements of microbiology.<br />When outside staff who have not received such training (e.g. building<br />or maintenance contractors) need to be brought in, particular care<br />should be taken over their instruction and supervision.<br />8.3 Staff who have been engaged in the processing of animal-tissue<br />materials or of cultures of microorganisms other than those used in<br />the current manufacturing process should not enter sterile-product<br />areas unless rigorous and clearly defined decontamination procedures<br />have been followed.<br />8.4 High standards of personal hygiene and cleanliness are essential,<br />and personnel involved in the manufacture of sterile preparations<br />should be instructed to report any conditions that may cause the<br />shedding of abnormal numbers or types of contaminants; periodic<br />health checks for such conditions are desirable. The action to be taken<br />in respect of personnel who might be introducing undue microbiologi-cal<br />hazards should be decided by a designated competent person.<br />8.5 Outdoor clothing should not be brought into clean areas, and<br />personnel entering changing rooms should already be clad in standard<br />factory protective garments. Changing and washing should follow a<br />written procedure designed to minimize the contamination of clean<br />area clothing or the carry-through of contaminants to clean areas.<br />8.6 Wrist-watches and jewellery should not be worn in clean areas,<br />and cosmetics that can shed particles should not be used..90<br />8.7 The clothing worn and its quality should be appropriate for the<br />process and the grade of the working area (workplace). It should be<br />worn in such a way as to protect the product from contamination. The<br />clothing required for each grade is as follows:<br />• Grade D. The hair and, where relevant, beard and moustache<br />should be covered. Protective clothing and appropriate shoes or<br />overshoes should be worn. Appropriate measures should be taken<br />to avoid any contamination from outside the clean area.<br />• Grade C. The hair and, where relevant, beard and moustache<br />should be covered. A single or two-piece trouser suit, gathered at<br />the wrists and with a high neck, and appropriate shoes or overshoes<br />should be worn. The clothing should shed virtually no fibres or<br />particulate matter.<br />• Grades A/B. Headgear should totally enclose the hair and, where<br />relevant, beard and moustache. A single or two-piece trouser suit,<br />gathered at the wrists and with a high neck, should be worn. The<br />headgear should be tucked into the neck of the suit. A face mask<br />should be worn to prevent the shedding of droplets. Appropriate,<br />sterilized, non-powdered rubber or plastic gloves and sterilized or<br />disinfected footwear should be worn. Trouser-bottoms should be<br />tucked inside the footwear and garment sleeves into the gloves. The<br />protective clothing should shed virtually no fibres or particulate<br />matter and should retain particles shed by the body.<br />8.8 Outdoor clothing should not be brought into changing rooms<br />leading to grade B and C rooms. For every worker in a grade A/B room,<br />clean sterilized or adequately sanitized protective garments should be<br />provided at each work session, or at least once a day if monitoring<br />results justify this. Gloves should be regularly disinfected during op-erations.<br />Masks and gloves should be changed at least at every working<br />session. The use of disposable clothing may be necessary.<br />8.9 Clothing used in clean areas should be laundered or cleaned in<br />such a way that it does not gather additional particulate contaminants<br />that can later be shed. Separate laundry facilities for such clothing are<br />desirable. If fibres are damaged by inappropriate cleaning or steriliza-tion,<br />there may be an increased risk of shedding particles. Washing<br />and sterilization operations should follow standard operating<br />procedures.<br />9. Premises<br />9.1 All premises should, as far as possible, be designed to avoid the<br />unnecessary entry of supervisory or control personnel. Grade B areas.91<br />should be designed so that all operations can be observed from<br />outside.<br />9.2 In clean areas, all exposed surfaces should be smooth, impervious<br />and unbroken in order to minimize the shedding or accumulation of<br />particles or microorganisms and to permit the repeated application of<br />cleaning agents and disinfectants, where used.<br />9.3 To reduce the accumulation of dust and to facilitate cleaning,<br />there should be no uncleanable recesses and a minimum of projecting<br />ledges, shelves, cupboards and equipment. Doors should be carefully<br />designed to avoid uncleanable recesses; sliding doors are undesirable<br />for this reason.<br />9.4 False ceilings should be sealed to prevent contamination from the<br />space above them.<br />9.5 Pipes and ducts and other utilities should be installed so that they<br />do not create recesses, unsealed openings and surfaces that are<br />difficult to clean.<br />9.6 Sinks and drains should be avoided wherever possible and should<br />be excluded from grade A/B areas where aseptic operations are car-ried<br />out. Where installed, they should be designed, located and main-tained<br />so as to minimize the risks of microbiological contamination;<br />they should be fitted with effective, easily cleanable traps and with air<br />breaks to prevent back-flow. Any floor channels should be open<br />and easily cleanable and be connected to drains outside the area in a<br />manner that prevents the ingress of microbiological contaminants.<br />9.7 Changing rooms should be designed as airlocks and used to sepa-rate<br />the different stages of changing, thus minimizing particulate and<br />microbiological contamination of protective clothing. They should be<br />effectively flushed with filtered air. The use of separate changing<br />rooms for entering and leaving clean areas is sometimes necessary.<br />Hand-washing facilities should be provided only in the changing<br />rooms, not in areas where aseptic work is done.<br />9.8 Airlock doors should not be opened simultaneously. An inter-locking<br />system and a visual and/or audible warning system can be<br />installed to prevent the opening of more than one door at a time.<br />9.9 A filtered air supply should be used to maintain a positive pres-sure<br />and an airflow relative to surrounding areas of a lower grade<br />under all operational conditions; it should flush the area effectively.<br />Adjacent rooms of different grades should have a pressure differen-tial<br />of approximately 10–15 pascals (guidance value). Particular atten-tion<br />should be paid to the protection of the zone of greatest risk,.92<br />i.e. the immediate environment to which the product and the cleaned<br />components in contact with it are exposed. The various recom-mendations<br />regarding air supplies and pressure differentials may<br />need to be modified where it becomes necessary to contain certain<br />materials, e.g. pathogenic, highly toxic, radioactive or live viral or<br />bacterial materials or products. The decontamination of the facilities<br />and the treatment of air leaving a clean area may be necessary for<br />some operations.<br />9.10 It should be demonstrated that airflow patterns do not present a<br />contamination risk; for example, care should be taken to ensure that<br />particles from a particle-generating person, operation or machine are<br />not conveyed to a zone of higher product risk.<br />9.11 A warning system should be included to indicate failure in the<br />air supply. An indicator of pressure difference should be fitted be-tween<br />areas where this difference is important, and the pressure<br />difference should be regularly recorded.<br />9.12 Consideration should be given to restricting unnecessary access<br />to critical filling areas, e.g. grade A filling zones, by means of a<br />physical barrier.<br />10. Equipment<br />10.1 A conveyor belt should not pass through a partition between a<br />grade A or B clean area and a processing area of lower air cleanliness,<br />unless the belt itself is continuously sterilized (e.g. in a sterilizing<br />tunnel).<br />10.2 Whenever possible, equipment used for processing sterile prod-ucts<br />should be chosen so that it can be effectively sterilized by steam<br />or dry heat or other methods.<br />10.3 As far as possible, equipment fittings and services should be<br />designed and installed so that operations, maintenance and repairs<br />can be carried out outside the clean area. Equipment that has to be<br />taken apart for maintenance should be resterilized after complete<br />reassembly, wherever possible.<br />10.4 When equipment maintenance is carried out within a clean area,<br />clean instruments and tools should be used, and the area should be<br />cleaned and disinfected again, where appropriate, before processing<br />recommences if the required standards of cleanliness and/or asepsis<br />have not been maintained during the maintenance work.<br />10.5 All equipment, including sterilizers, air-filtration systems, and<br />water-treatment systems, including stills, should be subject to planned.93<br />maintenance, validation and monitoring; its approved use following<br />maintenance work should be documented.<br />10.6 Water-treatment plants and distribution systems should be de-signed,<br />constructed and maintained so as to ensure a reliable source of<br />water of an appropriate quality. They should not be operated beyond<br />their designed capacity. Consideration should be given to including a<br />testing programme in the maintenance of a water system. Water for<br />injection should be produced, stored and distributed in a manner<br />which prevents the growth of microorganisms, e.g. by constant circu-lation<br />at a temperature above 70°C or not more than 4°C.<br />11. Finishing of sterile products<br />11.1 Containers should be closed by appropriately validated meth-ods.<br />Samples should be checked for integrity according to appropriate<br />procedures.<br />11.2 Containers sealed under vacuum should be sampled and the<br />samples tested, after an appropriate predetermined period, to ensure<br />that the vacuum has been maintained.<br />11.3 Filled containers of parenteral products should be inspected<br />individually. When inspection is done visually, it should be done<br />under suitable and controlled conditions of illumination and back-ground.<br />Operators doing the inspection should pass regular eyesight<br />checks, with spectacles if worn, and be allowed frequent breaks from<br />inspection. Where other methods of inspection are used, the process<br />should be validated and the performance of the equipment checked at<br />intervals. The results should be recorded.<br />References<br />1. Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second<br />report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823).<br />2. Airborne particulate cleanliness classes in cleanrooms and clean zones.<br />Federal Standard 209E. Mount Prospect, IL, Institute of Environmental<br />Sciences, 1992.<br />3. Cleanrooms and associated controlled environments. Part 1: classification of<br />airborne particulates. Geneva, International Organization for Standardization,<br />1999.<br />4. The rules governing medicinal products in the European Union. Vol. 4. Good<br />manufacturing practices: medicinal products for human and veterinary use.<br />Brussels, European Commission, 1998..94<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 7<br />Guidelines on pre-approval inspections<br />1. General 94<br />2. Glossary 94<br />3. Objectives 95<br />4. Priorities 96<br />5. Preparation for the inspection 96<br />6. Carrying out the inspection 97<br />7. Sample collection and testing 99<br />8. Follow-up regulatory/administrative decisions 100<br />References 100<br />1. General<br />The advice provided here extends that given in the “Provisional<br />guidelines on the inspection of pharmaceutical manufacturers” (1).<br />The objectives of an inspection, as given in the introduction to the<br />guidelines, are:<br />— to control and enforce compliance with general good manufactur-ing<br />practices (GMP) (2); and<br />— to authorize the manufacture of specific pharmaceutical products,<br />normally in response to a licensing application.<br />These guidelines are applicable mainly to inspections of the first type,<br />whether performed as a condition for the issue of a manufacturing<br />licence/authorization, or on a periodic, routine basis. They are essen-tially<br />concerned with inspections of manufacturing and quality-control<br />facilities conducted before a marketing authorization (product<br />licence or registration) for a pharmaceutical product is granted.<br />2. Glossary<br />The definitions given below apply to the terms used in this guide.<br />They may have different meanings in other contexts.<br />application<br />A marketing authorization for a new drug application..95<br />manufacturer<br />A company that carries out at least one step of manufacture (2).<br />manufacture<br />All operations concerned with the purchase of materials and prod-ucts,<br />production (including packaging), quality control, release,<br />storage, the distribution of pharmaceutical products, and the related<br />controls (2).<br />method validation/verification<br />Method validation is conducted where non-compendial analytical<br />methods are included in the application to confirm that the applicants’<br />proposed analytical methods are suitable for regulatory purposes. A<br />side-by-side comparison with a compendial method, if available,<br />should be included. Method verification is conducted where the meth-ods<br />are compendial, to confirm whether the product as compounded<br />can be analysed satisfactorily by the official method.<br />pre-approval batches<br />Pilot or laboratory-scale batches, upon which the application is based,<br />e.g. batches used for pivotal clinical trials and/or those used for<br />bioavailability, bioequivalence and stability studies, and scale-up<br />batches.<br />3. Objectives<br />Before any application is approved, it is necessary to determine<br />whether all establishments participating in the manufacture of the<br />finished dosage form are in compliance with GMP and the application<br />commitments. Pre-approval inspections have the following specific<br />objectives:<br />• Evaluation of the establishment’s compliance with GMP require-ments,<br />particularly regarding proper environment, quality manage-ment,<br />personnel, facilities and equipment.<br />• Evaluation of the procedures and controls implemented in the<br />manufacture of the product (pre-approval batches), to determine<br />whether they are in conformity with the application commitments.<br />• Audit of the completeness and accuracy of the manufacturing and<br />testing information submitted with the application, and of the con-formity<br />of pre-approval batches with planned commercial batches<br />(process validation protocol).<br />• The collection of samples for the validation or verification of the<br />analytical methods included in the application..96<br />4. Priorities<br />Pre-approval inspections are considered to be an important part of<br />the application review and approval process. However, since this<br />represents a considerable workload, inspections are not normally<br />carried out routinely, but rather only in specific cases where non-compliance<br />is possible. Thus inspections may be required for:<br />— new chemical entities;<br />— drugs of narrow therapeutic range, and drugs for serious condi-tions<br />requiring an assured therapeutic response;<br />— products previously associated with serious adverse effects, com-plaints,<br />recalls, etc.;<br />— products that are difficult to manufacture or test, or that are of<br />doubtful stability (and therefore associated with the risk of<br />defects);<br />— new applicants or manufacturers; and<br />— applications from manufacturers who have previously failed to<br />comply with GMP or official quality specifications.<br />For other applications, the drug regulatory authority will rely on the<br />results of recent inspections of the applicant’s or manufacturer’s<br />facilities for the production of dosage forms similar to that of the<br />proposed product.<br />5. Preparation for the inspection<br />An inspection team should, where possible, include analysts and<br />other specialists, e.g. in pharmaceutical technology, or if available,<br />persons with expertise in these fields, when needed. Team members<br />may be assigned to inspect new operations or manufacturing sites<br />associated with product failures. When possible, the analyst involved<br />in the laboratory evaluation of the product under review should par-ticipate<br />in the inspection. Pre-approval inspection is often carried out<br />by a single inspector.<br />It is necessary to verify that the applicant holds an appropriate manu-facturing<br />authorization and that manufacturing is carried out in con-formity<br />with that authorization (licence).<br />An essential step in the review of applications is determining whether<br />the commitments made by the manufacturer are reflected in actual<br />practice. A review of the application information is also important<br />in preparing for inspections of firms or processes with which the<br />inspector is unfamiliar. The drug regulatory authority should provide<br />inspectors with relevant information on the application. (Some<br />countries request an additional copy of this information from appli-cants<br />which is forwarded to the inspection team.) The information.97<br />provided should include a copy of the manufacturing and controls<br />section of the application, together with information relating to pre-approval<br />batches.<br />Reasonable efforts should be made to conduct pre-approval inspec-tions<br />at the earliest possible opportunity, since unnecessary delays<br />will prevent the timely review of applications. However, in some<br />facilities the development or the manufacturing processes may not<br />have been completed. In addition, changes may have occurred in the<br />status of the application, e.g. major deficiencies in the application or<br />the closure of an ancillary facility may affect the need for an inspec-tion.<br />In any case, the timing of the inspection should be coordinated<br />between the inspectorate and the applicant.<br />For the inspection of major new facilities involving many applications,<br />special coordination efforts are often beneficial.<br />When desirable, pre-approval inspections should be coordinated with<br />the laboratory scheduled for method validation so as to enable it to<br />participate in the inspection and in the collection of samples.<br />6. Carrying out the inspection<br />Emphasis should be placed on the evaluation of the manufacturing<br />process, including data verification and the assessment of compliance<br />with GMP. The production and control procedures described in the<br />application must be compared with those used for the manufacture of<br />pre-approval batches. If warranted by records of past label mix-ups,<br />packaging and labelling control procedures should be evaluated. A<br />programme of ongoing stability testing needs to be addressed.<br />The inspection team will determine whether the application provides<br />the scientific data justifying full-scale production procedures and<br />controls. The validation of pertinent manufacturing procedures,<br />including equipment qualification, will also be evaluated.<br />1<br />However,<br />inspectors should not recommend withholding approval of applica-tions<br />based on a lack of complete full-scale, multiple-batch validation<br />of sterile and non-sterile processes, unless the data submitted in the<br />application are found to be of questionable validity or completeness.<br />It should be understood that full-scale validation may be completed<br />after approval of the application, but before shipment of the first<br />commercial batches. Nevertheless, certain data must be included in<br />the application to demonstrate that the sterilization or aseptic fill<br />process has been qualified. The inspection team is expected to audit<br />the data to determine their authenticity, accuracy and completeness.<br />1<br />For details of recommended validation programmes, see reference 3..98<br />Investigational products are often produced in facilities other than<br />those used for full-scale production (4). These facilities and the asso-ciated<br />manufacturing and control procedures are not routinely in-spected<br />unless validation of the transfer of the methods from the<br />“investigational” facilities to the full-scale facilities is lacking or ques-tionable.<br />The facilities may be periodically inspected when this is<br />required by national legislation/regulation.<br />All suppliers and manufacturers of starting materials used in<br />the formulation of pre-approval batches should be identified. The<br />physical characteristics and specifications of the drug substance<br />should be reviewed. This is particularly important for solid oral dos-age<br />forms where the physical characteristics of the drug substance<br />often affect uniformity, dissolution and absorption of the dose.<br />When a pharmaceutical manufacturer replaces the supplier or<br />manufacturer of the drug substance used for the manufacture of the<br />pre-approval batches by another supplier or manufacturer, the<br />application should include data demonstrating that the dosage forms<br />formulated with the drug substance from the two different sources are<br />equivalent in terms of conformity with established specifications, in-cluding<br />those given in the application. Specifications should also cover<br />the physical characteristics of the drug substances.<br />The addition of any new drug substance and/or dosage form to a<br />production environment must be carefully evaluated in terms of its<br />impact on other products already under production. Any changes that<br />may be necessary in the building and facility must be assessed for<br />their effect on overall compliance with GMP requirements. For ex-ample,<br />a new toxic, potent or highly sensitizing product may require<br />additional measures against cross-contamination, and facilities al-ready<br />operating at full capacity may not have adequate space for<br />additional products. The evaluation should also include an assess-ment<br />of whether any change in the manufacturing authorization is<br />necessary.<br />Laboratory equipment and procedures must be qualified and vali-dated.<br />Every pre-approval inspection should include an evaluation of<br />laboratory controls and procedures, and a review of some of the raw<br />data used to generate results. The authenticity and accuracy of the<br />data used in the development of a test method should be reviewed.<br />The inspection team should pay special attention to any newly estab-lished<br />facilities, newly installed equipment and/or new raw material<br />suppliers. If unapproved facilities are in use, this should be reported<br />immediately. Inspections of these facilities are not normally required..99<br />7. Sample collection and testing<br />The pre-approval inspection may include the collection of samples for<br />validation of the analytical methods. Normally the sample size should<br />be sufficient for three full analyses. Unless otherwise indicated by the<br />laboratory, samples of the following sizes may be taken, depending on<br />the dosage form of the product:<br />— tablets and capsules: 300 units of production;<br />— injections (single component): 100 units of production;<br />— injections (combination): 100 units of production plus 10 samples<br />of each component;<br />— oral powders for reconstitution: 10 units of production;<br />— oral liquids: 1 litre.<br />It is important to collect, with the samples, the relevant manu-facturer’s<br />analytical documentation, namely a copy of the analytical<br />methods used by the inspected laboratory and the report of the analy-ses<br />performed by the applicant on the batch sampled. A method<br />validation report may be of some use in better understanding and<br />reproducing the analytical methods. Problems encountered in the<br />performance of the analyses may be resolved by an exchange of<br />information between the applicant and the government laboratory.<br />Samples are tested in accordance with methods described in the appli-cation.<br />If there are problems with the methods that require additional<br />information from the applicant, the laboratory director must review<br />the situation and decide whether the applicant should be contacted.<br />The written request should be included in the documentation submit-ted<br />to the review analyst.<br />Each method validation/verification report should contain the<br />following:<br />• The identification of the test samples received, a description of the<br />product tested, and confirmation of conformity with the product<br />described in the application.<br />• The original analytical worksheets with calculations, the results of<br />all tests performed, comments by the analyst(s), associated spectra,<br />chromatograms, etc., and a comparison of the results obtained with<br />the applicant’s data and with the applicable specifications.<br />• An evaluation of each test performed by the applicant and the<br />laboratory.<br />• A recommendation as to whether the methods are acceptable,<br />acceptable only after specified changes have been made, or<br />unacceptable.<br />If samples have not been collected in the course of a pre-approval<br />inspection, the results of the analytical examination of the samples.100<br />submitted by the applicant may nevertheless be used as supporting<br />information.<br />The reserve samples, associated documentation and copies of labora-tory<br />reports should be stored in an orderly and retrievable way for<br />a time period specified by national regulations. It is usually recom-mended<br />that all material should be kept for a minimum of 3 years or<br />for 1 year after the expiry date of the finished product.<br />8. Follow-up regulatory/administrative decisions<br />The inspectorate (inspection group of the drug regulatory authority)<br />should recommend withholding approval when significant deviations<br />from GMP requirements and other application commitments have<br />occurred having an adverse effect on the product covered by the<br />application. Examples of significant problems are:<br />• Misrepresentation of data or conditions relating to pre-approval<br />batches.<br />• Pre-approval batches not manufactured in accordance with GMP.<br />• Inconsistencies and/or discrepancies raising significant questions<br />concerning the validity of the records.<br />If applications are refused because of significant non-compliance with<br />GMP, action must be taken to ensure that the necessary corrective<br />measures are taken.<br />The drug regulatory authority is expected to advise the applicant that<br />the inspectorate has recommended withholding approval of the appli-cation<br />and give the reasons for this recommendation.<br />References<br />1. Provisional guidelines on the inspection of pharmaceutical manufacturers. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-second report. Geneva, World Health Organization, 1992, Annex 2<br />(WHO Technical Report Series, No. 823).<br />2. Quality assurance of pharmaceuticals. A compendium of guidelines and<br />related materials. Vol. 2. Good manufacturing practices and inspection.<br />Geneva, World Health Organization, 1999.<br />3. Good manufacturing practices: guidelines on the validation of manufacturing<br />processes. In: WHO Expert Committee on Specifications for Pharmaceutical<br />Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996,<br />Annex 6 (WHO Technical Report Series, No. 863).<br />4. Good manufacturing practices: supplementary guidelines for the manufacture<br />of investigational pharmaceutical products for clinical trials in humans. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 7 (WHO<br />Technical Report Series, No. 863)..101<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 8<br />Quality systems requirements for national good<br />manufacturing practice inspectorates<br />Background 101<br />1. Introduction 102<br />2. Glossary 102<br />3. Administrative structure 103<br />4. Terms of reference 104<br />5. Organizational structure 104<br />6. Inspection personnel 106<br />7. Documentation 107<br />8. Records 109<br />9. Inspection procedures 109<br />10. Inspection facilities required 112<br />11. Quality manual 113<br />12. Confidentiality 114<br />13. Publications 115<br />14. Appeals 115<br />15. Internal audit and periodic review 116<br />16. Complaints 117<br />17. Recalls 117<br />References 118<br />Background<br />Following the provisional guidelines on the inspection of pharmaceu-tical<br />manufacturers (1), the WHO Expert Committee on Specifica-tions<br />for Pharmaceutical Preparations acknowledged that additional<br />guidelines concerning national inspectorates would be of value in<br />strengthening the implementation of good manufacturing practices<br />(GMP) (2) and enhancing mutual recognition among inspectorates.<br />A trend has recently become apparent in WHO Member States<br />for non-commercial institutions, such as certification bodies, testing.102<br />laboratories, etc., to introduce quality systems principles in their inter-nal<br />operations. The same principles are also being applied by govern-mental<br />pharmaceutical inspectorates and drug control laboratories.<br />The Pharmaceutical Inspection Convention (PIC) has published a<br />document (3), with the objective of adapting the standards of the<br />International Organization for Standardization (ISO) of the 9000<br />series and related norms (4–8) to the activities of the GMP<br />inspectorates of Member States. It is based on European Standard<br />EN 45012, General criteria for certification bodies operating quality<br />systems certification (9), but has been modified for this particular<br />purpose.<br />1. Introduction<br />These requirements are applicable to quality systems for the opera-tion<br />of inspection services within competent authorities concerned<br />with GMP inspections. It is intended that each inspection service<br />should use these requirements as the basis for developing its own<br />quality system.<br />The establishment and operation of a quality system is an essential<br />element in the mutual recognition of national GMP inspections. The<br />willingness to accept national inspections is significantly enhanced<br />when it is known that the GMP inspectorate of the competent author-ity<br />follows uniform procedures incorporating quality system prin-ciples.<br />The quality system should include all the activities involved in<br />the inspection.<br />2. Glossary<br />authorized person<br />A person (among key personnel of a manufacturing establishment)<br />responsible for the release of batches of finished products for sale<br />(10).<br />quality audit<br />An examination and assessment of all or part of a quality system with<br />the specific purpose of improving it. A quality audit is usually con-ducted<br />by outside or independent specialists or a team designated by<br />the management for this purpose. Such audits may also be extended<br />to suppliers and contractors (2).<br />quality manual<br />A handbook that describes the various elements of the system for<br />assuring the quality of the test results generated by a laboratory (see<br />section 11)..103<br />quality system<br />An appropriate infrastructure, encompassing the organizational<br />structure, procedures, processes and resources necessary to ensure<br />adequate confidence that a product (or service) will satisfy given<br />requirements for quality (2).<br />standard operating procedure (SOP)<br />An authorized written procedure giving instructions for performing<br />operations not necessarily specific to a given product or material but<br />of a more general nature (e.g. equipment operation, maintenance and<br />cleaning; validation; cleaning of premises and environmental control;<br />sampling and inspection). Certain SOPs may be used to supplement<br />product-specific master and batch production documentation (2).<br />3. Administrative structure<br />3.1 The structure, membership and operation of the GMP inspec-torate<br />should be such that impartiality is safeguarded.<br />3.2 The national inspection services are responsible for ensuring that<br />the requirements of the relevant national legislation are satisfied.<br />3.3 All personnel employed or used by the GMP inspectorate, includ-ing<br />outside inspectors or subcontracted personnel, should not be<br />subject to any commercial, financial or other pressures which might<br />affect their judgement. They should not be under the control of<br />pharmaceutical manufacturers, and must be assessed and licensed.<br />3.4 The system for obtaining fees should not improperly influence the<br />inspection procedure.<br />Recommended procedure<br />The administrative structure, membership, operation and legal status<br />of the GMP inspectorate should be described in the quality manual<br />(see section 11).<br />The quality manual should show how all personnel working for the<br />GMP inspectorate, including subcontracted staff or advisers, and<br />persons serving on committees providing advice, can maintain their<br />impartiality. The GMP inspectorate should ensure that such persons:<br />(a) are not subject to any commercial, financial or other pressures<br />which might influence their judgement;<br />(b) are not improperly influenced in their inspection of pharmaceuti-cal<br />manufacturers or persons assessed;<br />(c) have not been involved in the design or maintenance of inspected<br />facilities by way of any consultancy service or commercial<br />arrangement..104<br />The remuneration of GMP inspectorate personnel engaged in inspec-tion<br />activities should not depend on the result of such activities or on<br />the granting of a marketing authorization.<br />Only in exceptional cases may GMP inspectorates provide advisory<br />or consultancy services. Where the GMP inspectorate does provide<br />such services, it should develop a code of conduct or defined policy<br />which clearly distinguishes between the process of inspection and that<br />of providing an advisory or consultancy service to clients. This service<br />should be of benefit to all of industry, and not solely to individual<br />manufacturers.<br />4. Terms of reference<br />4.1 The functions of the GMP inspectorate should be clearly defined<br />and should cover:<br />(a) legal responsibilities;<br />(b) the formulation of policies;<br />(c) an overview of the implementation of its policies;<br />(d) an overview of its finances;<br />(e) as required, the setting-up of committees to which defined activ-ities<br />are delegated.<br />Recommended procedure<br />The terms of reference, legal responsibilities and functions of the<br />GMP inspectorate and the way in which policy guidelines are estab-lished<br />should be documented in the quality manual.<br />For any committee established to advise the GMP inspectorate or the<br />chief inspector, the following details should be included:<br />(a) its role and function;<br />(b) the procedure for selecting and appointing the members (the<br />names of the chairperson, secretary and members, their current<br />appointments and the interests, if any, which they represent on<br />the committee, should be available);<br />(c) the rules of procedure.<br />5. Organizational structure<br />5.1 The GMP inspectorate should have an organization that enables<br />it to maintain the capability to perform its technical functions<br />satisfactorily..105<br />5.2 The GMP inspectorate should have:<br />(a) documentation clearly identifying its legal status;<br />(b) an organizational chart showing clearly the responsibility and<br />reporting structure of the inspectorate and, in particular, the<br />relationship between its inspection and authorization (licensing)<br />functions;<br />(c) a description of the means by which the inspectorate obtains<br />financial support;<br />(d) a description of the relationship between the GMP inspectorate and<br />other departments within the drug regulatory authority and other<br />government agencies, where they operate as separate bodies.<br />5.3 The GMP inspectorate should have and make available a formal<br />statement explaining how the results of inspections are taken into<br />account in granting and maintaining authorizations (licences).<br />5.4 The senior management of the GMP inspectorate should make a<br />formal commitment to the recommended principles by ensuring that<br />the quality policy of the inspectorate is documented, relevant to the<br />objectives, and implemented.<br />5.5 The responsibility, authority and reporting structure of the GMP<br />inspectorate should be clearly defined and documented (see above)<br />and should be supported by written job descriptions for each member<br />of staff.<br />5.6 An appropriately experienced, responsible and qualified person<br />(2) should be nominated to carry out the quality assurance function,<br />including implementing and maintaining the quality system. This per-son<br />should have direct access to senior management. If necessary, this<br />task may be assigned to more than one person.<br />5.7 The GMP inspectorate should have sufficient resources at all<br />levels to enable it to attain its objectives effectively and efficiently.<br />Senior management should ensure that all personnel are competent<br />to carry out their assigned duties. They should receive appropriate<br />training that should be documented and its effectiveness assessed.<br />5.8 Periodic management reviews of the quality system should be<br />conducted and documented; records of these reviews should be<br />retained for a specified period of time.<br />Recommended procedure<br />The above-mentioned recommendations are intended to ensure a<br />reasonable level of transparency, both nationally and internationally..106<br />The organizational chart, source(s) of finance, legal status of the GMP<br />inspectorate and its relationship with the drug regulatory authority<br />and other government agencies should be documented in the quality<br />manual, together with a description of the quality system.<br />6. Inspection personnel<br />6.1 The personnel of the GMP inspectorate should be competent to<br />perform the functions that they undertake.<br />6.2 The GMP inspectorate should maintain information on the<br />relevant qualifications, training and experience of each inspector.<br />Records of training and experience should be kept up to date.<br />6.3 Personnel should have clear, documented instructions specifying<br />their duties and responsibilities. These instructions should be kept up<br />to date.<br />6.4 When work is subcontracted to an external body or use is made of<br />experts, the inspectorate should ensure that the personnel employed<br />meet the relevant requirements of the quality system. The liability of<br />third party inspectors should be clearly defined in the contract or<br />agreement.<br />6.5 The GMP inspectorate should possess the required personnel,<br />expertise and other resources to perform inspections of manufactur-ers<br />and wholesale distributors to determine whether they comply with<br />the principles and guidelines of current good practices and with the<br />relevant legislation.<br />6.6 The staff responsible for inspections should have appropriate<br />qualifications, training, experience and knowledge of the inspection<br />process. They should have the ability to make professional judge-ments<br />as to the conformity of the inspected party with the require-ments<br />of good practices and the relevant legislation and be able to<br />make an appropriate risk assessment. Knowledge of current technol-ogy<br />is essential, including computerized systems and information<br />technology.<br />6.7 The GMP inspectorate should establish a documented system for<br />recruiting and training its personnel. The training received and the<br />training needs of each member of staff should be regularly reviewed,<br />and individual training records should be maintained.<br />Recommended procedure<br />The credibility of the GMP inspection process will depend to a large<br />degree on the technical competence and integrity of the inspectors.<br />The quality manual should provide up-to-date details of the names,.107<br />qualifications, experience and terms of reference (job description and<br />duties to be performed) of each member of staff engaged in the GMP<br />inspection process (see also section 10).<br />Formal arrangements should exist for personnel training, and details<br />of these arrangements should be documented. Training undertaken<br />by each member of staff engaged in GMP inspections should be<br />documented (see also “Recommended procedure” in section 10).<br />A documented procedure for selecting the members of an inspection<br />team and deciding on its size should be available. The inspection team<br />may include a person or persons with specialist knowledge and/or<br />experience of a particular area of technology.<br />If an inspection is carried out on behalf of the GMP inspectorate by<br />an external body or person, the GMP inspectorate should ensure that<br />the external personnel satisfy the relevant requirements contained in<br />these recommendations.<br />GMP inspectors working with or advising the GMP inspectorate<br />should:<br />(a) be academically qualified in a recognized scientific/technological<br />discipline related to pharmaceuticals (normally pharmacy, chemi-stry<br />or microbiology); direct personal experience of pharmaceuti-cal<br />manufacture or control is not a requirement but would be<br />considered as a valuable asset for an inspector;<br />(b) have satisfactorily completed a recognized training course on<br />auditing quality management systems;<br />(c) undergo at least 10 days of training per year (e.g. courses, sympo-sia,<br />conferences, etc.);<br />(d) have a competent working knowledge of the WHO guidelines on<br />GMP for pharmaceutical products (2) and/or the GMP inspection<br />procedures of the relevant national regulatory authority;<br />(e) have undergone appropriate training in the current procedures<br />and techniques of GMP inspections before conducting an inspec-tion<br />alone;<br />(f) have the necessary personal qualities of integrity, tact and charac-ter<br />to perform the duties of a GMP inspector.<br />7. Documentation<br />7.1 The GMP inspectorate should maintain a system for the control<br />of all documentation relating to GMP inspections of manufacturers<br />and recommendations relating to authorization holders, and should<br />ensure that:.108<br />(a) the current versions of the appropriate documentation are avail-able<br />at all relevant locations;<br />(b) all revised documents or amendments to documents are correctly<br />authorized and processed in a manner which ensures that they are<br />introduced without delay;<br />(c) superseded documents are removed from use throughout the<br />GMP inspectorate and elsewhere in the organization and its<br />agencies, but are retained for a defined period of time.<br />7.2 The GMP inspectorate should ensure that all of its activities<br />are described in SOPs that clearly describe the responsibilities, policy<br />and actions. These should include, but not be limited to, training<br />(introduction, GMP and task-related), inspections, reporting after<br />inspections, handling of complaints, licensing (issue, suspension, re-vocation),<br />certification, documentation control, planning and han-dling<br />of appeals.<br />7.3 Proper and accessible records should be maintained of the activ-ities<br />carried out, including training, as well as the assessment of<br />inspectors after training, the preparation of inspection reports, the<br />handling of complaints, and the drawing-up of authorized checklists<br />(where in use) and other related documents.<br />7.4 Reports should be prepared on all inspections performed. They<br />should be prepared in the approved format, and signed and dated by<br />the relevant inspector.<br />7.5 The documentation system should ensure that any changes to<br />documents are made in a controlled manner and are properly author-ized.<br />There should be a means of identifying changes in individual<br />documents.<br />Recommended procedure<br />The following information should be included or referred to in the<br />quality manual:<br />(a) a list of all the documents used;<br />(b) for each document, the name(s) or position(s) of the person(s)<br />responsible for authorizing its issue and any subsequent amend-ments<br />or changes;<br />(c) a description of the system whereby relevant documents and<br />subsequent amendments are made available at the appropriate<br />location from the point of view of the functioning of the inspec-tion<br />process;.109<br />(d) the method by which amendments and changes are made, so that<br />documents are speedily updated, changes recorded and super-seded<br />documents promptly withdrawn and archived.<br />8. Records<br />8.1 The GMP inspectorate should maintain a system of records to<br />suit its particular method of operation and circumstances. It must<br />comply with the relevant obligations under national legislation and<br />demonstrate that the quality system is operating satisfactorily.<br />8.2 Records should be available which demonstrate that all the<br />relevant procedures have been followed in the performance of each<br />GMP inspection, including the initial inspection, the recommendation<br />for issue of a marketing authorization, routine inspections and correc-tive<br />action.<br />8.3 All records should be safely stored for an adequate period, and<br />held under conditions that guarantee their security and confidential-ity,<br />unless otherwise required by the national legislation.<br />Recommended procedure<br />The quality manual should describe or refer to separate SOPs which<br />describe the system adopted by the GMP inspectorate for maintain-ing<br />its records. The manual should include blank specimen copies of<br />the various checklists, certificates and reports used during the inspec-tion<br />process and describe the way in which these are processed, stored<br />and archived, and/or disposed of.<br />The procedures for recommending to the authorization holder the<br />issue, suspension or revocation of marketing authorizations should be<br />described.<br />Documented staff instructions on security and on the use and<br />handling of inspection reports should be identified and described in<br />accordance with the confidentiality requirements specified in national<br />legislation. Information as to who should have access to confidential<br />information should be given and such access should be controlled.<br />Records associated with inspection activities should be retained for a<br />minimum period of three full inspection cycles or for 6 years, which-ever<br />is the longer.<br />9. Inspection procedures<br />9.1 The GMP inspectorate should have the required resources<br />(financial, human, facilities and others) and documented procedures<br />to enable the inspection of manufacturing operations to be carried out.110<br />in accordance with the requirements of the WHO guidelines on GMP<br />(2) and/or the national GMP guidelines.<br />9.2 The GMP inspectorate should require the manufacturer to have<br />documented procedures in accordance with a quality management<br />system, and complying with the WHO guidelines on GMP (2) and/or<br />the national GMP guidelines.<br />9.3 The GMP inspectorate should perform regular inspections of the<br />manufacturing premises, procedures and quality systems of authori-zation<br />holders at least once every 2 years in accordance with a written<br />inspection programme. Written inspection reports should be pre-pared<br />and sent to the national regulatory authority to keep it in-formed<br />of the outcome of such inspections.<br />9.4 The planning of inspections of manufacturers and the assessment<br />of compliance with the planning regarding the performance of the<br />different types of inspections should be documented. The types of<br />inspections should include as a minimum routine inspections, specific<br />inspections, follow-up inspections and concise inspections.<br />9.5 The activity of the GMP inspectorate should be described, indi-cating<br />how it relates to the system(s) for granting manufacturers’ and<br />product authorizations.<br />9.6 The activities relating to post-marketing surveillance and product<br />testing should be described. The description should also cover the<br />process of handling non-conforming products (e.g. substandard or<br />counterfeit products).<br />9.7 The procedure for operations in support of a surveillance sam-pling<br />programme should be documented.<br />9.8 The GMP inspectorate should have the documented procedures<br />and resources to enable the inspection of manufacturing and wholesale<br />distribution operations to be carried out in accordance with the official<br />guidelines and national legislation. A formal inspection plan should be<br />followed. All instructions, standards or written procedures, work-sheets,<br />checklists and reference data relevant to the work of the GMP<br />inspectorate should be kept up to date and be readily available to staff.<br />9.9 A chief inspector should be appointed to coordinate inspection<br />activities if more than one inspector is involved in an inspection. The<br />lead inspector, who should be selected by all the participating inspec-tors,<br />should normally prepare the inspection report.<br />9.10 Observations and/or data obtained in the course of inspections<br />should be recorded in a timely manner to prevent loss of relevant<br />information..111<br />9.11 Completed inspections should be reviewed to ensure that the<br />requirements have been met.<br />Recommended procedure<br />The procedures covering initial inspections of new applicants for<br />marketing authorizations and ongoing inspections of authorization<br />holders should be documented.<br />Manufacturers should be inspected at least every 1 or 2 years, al-though<br />new authorization holders should be inspected more fre-quently<br />until inspectors are confident that the manufacturers are<br />complying with the WHO guidelines on GMP and/or the national<br />GMP guidelines. The frequency of inspection should not normally fall<br />below once every 2 years as lack of continuity may give rise to a<br />reduced awareness of current GMP or allow significant deficiencies to<br />develop.<br />The time available for undertaking inspections should be adequate to<br />enable sufficient investigations and enquiries to be made to give<br />confidence in the findings of the inspection.<br />The report to the authorization holders following GMP inspections<br />should include as a minimum:<br />(a) the name and location of the manufacturing site(s);<br />(b) the date(s) of the inspection(s);<br />(c) the reason for the inspection and the product categories and<br />manufacturing areas inspected;<br />(d) the suitability of key personnel, including the authorized person;<br />(e) observations, failures to comply with the WHO guidelines on<br />GMP and/or the national GMP guidelines, and the recommended<br />frequency of reinspection;<br />(f) a recommendation on the issue/continuation, suspension or revo-cation<br />of the marketing authorization.<br />The GMP inspectorate should have the power, under the national or<br />regional legislation or other arrangements, to require reinspection of<br />a manufacturer’s premises if there are changes in personnel, facilities,<br />internal organization or scope of activity, or if analysis of a complaint<br />or any other information indicates that the manufacturer is failing to<br />comply with the requirements of the WHO guidelines on GMP and/<br />or the national GMP guidelines, or with the conditions imposed by<br />the marketing authorization..112<br />10. Inspection facilities required<br />10.1 The inspection service should have the required facilities in<br />terms of staff, expertise, equipment and other resources to perform<br />inspections of manufacturers to determine compliance with the re-quirements<br />of the WHO guidelines on GMP and/or the national GMP<br />guidelines. This does not preclude the use of external resources, when<br />necessary, provided that the requirements as described for “subcon-tracting”<br />are met (see section 3.3).<br />10.2 If inspections are carried out on behalf of the GMP inspectorate<br />by an external body or person, the GMP inspectorate should ensure<br />that this body or person satisfies the requirements specified in section<br />3.3. A properly documented agreement covering these arrangements,<br />including confidentiality aspects and the declaration of any conflict of<br />interests, should be drawn up.<br />Recommended procedure<br />A sufficient number of competent personnel should support the GMP<br />inspectorate, whether employed or contracted for the functions that<br />they undertake.<br />The quality manual should describe the procedures for the manage-ment<br />of the GMP inspectors and of the necessary records. A record<br />should be kept for each individual employed to carry out GMP in-spections<br />(whether an employee or under contract), which should<br />include the following information:<br />(a) the name;<br />(b) the designated area of responsibility within the declared scope of<br />the GMP inspectorate;<br />(c) the educational qualifications;<br />(d) the professional qualifications, where relevant to the activities of<br />the GMP inspectorate;<br />(e) the work experience;<br />(f) details of the GMP inspector training received, supported by<br />documentary evidence of course attendance and assessment<br />results.<br />Where an external body or person carries out a GMP inspection, the<br />quality manual should describe the process adopted by the GMP<br />inspectorate to comply with the above-mentioned requirements.<br />Whenever an external body or person is used to carry out any func-tion<br />on behalf of a GMP inspectorate, the GMP inspectorate should.113<br />have documented evidence to demonstrate that the external body or<br />person concerned is competent to do so.<br />Staff members authorized to carry out audits of external bodies or<br />persons should be identified.<br />Documented agreements with all external bodies or persons should<br />be available for scrutiny.<br />A register of all external bodies or persons employed by the GMP<br />inspectorate should be maintained. The register should include:<br />(a) the name of the external body or person;<br />(b) the legal status of the external body and details of any relation-ship<br />with a parent company, group of companies or any other<br />organization of which the external body or person is part, with<br />specific reference to possible conflicts of interest;<br />(c) the names and qualifications of all personnel engaged in GMP<br />inspection work for the GMP inspectorate.<br />11. Quality manual<br />11.1 The GMP inspectorate should define and document its policy<br />and objectives for, and commitment to, quality in a quality manual. It<br />should ensure that this policy is understood, implemented and main-tained<br />at all levels in the organization.<br />11.2 The information contained in the quality manual and proce-dures<br />should include at least:<br />(a) a quality policy statement;<br />(b) a brief description of the legal status of the GMP inspectorate<br />(see section 4.1(a));<br />(c) a code of ethics and conduct relating to GMP inspection<br />activities;<br />(d) a description of the organization of the GMP inspectorate,<br />including details of any governing board, its constitution, terms<br />of reference and rules of procedure (see section 5.2(b));<br />(e) the names, qualifications, experience and terms of reference<br />of the senior staff and other GMP inspection personnel, both<br />internal and external (see sections 6 and 10);<br />(f) details of training arrangements for inspection personnel (see<br />sections 6 and 10);<br />(g) an organizational chart showing the responsibility and reporting<br />structure of the inspectorate and the allocation of functions.114<br />stemming from the person in charge of the GMP inspectorate<br />(see section 5.2(b));<br />(h) details of the documented procedures for inspecting manufac-turers<br />under the WHO guidelines on GMP and/or the national<br />GMP guidelines (see section 8);<br />(i) details of the documented procedures for recommendations to<br />the authorization holder for the issue, suspension or revocation<br />of marketing authorizations (see sections 7.2 and 8.1);<br />(j) a list of any subcontractors used for GMP inspections and details<br />of the documented procedures for assessing and monitoring their<br />competence (see section 6);<br />(k) details of appeals procedures (see section 14);<br />(l) a procedure for ensuring that complaints made to the GMP<br />inspectorate are investigated so that any shortcomings of the<br />authorization holders are revealed (see section 16);<br />(m) a list of those staff members responsible for investigating com-plaints<br />and those with the authority to take remedial action (see<br />section 16);<br />(n) details of internal quality audits (see section 15);<br />(o) details of testing of samples (see sections 9.6–9.8);<br />(p) the control of non-conforming products (see section 9.6).<br />Recommended procedure<br />In order to keep the quality manual brief, reference may be made to<br />other documents and/or procedures contained in other manuals.<br />12. Confidentiality<br />12.1 The GMP inspectorate should have adequate arrangements<br />to ensure confidentiality of the information obtained in the course<br />of its inspection activities at all levels of its organization, including<br />committees.<br />12.2 The exchange of inspection reports between countries should be<br />described. The format and content of reports should be specified.<br />Recommended procedure<br />The quality manual should describe how the GMP inspectorate<br />discharges its responsibility for ensuring that all communications<br />between itself and the companies inspected are kept confidential. The<br />following are necessary:.115<br />(a) instructions to personnel on confidentiality;<br />(b) a written undertaking by all personnel not to divulge to third<br />parties any information gained about any business affairs of<br />clients;<br />(c) the inclusion of provisions in all subcontracts to maintain<br />confidentiality;<br />(d) provisions to ensure the physical security of all documents and<br />records relating to inspection activities.<br />13. Publications<br />13.1 The GMP inspectorate should produce and update, as neces-sary,<br />a list of authorization holders, together with an outline of the<br />scope of the marketing authorization issued to each manufacturer.<br />The extent to which this list will be distributed should be specified.<br />13.2 An outline of the inspection and marketing authorization system<br />should be available in published form.<br />13.3 Other publications, such as GMP guidelines and other guide-lines<br />and information brochures, should be available to industry and<br />other interested parties, as appropriate.<br />Recommended procedure<br />The quality manual should list the publications issued by the authori-zation<br />holder and GMP inspectorate. The following information<br />should also be provided:<br />(a) the name of the person responsible for compiling and updating<br />each publication;<br />(b) the frequency with which each publication is updated;<br />(c) how the publications are distributed and to whom;<br />(d) the procedure for issuing amendments.<br />14. Appeals<br />14.1 The GMP inspectorate should have procedures for the con-sideration<br />of appeals against its decisions.<br />Recommended procedure<br />Appeals procedures should be established by the GMP inspectorate<br />and should include:<br />(a) the method by which an appeal may be lodged;<br />(b) the method by which an impartial appeals panel, independent of<br />the activity under review, is selected;.116<br />(c) the names and positions of the members of the GMP inspectorate<br />to whom appeals are referred, and the procedure for handling<br />them;<br />(d) a register of all appeals and their outcome.<br />15. Internal audit and periodic review<br />15.1 The GMP inspectorate should implement a system of planned<br />and documented internal audits and periodic reviews of its compli-ance<br />with the criteria of these guidelines.<br />15.2 There should be procedures for corrective and preventive action<br />whenever faults are detected in the quality system, or in the perfor-mance<br />of inspections and the general performance of the inspection<br />service.<br />15.3 The management of the inspectorate should periodically review<br />the quality system for its continuing suitability and effectiveness.<br />15.4 Inspectors should be evaluated before being allowed to perform<br />inspections. Periodic reviews should also be undertaken to examine<br />the performance of individual inspectors in order to ensure consist-ency<br />among them, and in the operations and procedures of the GMP<br />inspectorate.<br />15.5 A record of all audits and reviews should be kept and should<br />include the findings, conclusions, recommendations and follow-up<br />action. These records should be retained for a specified period of<br />time.<br />Recommended procedure<br />Internal periodic review procedures should be documented. The<br />review procedure should include internal audits by staff competent<br />to ensure that all formulated procedures are adhered to. Based on<br />the results of these audits, management must ensure that the GMP<br />inspection system remains effective and that inspections conducted<br />by different inspectors arrive at similar conclusions when the same<br />operation is inspected under the same conditions.<br />Internal audit procedures should state:<br />(a) the names or positions of staff members authorized to conduct<br />internal audits;<br />(b) what is to be examined and how often (a schedule for the exami-nation<br />of the whole organization over a given period should be<br />drawn up);.117<br />(c) how the audit will be conducted;<br />(d) to whom the results will be reported;<br />(e) who will initiate any corrective action.<br />Management reviews should take account of the results of internal<br />audits and should include:<br />(a) consideration of the overall operation of the GMP inspectorate;<br />(b) uncovering defects or irregularities in the operation of the GMP<br />inspection system;<br />(c) ensuring that action has been taken to effectively correct defects<br />revealed in previous reviews and audits.<br />Periodic audit by an experienced person or persons from another<br />national regulatory authority is a useful means of providing an<br />independent review of the GMP inspectorate’s operations and<br />procedures.<br />16. Complaints<br />16.1 The GMP inspectorate should have documented procedures for<br />dealing with complaints arising from its activities.<br />16.2 A record should be maintained of all complaints received and<br />the actions taken by the GMP inspectorate. These records should be<br />retained for a specified period of time.<br />Recommended procedure<br />The GMP inspectorate should require each authorization holder to<br />keep a record of all complaints received, as well as remedial actions<br />relating to the manufacturing activities and products covered by the<br />marketing authorization.<br />The GMP inspectorate should have a procedure for recording and<br />investigating complaints received about its inspection activities. The<br />procedure should include a list of those staff members responsible for<br />investigating complaints and those with the authority to take remedial<br />action.<br />17. Recalls<br />17.1 The GMP inspectorate should have a documented procedure for<br />dealing with recalls and withdrawals of products from the market.<br />17.2 Records should be maintained of all recalls and withdrawals<br />registered and dealt with by the inspectorate..118<br />References<br />1. Provisional guidelines on the inspection of pharmaceutical manufacturers.<br />In: WHO Expert Committee on Specifications for Pharmaceutical<br />Preparations. Thirty-second report. Geneva, World Health Organization,<br />1992, Annex 2 (WHO Technical Report Series, No. 823).<br />2. Quality assurance of pharmaceuticals. A compendium of guidelines and<br />related materials. Vol. 2. Good manufacturing practices and inspection.<br />Geneva, World Health Organization, 1999.<br />3. Recommendations on quality system requirements for GMP inspectorates of<br />PIC Contracting States. Geneva, Pharmaceutical Inspection Convention,<br />1994 (unpublished document PH/7/94; available from EFTA Secretariat,<br />9–11 rue de Varembé, 1211 Geneva 20, Switzerland).<br />4. Quality management and quality assurance standards — guidelines for<br />selection and use. International Standard ISO 9000. Geneva, International<br />Organization for Standardization, 1990.<br />5. Quality systems — model for quality assurance in design/development,<br />production, installation and servicing. International Standard ISO 9001.<br />Geneva, International Organization for Standardization, 1994.<br />6. Quality systems — model for quality assurance in production, installation<br />and servicing. International Standard ISO 9002. Geneva, International<br />Organization for Standardization, 1994.<br />7. Quality systems — model for quality assurance in final inspection and test.<br />International Standard ISO 9003. Geneva, International Organization for<br />Standardization, 1994.<br />8. Quality management and quality system elements — guidelines.<br />International Standard ISO 9004. Geneva, International Organization for<br />Standardization, 1990.<br />9. General criteria for certification bodies operating quality systems<br />certification. European Standard EN 45012. Brussels, European Committee<br />for Standardization, 1989 (available from CEN Central Secretariat, 36 rue de<br />Stassart, B-1050 Brussels, Belgium).<br />10. Good manufacturing practices: authorized person — role, functions and<br />training. In: WHO Expert Committee on Specifications for Pharmaceutical<br />Preparations. Thirty-fifth report. Geneva, World Health Organization, 1999,<br />Annex 4 (WHO Technical Report Series, No. 885)..119<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 9<br />Guidelines on packaging for pharmaceutical<br />products<br />Introductory note 120<br />Glossary 121<br />1. Aspects of packaging 125<br />1.1 General considerations 125<br />1.2 Functions of packaging 127<br />1.2.1 Containment 127<br />1.2.2 Protection 127<br />1.3 Presentation and information 129<br />1.3.1 Labels 129<br />1.3.2 Repacking, relabelling and dispensing 130<br />1.3.3 Package inserts for patients (patient information leaflets) 131<br />1.4 Compliance 131<br />1.5 Protection of patients 131<br />1.6 Detection of counterfeiting 131<br />2. Packaging materials and closures 132<br />2.1 Types of material 132<br />2.1.1 Glass 132<br />2.1.2 Plastics 133<br />2.1.3 Metal 133<br />2.2 Closures 134<br />2.2.1 Rubber closures 134<br />2.2.2 Caps or overseals 135<br />2.2.3 Special types of closure 135<br />3. Quality assurance aspects of packaging 137<br />3.1 General considerations 137<br />3.2 Quality control 137<br />3.2.1 Sampling 138<br />3.2.2 Testing programme 139<br />3.3 Inspection and audit 139<br />3.3.1 Rules 139<br />3.3.2 Audits of suppliers 140<br />4. Protection of the environment 140<br />4.1 Packaging waste 140<br />4.2 Waste policies 141<br />5. Quality specifications 142<br />5.1 Requirements in The international pharmacopoeia 142<br />5.1.1 Packaging materials 142<br />5.1.2 Requirements for dosage form containers 142.120<br />5.2 Pharmacopoeial requirements for containers in Europe, Japan<br />and the USA 144<br />5.2.1 Glass containers 144<br />5.2.2 Plastic containers 144<br />5.2.3 Rubber closures 144<br />5.3 International Standards 145<br />References 145<br />Bibliography 147<br />Appendix 1<br />Storage areas 150<br />Appendix 2<br />Labels 151<br />Appendix 3<br />Self-inspection and quality audits 152<br />Appendix 4<br />International Standards on packaging 154<br />Introductory note<br />This review of the various elements of the packaging of a pharmaceu-tical<br />product is aimed at ensuring that medicines arrive safely in the<br />hands of the patients for whom they are prescribed.<br />In the manufacture of pharmaceutical products, quality assurance is<br />defined as “the totality of the arrangements made with the object of<br />ensuring that pharmaceutical products are of the quality required for<br />their intended use” (1).<br />In addition, the system of quality assurance for the manufacture of<br />pharmaceutical products should ensure that “arrangements are made<br />for the manufacture, supply and use of the correct starting and pack-aging<br />materials” (1).<br />Public opinion sometimes considers packaging to be superfluous.<br />However, it must be emphasized that packaging preserves the stabil-ity<br />and quality of medicinal products and protects them against all<br />forms of spoilage and tampering.<br />All medicinal products need to be protected and “consequently need<br />to be packaged in containers that conform to prescribed standards,<br />particularly with respect to the exclusion of moisture and light and the<br />prevention of leaching of extractable substances into the contents and<br />of chemical interaction with the contents. . . . However, the limits of<br />acceptability in these various respects depend, at least in part, on<br />climatic variables. Recommendations in The international pharmaco-poeia<br />can only be advisory; precise quantitative standards will have to<br />be locally determined” (2)..121<br />The complexity of packaging materials and the highly technological<br />nature of medicinal products is such that manufacturers are con-fronted<br />with significant problems. Interaction between packaging and<br />such products is possible due to the combination of a multiplicity of<br />container components and active pharmaceutical ingredients, excipi-ents<br />and solvents used in a variety of dosage forms.<br />The quality of the packaging of pharmaceutical products plays a very<br />important role in the quality of such products. It must:<br />— protect against all adverse external influences that can alter the<br />properties of the product, e.g. moisture, light, oxygen and tem-perature<br />variations;<br />— protect against biological contamination;<br />— protect against physical damage;<br />— carry the correct information and identification of the product.<br />The kind of packaging and the materials used must be chosen in such<br />a way that:<br />— the packaging itself does not have an adverse effect on the product<br />(e.g. through chemical reactions, leaching of packaging materials<br />or absorption);<br />— the product does not have an adverse effect on the packaging,<br />changing its properties or affecting its protective function.<br />The resulting requirements must be met throughout the whole of the<br />intended shelf-life of the product. Given the link between the quality<br />of a pharmaceutical product and the quality of its packaging, phar-maceutical<br />packaging materials and systems must be subject, in<br />principle, to the same quality assurance requirements as pharmaceu-tical<br />products.<br />The appropriate system of quality assurance for the manufacture of<br />pharmaceutical products should therefore follow the WHO guide-lines<br />for good manufacturing practices (GMP) (1).<br />The requirements to be met by pharmaceutical packaging and pack-aging<br />materials as described in compendia (pharmacopoeias) and<br />standards (e.g. those of the International Organization for Standard-ization<br />(ISO)) must be considered only as general in character. The<br />suitability of packaging or packaging material for any particular<br />requirements and conditions can only be ascertained through detailed<br />packaging and stability studies on the product concerned.<br />Glossary<br />The definitions given below apply specifically to the terms used in<br />these guidelines. They may have different meanings in other contexts..122<br />General<br />bulk product<br />Any product that has completed all the processing stages up to, but<br />not including, final packaging (1).<br />containers<br />A container for pharmaceutical use is an article which holds or is<br />intended to contain and protect a drug and is or may be in direct<br />contact with it. The closure is a part of the container. The container<br />and its closure must not interact physically or chemically with the<br />substance within in any way that would alter its quality. The following<br />terms include general requirements for the permeability of containers<br />(3):<br />• Well-closed containers must protect the contents from extraneous<br />matter or from loss of the substance under normal conditions of<br />handling, shipment or storage.<br />• Tightly closed containers must protect the contents from extraneous<br />matter, from loss of the substance, and from efflorescence, deli-quescence<br />or evaporation under normal conditions of handling,<br />shipment or storage. If the container is intended to be opened on<br />several occasions, it must be designed to be airtight after reclosure.<br />• Hermetically closed containers must protect the contents from ex-traneous<br />matter and from loss of the substance, and be impervious<br />to air or any other gas under normal conditions of handling, ship-ment<br />or storage.<br />Substances and dosage forms requiring protection from light should<br />be maintained in a light-resistant container that — either by reason of<br />the inherent properties of the material of which it is composed, or<br />because a special coating has been applied to it — shields the contents<br />from the effects of light. Alternatively, the container may be placed<br />inside a suitable light-resistant (opaque) covering and/or stored in a<br />dark place (3).<br />labels<br />All finished drug products should be identified by labelling, as<br />required by the national legislation, bearing at least the following<br />information:<br />(a) the name of the drug product;<br />(b) a list of the active ingredients (if applicable, with the Interna-tional<br />Nonproprietary Names (INNs)), showing the amount of.123<br />each present, and a statement of the net contents, e.g. number of<br />dosage units, mass or volume;<br />(c) the batch number assigned by the manufacturer;<br />(d) the expiry date in an uncoded form;<br />(e) any special storage conditions or handling precautions that may<br />be necessary;<br />(f) the directions for use, and any warnings and precautions that may<br />be necessary;<br />(g) the name and address of the manufacturer or the company or<br />person responsible for placing the product on the market.<br />marketing authorization (product licence, registration certificate)<br />A legal document issued by the competent drug regulatory authority<br />that establishes the detailed composition and formulation of the prod-uct<br />and the pharmacopoeial or other recognized specifications of<br />its ingredients and of the final product itself, and includes details of<br />packaging, information given on the label, product information and<br />shelf-life (1).<br />materials<br />A term used to denote starting materials, process aids, intermediates,<br />active pharmaceutical ingredients, packaging and labelling materials.<br />packaging material<br />Any material, including printed material, employed in the packaging<br />of a pharmaceutical product, excluding any outer packaging used for<br />transportation or shipment. Primary packaging materials are those<br />that are in direct contact with the product (1).<br />packaging process<br />All operations, including filling and labelling, that a bulk product has<br />to undergo in order to become a finished product (1).<br />production<br />All operations involved in the preparation of a pharmaceutical prod-uct,<br />from receipt of the starting materials, through processing and<br />packaging, to completion of the finished product (1).<br />quarantine<br />The status of starting or packaging materials, intermediates, or bulk<br />or finished products isolated physically or by other effective means<br />while a decision is awaited on their release, rejection or reprocessing<br />(1)..124<br />Containers for pharmaceuticals<br />1<br />ampoule<br />A container sealed by fusion and to be opened exclusively by break-ing.<br />The contents are intended for use on one occasion only.<br />bag<br />A container consisting of surfaces, whether or not with a flat bottom,<br />made of flexible material, closed at the bottom and at the sides by<br />sealing; the top may be closed by fusion of the material, depending on<br />the intended use.<br />blister<br />A multi-dose container consisting of two layers, of which one is<br />shaped to contain the individual doses. Strips are excluded.<br />bottle<br />A container with a more or less pronounced neck and usually a flat<br />bottom.<br />cartridge<br />A container, usually cylindrical, suitable for liquid or solid pharma-ceutical<br />dosage forms; generally for use in a specially designed appa-ratus<br />(e.g. a prefilled syringe).<br />gas cylinder<br />A container, usually cylindrical, suitable for compressed, liquefied or<br />dissolved gas, fitted with a device to regulate the spontaneous outflow<br />of gas at atmospheric pressure and room temperature.<br />injection needle<br />A hollow needle with a locking device intended for the administration<br />of liquid pharmaceutical dosage forms.<br />injection syringe<br />A cylindrical device with a cannula-like nozzle, with or without a fixed<br />needle and a movable piston, used for the administration, usually<br />parenteral, of an accurately measured quantity of a liquid pharmaceu-tical<br />form. The syringe may be prefilled, and can be for single-dose or<br />multi-dose use.<br />1<br />Based on a list of terms drawn up in response to a request from the European<br />Commission to revise and replace the guidelines of the Committee for Proprietary<br />Medicinal Preparations (III/3593/91)..125<br />pressurized container<br />A container suitable for compressed, liquefied or dissolved gas fitted<br />with a device that, after its actuation, produces a controlled spon-taneous<br />release of the contents at atmospheric pressure and room<br />temperature.<br />single-dose container<br />A container for single doses of solid, semi-solid or liquid preparations.<br />strip<br />A multi-dose container consisting of two layers, usually provided with<br />perforations, suitable for containing single doses of solid or semi-solid<br />preparations. Blisters are excluded.<br />tube<br />A container for multi-dose semi-solid pharmaceutical forms consist-ing<br />of collapsible material; the contents are released via a nozzle by<br />squeezing the package.<br />vial<br />A small container for parenteral medicinal products, with a stopper<br />and overseal; the contents are removed after piercing the stopper.<br />Both single-dose and multi-dose types exist.<br />1. Aspects of packaging<br />1.1 General considerations<br />Packaging may be defined as the collection of different components<br />(e.g. bottle, vial, closure, cap, ampoule, blister) which surround the<br />pharmaceutical product from the time of production until its use.<br />The aspects of packaging to be considered (4) include:<br />— the functions of packaging;<br />— the selection of a packaging material;<br />— the testing of the material selected;<br />—filling and assembling;<br />— sterilization;<br />— storage and stability.<br />Packaging materials (see section 2) include printed material em-ployed<br />in the packaging of a pharmaceutical product, but not any<br />outer packaging used for transportation or shipment. Examples of the<br />types of materials used are shown in Table 1.<br />A distinction must be made between primary and secondary packag-ing<br />components. The primary packaging components (e.g. bottles,.126<br />vials, closures, blisters) are in direct physical contact with the product,<br />whereas the secondary components are not (e.g. aluminium caps,<br />cardboard boxes). The choice of primary and/or secondary packaging<br />materials will depend on the degree of protection required, compat-ibility<br />with the contents, the filling method and cost, but also the<br />presentation for over-the-counter (OTC) drugs and the convenience<br />of the packaging for the user (e.g. size, weight, method of opening/<br />reclosing (if appropriate), legibility of printing).<br />Containers may be referred to as primary or secondary, depending on<br />whether they are for immediate use after production of the finished<br />product or not. Both single-dose and multi-dose containers exist.<br />Containers may be well-closed, tightly closed, hermetically closed or<br />light-resistant, as defined in the glossary (3).<br />The packaging process, as defined in the glossary, is the process<br />that a bulk material must undergo to become a finished product. The<br />properties and attributes of the product should be as specified by the<br />manufacturer and required by the user. The packaging process con-sists<br />of the following stages:<br />Table 1<br />Types of raw materials used in packaging<br />Types of materials Uses<br />Cardboard Boxes<br />Display units<br />Paper Labels<br />Leaflets<br />Glass Ampoules<br />Bottles<br />Vials<br />Syringes<br />Cartridges<br />Plastic Closures<br />Bottles<br />Bags<br />Tubes<br />Laminates with paper or foil<br />Metal, e.g. aluminium Collapsible tubes<br />Rigid cans<br />Foils<br />Needles<br />Gas cylinders<br />Pressurized containers<br />Rubber Closures, including plungers.127<br />—filling and assembling;<br />— sterilization in the final container, if applicable;<br />— placing labels on the container;<br />— storage at the manufacturing and shipping sites.<br />Packaging documentation (1) includes aspects related to:<br />— specifications and quality control, including batch records;<br />— labels, inks and adhesive materials (e.g. glue);<br />— package inserts for patients.<br />Apart from primary and secondary packaging, two types of special<br />packaging are currently in use, as follows:<br />• Unit-dose packaging. This packaging guarantees safer medication<br />by reducing medication errors; it is also more practical for the<br />patient. It may be very useful in improving compliance with treat-ment<br />and may also be useful for less stable products.<br />• “Device” packaging. Packaging with the aid of an administration<br />device is user-friendly and also improves compliance. This type<br />of packaging permits easier administration by means of devices<br />such as prefilled syringes, droppers, transdermal delivery systems,<br />pumps and aerosol sprays. Such devices ensure that the medicinal<br />product is administered correctly and in the right amount.<br />1.2 Functions of packaging<br />1.2.1 Containment<br />The containment of the product is the most fundamental function of<br />packaging for medicinal products. The design of high-quality packag-ing<br />must take into account both the needs of the product and of the<br />manufacturing and distribution system. This requires the packaging:<br />— not to leak, nor allow diffusion and permeation of the product;<br />— to be strong enough to hold the contents when subjected to nor-mal<br />handling;<br />— not to be altered by the ingredients of the formulation in its final<br />dosage form.<br />1.2.2 Protection<br />The packaging must protect the product against all adverse external<br />influences that may affect its quality or potency, such as:<br />— light<br />— moisture<br />— oxygen<br />— biological contamination<br />— mechanical damage..128<br />The compatibility of the packaging with the active pharmaceutical<br />ingredients is very important in maintaining the integrity of the<br />product.<br />Stability. Information on stability is given in the guidelines for stabil-ity<br />testing of pharmaceutical products containing well-established<br />drug substances in conventional dosage forms (4).<br />For primary packaging, it is necessary to know the possible interac-tions<br />between the container and the contents. Normally, product/<br />component stability and compatibility are confirmed during the pri-mary<br />research and development stage.<br />While excluding the effect of external factors on the product, the<br />packaging itself should not interact with it so as to introduce unac-ceptable<br />changes. There are numerous possibilities of interactions<br />between (primary) packaging materials and pharmaceutical products,<br />such as:<br />— the release of chemicals from components of the packaging<br />materials;<br />— the release of visible and/or subvisible particles;<br />— the absorption or adsorption of pharmaceutical components by<br />the packaging materials;<br />— chemical reactions between the pharmaceutical product and the<br />packaging materials;<br />— the degradation of packaging components in contact with the<br />pharmaceutical products;<br />— the influence of the manufacturing process (e.g. sterilization) on<br />the container.<br />The active pharmaceutical ingredients should remain within their<br />specification limits over the shelf-life of the pharmaceutical product.<br />The question of whether a packaging will provide the required protec-tion<br />for the pharmaceutical product and the required stability over<br />a certain time period can only be answered by means of real-time<br />stability studies. Such studies must evaluate the changes in the quality<br />of the product, in contact with its packaging, during a period equiva-lent<br />to its intended shelf-life.<br />In addition, packaging must meet the following requirements:<br />— it must preserve the physical properties of all dosage forms and<br />protect them against damage or breakage;<br />— it must not alter the identity of the product;<br />— it must preserve the characteristic properties of the product, so<br />that the latter complies with its specifications;.129<br />— it must protect the product against undesirable or adulterating<br />chemical, biological or physical entities.<br />Storage. Packaging materials should be stored in accordance with<br />GMP for storage areas (1; see Appendix 1). The characteristics of the<br />active pharmaceutical ingredients will determine whether different<br />packaging will be needed. For example, the packaging requirements<br />of medicinal products kept at temperatures between 2 and 8°C may<br />differ from those of products intended for tropical countries or light-sensitive<br />products. If the contents are sterile, sterility must be main-tained,<br />including that of any unused remaining product.<br />The shelf-life and utilization period are always determined in relation<br />to storage conditions and the stability of the active pharmaceutical<br />ingredient.<br />Normal storage conditions are defined as “storage in dry, well-ventilated<br />premises at temperatures of 15–25°C or, depending on<br />climatic conditions, up to 30 °C. Extraneous odours, other indications<br />of contamination, and intense light have to be excluded” (5).<br />1.3 Presentation and information<br />Packaging is also an essential source of information on medicinal<br />products. Such information is provided by labels and package inserts<br />for patients.<br />The information provided to the patient may include the following:<br />— the name of the patient;<br />— the identification number for dispensing records;<br />— the name, strength, quantity and physical description or identifica-tion<br />of the medicinal product;<br />— directions for use and cautionary statements, if applicable;<br />— the storage instructions;<br />— the date of dispensing and period of use (related to the expiry<br />date);<br />— the name and address of the dispenser.<br />1.3.1 Labels<br />Throughout manufacturing, a succession of specific outer labels are<br />applied to the container of the medicinal product. The level of pro-cessing<br />is indicated by the following words:<br />— quarantine<br />— storage<br />— distribution..130<br />Specifications for labels for finished drug products are defined in<br />the WHO guidelines on GMP for pharmaceutical products (1; see<br />Appendix 2).<br />Written labels on the packaging:<br />• Permit the identification of each active ingredient by means of its<br />INN, and also give the dosage form and the trade name/trademark.<br />All information concerning the medicinal product, as required by<br />national legislation, must be stated on the packaging.<br />• Preserve the stability of the medicinal product by giving advice on<br />its storage (4):<br />After the stability of the product has been evaluated, one of the following<br />recommendations as to storage conditions can be prominently indicated on<br />the label:<br />— store under normal storage conditions;<br />— store between 2 and 8 °C (under refrigeration, no freezing);<br />— store below 8 °C (under refrigeration);<br />— store between -5 and -20 °C (in a freezer);<br />— store below -18 °C (in a deep freezer).<br />• Permit the follow-up of a specific medicinal product by means of<br />the batch number on the labels. It must be possible to follow the<br />route of distribution of a product from the manufacturing process<br />to its administration to the patient with the aim of locating and<br />identifying products that are of potential risk (e.g. blood products,<br />blood-derived products).<br />• Mask the real identity of the medicinal product in clinical studies.<br />This is extremely important in clinical trials in determining the real<br />efficacy of a medicinal product in blinded studies. If the identity is<br />masked by a code, it must be possible to disclose it at any time in a<br />medical emergency.<br />National legislation must be followed with regard to the information<br />provided to the patient, as well as the record-keeping and packaging<br />instructions.<br />1.3.2 Repacking, relabelling and dispensing<br />In some countries, it is common practice not to dispense drugs in the<br />original packaging, but rather in a personalized manner to each pa-tient.<br />This applies especially to solid oral dosage forms, and involves<br />the “repacking” and “relabelling” of drugs in small quantities. Differ-ent<br />drugs may even be included in “customized” medication pack-ages,<br />also referred to as “patient med packs”. The quantities of drugs<br />supplied in this way are usually enough only for a short period of time,.131<br />i.e. to provide drugs for immediate use. It should be remembered,<br />however, that data obtained in stability studies undertaken by the<br />manufacturer are no longer valid for drugs removed from the original<br />package.<br />Where repacking and relabelling are necessary, the WHO guidelines<br />on GMP for pharmaceutical products (1) should be followed to avoid<br />any mix-up or contamination of the product, which could place the<br />patients’ safety at risk.<br />1.3.3 Package inserts for patients (patient information leaflets)<br />Product information must help patients and other users to understand<br />the medication. The patient package insert, together with the label,<br />provides the patient with key information concerning the proper use<br />of the product, potential adverse drug reactions and interactions,<br />storage conditions and the expiry date.<br />In OTC medicinal products, the package insert, together with the<br />label, may constitute the only pharmaceutical advice that the patient<br />receives.<br />1.4 Compliance<br />Packaging and labelling may help to reinforce the instructions given<br />by the physician or the pharmacist, and improve compliance with<br />drug therapy. In this respect, packaging becomes a compliance aid.<br />The design of pharmaceutical packaging should be such that the<br />product can easily be administered in a safe manner to the patient. If<br />the patient feels at ease with the packaging and route of administra-tion,<br />the design of the packaging may become a key factor in increas-ing<br />compliance. This is also an important factor in clinical trials.<br />1.5 Protection of patients<br />Packaging must not only increase compliance through its design, but<br />must also protect the patient and indicate the integrity of the product.<br />Packaging equipped with a tamper-evident device protects against<br />incidental and accidental poisoning. To protect children, several<br />child-resistant closures have been developed (see section 2.2.3).<br />1.6 Detection of counterfeiting<br />The Forty-first World Health Assembly, after reviewing the report of<br />the Executive Board on the implementation of WHO’s revised drug<br />strategy, requested: “. . . governments and pharmaceutical manufac-turers<br />to cooperate in the detection and prevention of the increasing.132<br />incidence of the export or smuggling of falsely labelled, spurious,<br />counterfeited or substandard pharmaceutical preparations” (6).<br />Several documents (2, 6–9) show that counterfeit pharmaceutical<br />products are in wide circulation. In November 1985, during the WHO<br />Conference of Experts on the Rational Use of Drugs in Nairobi,<br />Kenya, concern was expressed regarding the extent to which counter-feit<br />pharmaceutical products were in circulation in developing coun-tries<br />(10). In view of the importance of this issue, a text has been drafted<br />to provide model provisions to deal with counterfeit drugs (11).<br />The design of the packaging must therefore contribute to preventing<br />tampering with, or the counterfeiting of, certain medicinal products.<br />Such tamper-evident containers can allow the visual inspection of the<br />medicinal product before use, and this may serve as a first stage in<br />detecting counterfeit drugs.<br />2. Packaging materials and closures<br />In accordance with the methods of use and administration of medici-nal<br />products, packaging materials, closures and containers vary a<br />great deal and have to meet a wide variety of different requirements.<br />All the routes used for systemic access have demanding requirements,<br />which often can only be met by complex structured and formulated<br />medicinal products. This is particularly true of the new medicinal<br />products that are now appearing, such as those administered via<br />transdermal delivery systems.<br />To ensure the efficacy of a product during its total shelf-life, pharma-ceuticals<br />must be regarded as a combination of the medicinal product<br />itself and the packaging.<br />2.1 Types of material<br />Only the most commonly used packaging materials and containers<br />are described here.<br />2.1.1 Glass<br />For a large number of pharmaceuticals, including medicinal products<br />for oral and local administration, glass containers are usually the first<br />choice (e.g. bottles for tablets, injection syringes for unit- or multi-dose<br />administration). Different types of glass may be necessary,<br />depending on the characteristics and the intended use of the medici-nal<br />products concerned.<br />Manufacturers should arrange with their suppliers to obtain the<br />appropriate type of glass container for the intended use. Suppliers.133<br />should provide the raw and packaging materials in conformity with<br />industrial norms. Classifications of types of glass are given in the<br />European and United States pharmacopoeias, whereas no such<br />classification exists in the Japanese pharmacopoeia.<br />Glass can be tested for light transmission and hydrolytic resistance. In<br />the Japanese pharmacopoeia, such tests are described only for glass<br />containers for injection, whereas in the European and United States<br />pharmacopoeias they are given for all types of glass containers.<br />2.1.2 Plastics<br />Some containers are now being made of plastics; the main use is for<br />bags for parenteral solutions. Plastic containers have several advan-tages<br />compared with glass containers:<br />— they are unbreakable<br />— they are collapsible<br />— they are light.<br />The European, Japanese and United States pharmacopoeias all de-scribe<br />materials of the same type, but there are considerable differ-ences<br />in the classification and presentation.<br />As far as tests are concerned, the three pharmacopoeias are<br />extremely difficult to compare. The European pharmacopoeia is the<br />most detailed and requires tests in relation to the use and routes of<br />administration of the medicinal product. Moreover, the same concept<br />is extended to bulk containers for active ingredients.<br />2.1.3 Metal<br />Metal containers are used solely for medicinal products for non-parenteral<br />administration. They include tubes, packs made from foil<br />or blisters, cans, and aerosol and gas cylinders. Aluminium and stain-less<br />steel are the metals of choice for both primary and secondary<br />packaging for medicinal products. They have certain advantages and<br />provide excellent tamper-evident containers.<br />Since metal is strong, impermeable to gases and shatterproof, it is the<br />ideal packaging material for pressurized containers.<br />Descriptions and tests can be found in the norms and standards of the<br />ISO; these have been established in collaboration with manufactur-ers.<br />Requirements are not given in pharmacopoeias; the suitability of<br />a particular material for a container is normally established by con-ducting<br />stability studies in which the material is in contact with the<br />drug in question..134<br />2.2 Closures<br />Closures used for the purpose of covering drug containers after the<br />filling process should be as inert as possible. They should not give rise<br />to undesired interactions between the contents and the outside envi-ronment,<br />and should provide a complete seal. Besides their protective<br />function, closures must also allow the easy and safe administration of<br />the drug.<br />Depending on the application, closures may have to be pierced with a<br />needle for intravenous sets. Such closures are made from elastomeric<br />materials (rubbers), while those that cannot be pierced are generally<br />made from plastics such as polyethylene or polypropylene.<br />Depending on the type of container, closures may have different<br />shapes and sizes, e.g. stoppers for infusion or injection bottles or<br />plungers for prefilled syringes. A special design of stopper may also<br />be required for some pharmaceutical production processes such as<br />lyophilization.<br />Closures, as primary packaging components, are of critical impor-tance<br />and must be carefully selected. They are an essential compo-nent<br />of the container and, as such, an integral part of the drug<br />preparation.<br />A container type which does not require a removable closure at the<br />time of administration is usually preferred since such a container/<br />closure system avoids, or at least minimizes, the risk of biological and<br />other contamination as well as tampering.<br />For parenteral preparations, the combination of glass containers and<br />elastomeric closures, usually secured by an aluminium cap, is widely<br />used. Typical examples are infusion bottles, injection vials and<br />prefilled syringes. The rubber closures used within such a system must<br />be carefully selected in accordance with the intended purpose. Most<br />often, improper rubber closures are the cause of incompatibility<br />between the packaging and the drug.<br />2.2.1 Rubber closures<br />Rubber consists of several ingredients, one of which is elastomer.<br />Modern rubber compounds used in packaging pharmaceuticals con-tain<br />only a limited number of ingredients, which are very difficult to<br />extract. Closures made from such materials generally do not pose any<br />problems, and can be used in contact with a large number of drug<br />preparations.<br />Rubber closures for pharmaceutical use must meet the relevant re-quirements<br />of the most important pharmacopoeias (the European,.135<br />Japanese and United States pharmacopoeias). International stan-dards<br />have also been established (ISO 8871). It should be emphasized<br />that the requirements of pharmacopoeias and standards must be<br />seen as minimal requirements. The suitability of a rubber closure for<br />a given application can only be established by means of stability<br />studies.<br />2.2.2 Caps or overseals<br />Caps or overseals are used to secure the rubber closure to the<br />container in order to maintain the integrity of the seal under<br />normal conditions of transport, handling and storage during the in-tended<br />shelf-life of the product. Such caps are usually made of alu-minium<br />and can be equipped with a plastic top to facilitate opening.<br />Caps also provide evidence of tampering: once opened or removed<br />they cannot be repositioned. This is especially true for caps with a<br />plastic top.<br />2.2.3 Special types of closure<br />Demographic trends are causing new problems for packaging design-ers.<br />Thus while child-resistant closures safeguard children against<br />drug intoxication, opening such packaging may prove difficult for the<br />increasing number of elderly persons in the population.<br />Tamper-evident closures. Tampering includes three aspects, namely<br />altering, pilfering and falsifying the pharmaceutical product.<br />To prevent tragic accidents and especially malicious tampering,<br />manufacturers try to create safe packaging and governments con-tinue<br />to update regulations to include new tamper-evident technol-ogy.<br />In 1975, the United States Food and Drug Administration issued<br />a regulatory requirement for tamper-evident packaging to be used<br />for ophthalmic preparations, thus ensuring that such preparations<br />remained sterile until their use (12). This regulation specifies that<br />the closures must be sealed in such a manner that the contents<br />cannot be used without destroying the seal. In 1982, a further regula-tion<br />(13) on tamper-evident packaging for OTC human drug products<br />described such packaging as “having an indicator or barrier to entry<br />which, if breached or missing, can reasonably be expected to provide<br />visible evidence to consumers that tampering has occurred”.<br />The concept of tamper-evident packaging is also found in the “Gen-eral<br />Notice” and “Requirements” of the United States pharmaco-poeia,<br />which stipulate that all OTC drugs must comply with the<br />tamper-evident packaging and labelling requirements of the Food<br />and Drug Administration, unless specifically exempted. Products cov-ered<br />by the regulation include all OTC drugs, toothpaste and topical.136<br />dermatological products, oral cosmetic liquids, contact lens solutions<br />and tablets.<br />In May 1992, the Food and Drug Administration (14) listed 11 tech-nologies<br />capable of satisfying the definition of tamper-evident pack-aging,<br />while a twelfth was added for sealed cartons. The list includes<br />film wrappers, blister packs, bubble packs, heat-shrunk bands or<br />wrappers, paper foil or plastic packs, bottles with inner mouth seals,<br />tape seals, breakable cap-ring systems, sealed tubes or plastic blind-end<br />heat-sealed tubes, sealed cartons, aerosol containers and all metal<br />and composite cans.<br />Child-resistant closures. Tragic accidents involving the drug intoxica-tion<br />of children has led to new legislation making it difficult for drug<br />packaging to be opened by young children, while allowing adults easy<br />access. Such packaging is designated as child-resistant.<br />Certain protocols for child-resistant packaging were established in<br />the USA in 1966. In 1970, the Poison-Prevention Packaging Act was<br />passed and placed under the jurisdiction of the Food and Drug<br />Administration. This Act was transferred in 1973 to the Consumer<br />Product Safety Commission, which is responsible for drugs and<br />household substances (15). The use of child-resistant packaging has<br />proved effective in reducing child mortality from intoxication by oral<br />prescription drugs, and it is now recognized worldwide that children<br />must be protected against such intoxication.<br />The ISO has published an internationally agreed standard test proce-dure<br />for reclosable child-resistant packaging (16). In Europe several<br />norms have been introduced, which complement the ISO standard<br />(17, 18).<br />The European Committee for Standardization (CEN) has defined a<br />child-resistant package as one “which makes it difficult for young<br />children to gain access to the contents, but which is not too difficult<br />for adults to use properly in accordance with the requirement of this<br />European standard” (19).<br />The three most common reclosable child-resistant types of closure are<br />the “press–turn”, the “squeeze–turn” and a combination lock.<br />To determine whether a packaging is child-resistant, it must be<br />subjected to the ISO test procedure for reclosable child-resistant<br />packaging (14).<br />Most designs that are child-resistant require two hands to open the<br />closure. Such packaging can cause problems for elderly people, and<br />can even lead to the deliberate purchase of drugs with packaging that.137<br />is not child-resistant; alternatively, the child-resistant closure may not<br />be replaced on the container. An optional “elderly adult test” has<br />been inserted in the ISO standard to deal with this problem.<br />3. Quality assurance aspects of packaging<br />3.1 General considerations<br />To ensure that patients and consumers receive high-quality drugs, the<br />quality management system must take the following considerations<br />into account if the required quality of packaging is to be obtained:<br />— the requirements of the national authorities and the relevant<br />legislation<br />— the product<br />— the production process<br />— the manufacturers’ internal policies (safety, marketing, etc.).<br />Bad packaging which is the result of deficiencies in the quality as-surance<br />system for packaging can have serious consequences, and<br />packaging defects can create problems that may result in drug recalls.<br />Such defects may include breakage, and problems relating to printing<br />or inks, or errors on labels and package inserts (patient information<br />leaflets). The use of GMP and quality control will prevent the release<br />of a defective medicinal product.<br />Packaging processes and equipment need validation/qualification in<br />the same way as any other part of processing within a pharmaceutical<br />facility.<br />3.2 Quality control<br />Pharmacopoeial specifications and standards for quality control<br />established by national drug quality control laboratories, as already<br />mentioned, can only be regarded as general in character and must<br />be interpreted as minimum standards. The essential part of quality<br />control is performed by the manufacturer during the development,<br />production, release and post-marketing surveillance of the entire<br />medicinal product, i.e. the finished dosage form in its primary and<br />secondary packaging. As pointed out by the WHO Expert Committee<br />on Specifications for Pharmaceutical Preparations at its thirty-second<br />meeting (1):<br />Quality control is the part of GMP concerned with sampling, specifications<br />and testing, and with the organization, documentation and release<br />procedures which ensure that the necessary and relevant tests are actually<br />carried out and that materials are not released for use, nor products<br />released for sale or supply, until their quality has been judged to be<br />satisfactory. Quality control is not confined to laboratory operations but<br />must be involved in all decisions concerning the quality of the product..138<br />In the production chain, quality control for packaging contains sev-eral<br />critical points. The basic requirements for quality control are as<br />follows (1):<br />(a) Adequate facilities, trained personnel and approved procedures<br />must be available for sampling, inspecting and testing starting<br />materials, packaging materials, and intermediate, bulk and finished<br />products, and where appropriate for monitoring environmental<br />conditions for GMP purposes.<br />(b) Samples of starting materials, packaging materials, intermediate<br />products, bulk products and finished products must be taken<br />by methods and personnel approved of by the quality control<br />department.<br />(c) Test methods must be validated.<br />(d) Records must be made (manually and/or by recording instruments)<br />demonstrating that all the required sampling, inspecting and testing<br />procedures have actually been carried out and that any deviations<br />have been fully recorded and investigated.<br />(e) The finished products must contain ingredients complying with the<br />qualitative and quantitative composition of the product described in<br />the marketing authorization; the ingredients must be of the required<br />purity, in their proper container, and correctly labelled.<br />(f) Records must be made of the results of inspecting and testing<br />materials and intermediate, bulk and finished products against<br />specifications; product assessment must include a review and<br />evaluation of the relevant production documentation and an<br />assessment of deviations from specified procedures.<br />. . . The quality control department as a whole will also have other duties,<br />such as to establish, validate and implement all quality control procedures,<br />to evaluate, maintain and store the reference standards for substances, to<br />ensure the correct labelling of containers of materials and products, to<br />ensure that the stability of the active pharmaceutical ingredients and<br />products is monitored, to participate in the investigation of complaints<br />related to the quality of the product, and to participate in the environmental<br />monitoring. All these operations should be carried out in accordance with<br />written procedures and, where necessary, recorded.<br />Tests and assays are normally carried out at room temperature (be-tween<br />15 and 25°C, or up to 30°C in some climatic zones), unless<br />otherwise indicated. The international pharmacopoeia gives alterna-tive<br />methods to be used if certain instruments are not available.<br />3.2.1 Sampling<br />Sampling is used to check the correctness of the label, packaging<br />material or container reference, as well as in the acceptance of con-signments,<br />detecting adulteration of the medicinal product, obtaining<br />a sample for retention, etc.<br />The sampling procedure must take into account the homogeneity and<br />uniformity of the material so as to ensure that the sample is represen-tative<br />of the entire batch..139<br />The sampling procedure should be described in a written protocol.<br />Further details are given in “Sampling procedure for industrially<br />manufactured pharmaceuticals” (20).<br />3.2.2 Testing programme<br />The testing programme for quality control purposes may vary from<br />one manufacturer to another. Quality control tests are intended to<br />check the identity of the material concerned. Complete pharmaco-poeial<br />or analogous testing may also be carried out, as may special<br />tests, where necessary.<br />All written specifications for packaging materials and containers<br />should include the nature, extent and frequency of routine tests.<br />Routine tests vary according to the type of material and its immediate<br />packaging, the use of the product, and the route of administration.<br />Nevertheless, such tests usually include the following (21):<br />— visual inspection (cleanliness, defects)<br />— tests to identify the material<br />— dimensional tests<br />— physical tests<br />— chemical tests<br />— microbiological tests.<br />3.3 Inspection and audit<br />Self-inspection is covered in Appendix 3, which is taken from Annex<br />1 of the thirty-second report of the Committee (1).<br />3.3.1 Rules<br />It is extremely important to control the security and quality of pack-aging.<br />The requirements to be met by packaging for pharmaceutical<br />products are more stringent than those for the packaging of food<br />products, although many similarities exist. The goal of inspection is to<br />ascertain the quality of the products, and especially the quality of the<br />packaging. Items for self-inspection include documentation, storage<br />of starting materials and finished products, validation of programmes,<br />production and in-process controls, calibration of instruments or<br />measurement systems, control of labels, sanitation and hygiene, recall<br />procedures, premises (including personnel facilities), and mainte-nance<br />of buildings and equipment.<br />Labels play an important part in the quality of packaging. Packaging<br />and labelling errors in the manufacture of pharmaceutical products<br />are often reported..140<br />3.3.2 Audits of suppliers<br />Pharmaceutical manufacturers are usually audited or inspected by<br />national or international licensing authorities; the same applies to<br />suppliers of starting materials, active pharmaceutical ingredients,<br />excipients and packaging materials. All suppliers of pharmaceuticals<br />and packaging materials play an important role in the chain of quality<br />assurance of the final medicinal product.<br />Further details can be found in the twenty-fifth and thirtieth reports<br />of the Committee (2, 22), and “General requirements for dosage<br />forms” in The international pharmacopoeia (3).<br />4. Protection of the environment<br />The protection of the environment has become increasingly impor-tant<br />in many countries in recent years. Greater attention has been<br />paid to the disposal and recycling of waste, and legislation has been<br />introduced in many countries.<br />4.1 Packaging waste<br />Pharmaceutical packaging represents a very small percentage of<br />waste, but its disposal can cause problems for the environment. For<br />this reason, the Committee, at its thirty-second meeting (1), decided<br />that:<br />. . . Provisions should be made for the proper and safe storage of waste<br />materials awaiting disposal. Toxic substances and flammable materials<br />should be stored in suitably designed, separated, enclosed cupboards, as<br />required by national legislation.<br />. . . Waste material should not be allowed to accumulate. It should be<br />collected in suitable receptacles for removal to collection points outside the<br />buildings and disposed of safely and in a sanitary manner at regular and<br />frequent intervals.<br />Environmental problems result from the methods used for waste<br />disposal, and will depend on the type of packaging waste concerned.<br />Such waste may include:<br />— uncontaminated waste (assimilated to domestic waste: paper,<br />cardboard, glass, plastic);<br />— contaminated waste (paper, cardboard, glass, plastic), e.g. waste<br />that has been in contact with blood, blood-derived products,<br />radioactive products or cytotoxic products.<br />The method of disposal will therefore vary but should always be in<br />accordance with national legislation. Contaminated packaging is<br />often incinerated. The methods of disposal of uncontaminated<br />packaging are shown in Table 2..141<br />4.2 Waste policies<br />Waste is created at all stages in the production, supply and use of<br />a pharmaceutical product. At each step, care therefore needs to be<br />taken, either by the manufacturer or the end-user, to protect the<br />environment.<br />Environmental concerns in the international community have led to<br />certain changes in the conditions for the licensing of medicines (23).<br />Thus an environmental risk assessment may have to be carried out in<br />some cases in order to identify potential risks to the environment<br />arising from the storage, use and disposal of medicinal products. The<br />medicinal product as a whole may become the subject of the environ-mental<br />risk assessment so that consideration has to be given not only<br />to the active ingredient but also to the adjuvants/excipients in the<br />formulation, and the primary and secondary packaging.<br />Another major environmental issue affecting certain types of phar-maceutical<br />products concerns the chlorofluorocarbon (CFC) propel-lants,<br />and the threat that they represent to the ozone layer (24). A<br />European directive has been published on this subject (25).<br />In several European countries, manufacturers must dispose of their<br />drug waste, or must pay a specialized company to do so for them, and<br />are encouraged to salvage packaging waste. Faced with this problem,<br />manufacturers and pharmacists have, respectively, introduced new<br />directives and new process policies aimed at:<br />• Reducing packaging. Efforts should be made to reduce the volume<br />and weight of packaging materials, and to eliminate packaging<br />which is not essential for the protection of the contents of medicinal<br />products.<br />• Salvaging and recycling packaging. The use of environmental-friendly<br />packaging needs to be considered, i.e. recyclable or<br />degradable packaging. (Valuable packaging materials, such as<br />Table 2<br />Methods of disposal of uncontaminated packaging<br />Material Recycling Landfill Incineration<br />Paper, cardboard +++++++<br />Plastics ++++++<br />Glass +++++NA<br />Rubber ++++++<br />Metal ++++NA<br />+++: Highly recommended; ++: recommended; +: acceptable; NA: not applicable..142<br />aluminium, have been extensively recycled for many years. Recently,<br />paper, glass and plastic materials have joined the list of recyclable<br />packaging materials.) However, materials that have been in contact<br />with toxic or highly potent drugs require special consideration.<br />• Eliminating and incinerating packaging. Some plastic materials<br />cannot be recycled and are therefore incinerated. The burning<br />of polyvinyl chloride (PVC) is controversial since, if combustion is<br />not complete, it causes a potential increase in the levels of dioxin in<br />the environment. Incineration can be recommended if the combus-tion<br />heat produced by it can also be used for other purposes.<br />Developing countries are often short of incinerators. This method<br />is nevertheless regarded as the best available for the elimination of<br />contaminated packaging.<br />5. Quality specifications<br />5.1 Requirements in The international pharmacopoeia<br />5.1.1 Packaging materials<br />Monographs for inclusion in Volume 6 of The international pharma-copoeia<br />(3) have been proposed for glass containers and rubber<br />closures.<br />5.1.2 Requirements for dosage form containers<br />Every pharmaceutical preparation must comply with the labelling<br />requirements laid down in the WHO guidelines on GMP for pharma-ceutical<br />products (1).<br />Tablets. These should be kept in well-closed containers and protected<br />from light, moisture, crushing and mechanical shock. Any special<br />storage conditions should be stated on the label. Tablets should be<br />able to withstand handling, including packaging and transportation,<br />without losing their integrity. Moisture-sensitive forms, such as effer-vescent<br />tablets, should be stored in tightly closed containers or<br />moisture-proof packs, and may require the use of separate packages<br />containing water-adsorbent agents, such as silica gel.<br />Additional special recommendations for packaging, storage and<br />transportation are specified in the relevant individual monographs.<br />For effervescent tablets, the label should state “Not to be swallowed<br />directly”.<br />Capsules. These should be packaged and stored in a manner that<br />protects them from microbial contamination. Capsules should be kept<br />in well-closed containers. They should be protected from light, exces-sive<br />moisture, or dryness, and should not be subjected to tempera-tures<br />above 30°C..143<br />Additional special recommendations for packaging, storage and<br />transportation are specified in the relevant individual monographs.<br />Parenteral preparations. These are usually supplied in glass ampoules,<br />bottles or vials, plastic bottles or bags, and prefilled syringes, which<br />are coloured in the case of light-sensitive substances.<br />Except where otherwise indicated in the relevant individual mono-graphs,<br />the containers for parenteral preparations should be made<br />from a material that is sufficiently transparent to permit the visual<br />inspection of the contents. They should not adversely affect the qual-ity<br />of the preparation, allow diffusion of any kind into or across the<br />container, or release foreign substances into the preparation.<br />Closures for containers for parenteral preparations should be<br />equipped with a firm seal to prevent the entry of microorganisms and<br />other contaminants while permitting the withdrawal of a part or the<br />whole of the contents without removal of the closure. They should not<br />be made of materials that react with the contents, nor should they<br />allow foreign substances to diffuse into the preparation. The elas-tomers<br />of which the closure is made should be sufficiently firm to<br />allow the passage of a needle with the least possible shedding of<br />particles. Closures for multi-dose containers should be sufficiently<br />elastic to allow the puncture to reseal when the needle is withdrawn<br />and thus protect the contents from airborne contamination. A<br />tamper-evident container is fitted with a device that reveals clearly<br />whether it has ever been opened.<br />On visual inspection, solutions, reconstituted solutions and intrave-nous<br />infusions (except dispersions) should be clear and free from<br />visible particulate matter.<br />Topical semi-solid dosage forms. Containers for these dosage forms<br />should be made from a material that does not adversely affect the<br />quality of the preparation or allow diffusion of any kind into or across<br />the container into the preparation. Closures for these containers<br />should be of a design that minimizes microbial contamination and be<br />equipped with a device that reveals whether the container has ever<br />been opened.<br />Containers for topical semi-solid dosage forms should protect the<br />preparation from light, moisture, and damage during handling and<br />transportation. The use of suitable metal or plastic flexible tubes is<br />preferred. Preparations for nasal, aural, vaginal or rectal use should<br />be supplied in containers adapted for the appropriate delivery of the<br />product to the site of application, or should be supplied with a suitable<br />applicator..144<br />Topical semi-solid dosage forms should be kept in well-closed con-tainers.<br />The preparation should maintain its pharmaceutical integrity<br />throughout the shelf-life when stored at the temperature indicated on<br />the label; this should normally not exceed 25 °C. Special storage rec-ommendations<br />or limitations are indicated in the relevant individual<br />monographs.<br />5.2 Pharmacopoeial requirements for containers in Europe, Japan and<br />the USA<br />5.2.1 Glass containers<br />As previously mentioned in section 2.1.1, a classification of types of<br />glass for containers for pharmaceutical products does not exist in the<br />Japanese pharmacopoeia, while those given in the European and<br />United States pharmacopoeias are very similar.<br />Both the European and United States pharmacopoeias provide<br />specifications for glass containers for injections. The latter publication<br />also gives specific guidance for the packaging, repackaging and dis-pensing<br />of medicinal products. Both the European and United States<br />pharmacopoeias also provide specifications for light-resistant con-tainers<br />and tightly or well-closed closures for capsules and tablets.<br />The European pharmacopoeia gives a general account of the require-ments<br />for glass containers for pharmaceutical use, together with those<br />specifically applicable to glass containers for human blood and blood<br />products.<br />5.2.2 Plastic containers<br />Many different plastics are used for containers for medicinal products<br />and the requirements applicable to them differ greatly in the various<br />pharmacopoeias. It is very difficult to compare the tests described.<br />Other and possibly different requirements may be found in interna-tional<br />standards.<br />5.2.3 Rubber closures<br />A comparison of the requirements for rubber closures is as diffi-cult<br />as that for plastic containers. The European and Japanese<br />pharmacopoeias contain special requirements for rubber closures<br />intended for containers of aqueous parenteral preparations. The<br />United States pharmacopoeia describes more generally the use of<br />closures made from elastomers for injection bottles, but does not<br />specify the preparations for which they can be used.<br />Similarities exist between the tests given in the European, Japanese<br />and United States pharmacopoeias, but international standards also<br />exist which differ considerably from one another..145<br />5.3 International Standards<br />A list of recent International Standards on packaging is given in<br />Appendix 4.<br />References<br />1. Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second<br />report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823).<br />2. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirtieth report. Geneva, World Health Organization, 1987 (WHO Technical<br />Report Series, No. 748).<br />3. The international pharmacopoeia, 3rd ed. Vol. 4. Tests, methods, and<br />general requirements. Quality specifications for pharmaceutical substances,<br />excipients, and dosage forms. Geneva, World Health Organization, 1994.<br />4. Guidelines for stability testing of pharmaceutical products containing well<br />established drug substances in conventional dosage forms. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth<br />report. Geneva, World Health Organization, 1996, Annex 5 (WHO Technical<br />Report Series, No. 863).<br />5. Stability of drug dosage forms. In: WHO Expert Committee on<br />Speci-fications for Pharmaceutical Preparations. Thirty-first report. Geneva, World<br />Health Organization, 1990, Annex 1 (WHO Technical Report Series, No.<br />790).<br />6. WHA41.16. In: Handbook of resolutions and decisions of the World Health<br />Assembly and the Executive Board, Volume III, 3rd ed. (1985–1992).<br />Geneva, World Health Organization, 1993:89.<br />7. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical<br />Report Series, No. 790).<br />8. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996 (WHO Techni-cal<br />Report Series, No. 863).<br />9. Report of the international workshop on counterfeit drugs, Geneva, 26–28<br />November 1997. Geneva, World Health Organization, 1998 (unpublished<br />document WHO/DRS/CFD/98.1; available from Essential Drugs and<br />Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />10. The rational use of drugs: report of the Conference of Experts, Nairobi, 25–<br />29 November 1985. Geneva, World Health Organization, 1987.<br />11. Counterfeit drugs: guidelines for the development of measures to combat<br />counterfeit drugs. Geneva, World Health Organization, 1999 (unpublished<br />document WHO/EDM/QSM/99.1; available from Essential Drugs and<br />Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />12. Department of Health and Human Services, Food and Drug Administration.<br />Section 200.50. Ophthalmic preparations and dispensers. In: U.S. Code of.146<br />Federal Regulations. Title 21. Food and drugs. Vol. 4. Parts 200 to 299.<br />Washington, DC, United States Government Printing Office, 2000:6–7.<br />13. Department of Health and Human Services, Food and Drug Administration.<br />Section 211.132. Tamper-evident packaging requirements for over-the-counter<br />(OTC) human drug products. In: U.S. Code of Federal Regulations.<br />Title 21. Food and drugs. Vol. 4. Parts 200 to 299. Washington, DC, United<br />States Government Printing Office, 2000:125–126.<br />14. Department of Health and Human Services, Food and Drug Administration.<br />Tamper-resistant packaging requirements for certain over-the-counter (OTC)<br />human drug products. Washington, DC, United States Government Printing<br />Office, 1992 (FDA Compliance Policy Guide, 7132a.17).<br />15. Department of Health and Human Services, Food and Drug Administration.<br />Part 1700. Poison-Prevention Act of 1970 Regulations. In: U.S. Code of<br />Federal Regulations. Title 16. Commercial practices. Chapter 2. Consumer<br />Product Safety Commission. Washington, DC, United States Government<br />Printing Office, 1999:690–705.<br />16. Child-resistant packaging — requirements and testing procedures for<br />reclosable packages. International Standard ISO 8317. Geneva,<br />International Organization for Standardization, 1989.<br />17. Specifications for packagings resistant to opening by children. British<br />Standard BS 6652. London, British Standards Institution, 1985.<br />18. Packaging — child-resistant packages — requirements, testing procedures,<br />non-reclosable packages for pharmaceutical products. DIN 55559. Berlin,<br />German Standardization Institute, 1998.<br />19. Packaging — child-resistant packaging — requirements and testing<br />procedures for non-reclosable packages for pharmaceutical products.<br />European Protocol prEN862. Brussels, European Committee for<br />Standardization, 2000.<br />20. Sampling procedure for industrially manufactured pharmaceuticals. In: WHO<br />Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-first report. Geneva, World Health Organization, 1990, Annex 2 (WHO<br />Technical Report Series, No. 790).<br />21. Plastic primary packaging materials. In: The rules governing medicinal<br />products in the European Union. Vol. 3. Guidelines on the quality, safety<br />and efficacy of medicinal products for human use. Brussels, European<br />Commission, 1998:75–82.<br />22. WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Twenty-fifth report. Geneva, World Health Organization, 1975 (WHO<br />Technical Report Series, No. 567).<br />23. Council Directive 93/39/EEC of 14 June 1993 amending Directives 65/65/<br />EEC, 75/318/EEC and 75/319/EEC in respect of medicinal products. Official<br />Journal of the European Communities, 1993, 214:22–30.<br />24. Matters relating to the replacement of CFCs in medicinal products (3BR2a).<br />In: The rules governing medicinal products in the European Union. Vol. 3B.<br />Safety, environment and information. Brussels, European Commission, 1998.<br />25. Assessment of potential risk to the environment posed by medicinal<br />products. European Directive No. 5504/94. London, Medicines Control<br />Agency, 1994..147<br />Bibliography<br />Good manufacturing practices<br />Department of Health and Human Services, Food and Drug Administration. Part<br />210. Current good manufacturing practice in manufacturing, processing,<br />packing, or holding of drugs; general. In: U.S. Code of Federal Regulations.<br />Title 21. Food and drugs. Vol. 4. Parts 200 to 299. Washington, DC, United<br />States Government Printing Office, 2000:113.<br />Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second<br />report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823).<br />Good manufacturing practices: supplementary guidelines for the manufacture of<br />investigational pharmaceutical products for clinical trials in humans. In: WHO<br />Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 7 (WHO<br />Technical Report Series, No. 863).<br />Guidelines for good clinical practice (GCP) for trials on pharmaceutical<br />products. In: WHO Expert Committee on the Use of Essential Drugs. Sixth<br />report. Geneva, World Health Organization, 1995, Annex 3 (WHO Technical<br />Report Series, No. 850).<br />Quality assurance of pharmaceuticals: a compendium of guidelines and related<br />materials. Vol. 1. Geneva, World Health Organization, 1997.<br />Quality assurance of pharmaceuticals: a compendium of guidelines and related<br />materials. Vol. 2. Good manufacturing practices and inspection. Geneva, World<br />Health Organization, 1999.<br />The rules governing medicinal products in the European Union. Vol. IV. Good<br />manufacturing practices: medicinal products for human and veterinary use.<br />Brussels, European Commission, 1998.<br />Regulations for buildings and facilities of pharmacies and manufacturing plants<br />of drugs, medical devices, quasi-drugs and cosmetics. (MHW Ordinance No. 2,<br />dated 1 February 1961; amended by MHW Ordinance No. 54, dated 28 March<br />2001.) Tokyo, Ministry of Health, Labour and Welfare, 2001.<br />Regulations for manufacturing control and quality control of drugs and<br />quasi-drugs. (MHW Ordinance No. 3, dated 27 January 1994; amended by MHW<br />Ordinance No. 16, dated 12 March 1999.) Tokyo, Ministry of Health and<br />Welfare, 1999.<br />Pharmacopoeias<br />European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1997;<br />Supplements 1998, 1999.<br />The international pharmacopoeia, 3rd ed. Vol. 4. Tests, methods and general<br />requirements. Quality specifications for pharmaceutical substances, excipients,<br />and dosage forms. Geneva, World Health Organization, 1994.<br />The Japanese pharmacopoeia, 13th ed. Tokyo, Ministry of Health and Welfare,<br />1996; Supplement 1, 1998.<br />The United States pharmacopeia, 23rd ed. Rockville, MD, The United States<br />Pharmacopeial Convention, 1995; Supplements 1–9, 1995–1998..148<br />Guidelines and documents<br />Guideline for submitting documentation for packaging for human drugs and<br />biologics. Washington, DC, Center for Drug Evaluation and Research, Food and<br />Drug Administration, 1987.<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Twenty-sixth report. Geneva, World Health Organization, 1977 (WHO Technical<br />Report Series, No. 614).<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirtieth report. Geneva, World Health Organization, 1987 (WHO Technical<br />Report Series, No. 748).<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical<br />Report Series, No. 790).<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-second report. Geneva, World Health Organization, 1992 (WHO Technical<br />Report Series, No. 823).<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fourth report. Geneva, World Health Organization, 1996 (WHO Technical<br />Report Series, No. 863).<br />Books<br />Banker GS, Rhodes CT, eds. Modern pharmaceutics, 3rd ed. Vol. 40. Drugs<br />and the pharmaceutical sciences. New York, NY, Dekker, 1996.<br />Cooper J. Plastic containers for pharmaceuticals: testing and control. Geneva,<br />World Health Organization, 1974 (WHO Offset Publication, No. 4).<br />Gennaro AR, ed. Remington’s pharmaceutical sciences, 18th ed. Easton, PA,<br />Mack, 1990.<br />[Guide to packaging.] Guide de l’emballage. Paris, Usine Nouvelle (annual).<br />Jenkins WA, Osborn KR. Packaging drugs and pharmaceuticals. Buffalo, NY,<br />Technomic, 1993.<br />Leonard EA. Packaging: specifications, purchasing, and quality control, 4th ed.<br />New York, NY, Dekker, 1996.<br />Lockhart H, Paine FA. Packaging of pharmaceuticals and healthcare products,<br />1st ed. Glasgow, Blackie Academic & Professional, 1996.<br />Reinhardt PA, Gordon JG. Infectious and medical waste management. Chelsea,<br />MI, Lewis Publishers, 1991.<br />Ross CF. Packaging of pharmaceuticals. Melton Mowbray, Institute of<br />Packaging, 1975.<br />Snyder D, ed. FDA-Speak. The Interpharm glossary of FDA acronyms and<br />regulatory terms. Buffalo, NY, Interpharm, 1992.<br />Snyder DE. Interpharm international dictionary of biotechnology and<br />pharmaceutical manufacturing. Buffalo, NY, Interpharm, 1992..149<br />Reviews and articles<br />Casola AR. FDA’s guidelines for pharmaceutical packaging. Pharmaceutical<br />Engineering, 1989, 9:15–19.<br />Child-resistant containers. Pharmaceutical Journal, 1988, 241:219.<br />Choppen DF. Packaging and labelling for patient and site compliance. Clinical<br />Research and Regulatory Affairs, 1994, 11(1):61–65.<br />Department of Health and Human Services, Food and Drug Administration.<br />Section 211.132. Tamper-evident packaging requirements for over-the-counter<br />(OTC) human drug products. In: U.S. Code of Federal Regulations. Title 21.<br />Food and drugs. Vol. 4. Parts 200 to 299. Washington, DC, United States<br />Government Printing Office, 2000:125–126.<br />Rodgers GB. The safety effects of child-resistant packaging for oral prescription<br />drugs: two decades of experience. Journal of the American Medical Association,<br />1996, 275:1661–1665.<br />Tighter standards for blister packs wanted. Pharmaceutical Journal, 1995,<br />255:232.<br />USP Subcommittee on Packaging, Storage, and Distribution. Survey on the<br />practice of repackaging solid oral dosage forms in blister packs. Pharmacopeial<br />Forum, 1996, 22(6):3265–3267..150<br />Appendix 1<br />Storage areas<br />1<br />1. Storage areas should be of sufficient capacity to allow orderly<br />storage of the various categories of materials and products: starting<br />and packaging materials, intermediates, bulk and finished products,<br />products in quarantine, and released, rejected, returned or recalled<br />products.<br />2. Storage areas should be designed or adapted to ensure good<br />storage conditions. In particular, they should be clean and dry and<br />maintained within acceptable temperature limits. Where special<br />storage conditions are required (e.g. temperature, humidity) these<br />should be provided, checked and monitored.<br />3. Receiving and dispatch bays should protect materials and products<br />from the weather. Reception areas should be designed and equipped<br />to allow containers of incoming materials to be cleaned if necessary<br />before storage.<br />4. Where quarantine status is ensured by storage in separate<br />areas, these areas must be clearly marked and their access restricted<br />to authorized personnel. Any system replacing the physical quaran-tine<br />should give equivalent security.<br />5. There should normally be a separate sampling area for starting<br />materials. If sampling is performed in the storage area, it should<br />be conducted in such a way as to prevent contamination or cross-contamination.<br />6. Segregation should be provided for the storage of rejected, re-called<br />or returned materials or products.<br />7. Highly active materials, narcotics, other dangerous drugs, and sub-stances<br />presenting special risks of abuse, fire or explosion should be<br />stored in safe and secure areas.<br />8. Printed packaging materials are considered critical to the confor-mity<br />of the pharmaceutical product to its labelling, and special atten-tion<br />should be paid to the safe and secure storage of these materials.<br />1<br />Previously published in “Good manufacturing practices for pharmaceutical products”. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-<br />second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823)..151<br />Appendix 2<br />Labels<br />1<br />1. All finished drug products should be identified by labelling, as<br />required by the national legislation, bearing at least the following<br />information:<br />(a) the name of the drug product;<br />(b) a list of the active ingredients (if applicable, with the Interna-tional<br />Nonproprietary Names), showing the amount of each<br />present, and a statement of the net contents, e.g. number of<br />dosage units, weight or volume;<br />(c) the batch number assigned by the manufacturer;<br />(d) the expiry date in an uncoded form;<br />(e) any special storage conditions or handling precautions that may<br />be necessary;<br />(f) directions for use, and warnings and precautions that may be<br />necessary; and<br />(g) the name and address of the manufacturer or the company or the<br />person responsible for placing the product on the market.<br />1<br />Previously published in “Good manufacturing practices for pharmaceutical products”. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-<br />second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823)..152<br />Appendix 3<br />Self-inspection and quality audits<br />1<br />1. Principle. The purpose of self-inspection is to evaluate the<br />manufacturer’s compliance with GMP in all aspects of production and<br />quality control. The self-inspection programme should be designed to<br />detect any shortcomings in the implementation of GMP and to rec-ommend<br />the necessary corrective actions. Self-inspections should be<br />performed routinely, and may be, in addition, performed on special<br />occasions, e.g. in the case of product recalls or repeated rejections, or<br />when an inspection by the health authorities is announced. The team<br />responsible for self-inspection should consist of personnel who can<br />evaluate the implementation of GMP objectively; all recommenda-tions<br />for corrective action should be implemented. The procedure for<br />self-inspection should be documented, and there should be an effec-tive<br />follow-up programme.<br />Items for self-inspection<br />2. Written instructions for self-inspection should be established to<br />provide a minimum and uniform standard of requirements. These<br />may include questionnaires on GMP requirements covering at least<br />the following items:<br />(a) personnel<br />(b) premises including personnel facilities<br />(c) maintenance of buildings and equipment<br />(d) storage of starting materials and finished products<br />(e) equipment<br />(f) production and in-process controls<br />(g) quality control<br />(h) documentation<br />(i) sanitation and hygiene<br />(j) validation and revalidation programmes<br />(k) calibration of instruments or measurements systems<br />(l) recall procedures<br />(m) complaints management<br />(n) labels control<br />(o) results of previous self-inspections and any corrective steps<br />taken.<br />1<br />Previously published in “Good manufacturing practices for pharmaceutical products”. In:<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-<br />second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823)..153<br />Self-inspection team<br />3. Management should appoint a self-inspection team from local<br />staff who are expert in their own fields and familiar with GMP. The<br />members of the team may be appointed from inside or outside the<br />company.<br />Frequency of self-inspection<br />4. The frequency at which self-inspections are conducted may de-pend<br />on company requirements.<br />Self-inspection report<br />5. A report should be made at the completion of a self-inspection.<br />The report should include:<br />(a) self-inspection results<br />(b) evaluation and conclusions<br />(c) recommended corrective actions.<br />Follow-up action<br />6. The company management should evaluate both the self-inspection<br />report and the corrective actions as necessary.<br />Quality audit<br />7. It may be useful to supplement self-inspections with a quality<br />audit. A quality audit consists of an examination and assessment of all<br />or part of a quality system with the specific purpose of improving it. A<br />quality audit is usually conducted by outside or independent special-ists<br />or a team designated by the management for this purpose. Such<br />audits may also be extended to suppliers and contractors.<br />Suppliers’ audits<br />8. The quality control department should have responsibility to-gether<br />with other relevant departments for approving suppliers who<br />can reliably supply starting and packaging materials that meet estab-lished<br />specifications.<br />9. Before suppliers are approved and included in the specifications<br />they should be evaluated. The evaluation should take into account a<br />supplier’s history and the nature of the materials to be supplied. If the<br />audit is required, it should determine the supplier’s ability to conform<br />with GMP standards for active pharmaceutical ingredients..154<br />Appendix 4<br />International standards on packaging<br />A list is given below of the standards on packaging issued by the<br />International Organization for Standardization (ISO), as of 10 Octo-ber<br />1998, starting with the four main standards, after which they are<br />listed in numerical order.<br />Quality systems — model for quality assurance in design, development,<br />production, installation and servicing. International Standard ISO<br />9001. 1994.<br />Quality systems — model for quality assurance in production, installa-tion<br />and servicing. International Standard ISO 9002. 1994.<br />Quality systems — model for quality assurance in final inspection and<br />test. International Standard ISO 9003. 1994.<br />Quality management and quality systems elements. Part 1: Guidelines.<br />International Standard ISO 9004-1. 1994.<br />Quality management and quality systems elements. Part 2: Guidelines<br />for service. International Standard ISO 9004-2. 1994.<br />Quality management and quality systems elements. Part 3: Guidelines<br />for processed materials. International Standard ISO 9004-3. 1994.<br />Quality management and quality systems elements. Part 4: Guidelines<br />for quality improvement. International Standard ISO 9004-4. 1994.<br />Reusable all-glass or metal-and-glass syringes for medical use. Part 1:<br />Dimensions. International Standard ISO 595-1. 1986.<br />Reusable all-glass or metal-and-glass syringes for medical use. Part 2:<br />Design, performance requirements and tests. International Standard<br />ISO 595-2. 1987.<br />Transfusion equipment for medical use. Part 1: Glass transfusion<br />bottles, closures and caps. International Standard ISO 1135-1. 1987.<br />Plastics collapsible containers for human blood and blood com-ponents.<br />International Standard ISO 3826. 1993.<br />Injection containers for injectables and accessories. Part 1: Injection vials<br />made of glass tubing. International Standard ISO 8362-1. 1989.<br />Injection containers for injectables and accessories. Part 2: Closures for<br />injection vials. International Standard ISO 8362-2. 1988.<br />Injection containers for injectables and accessories. Part 3: Aluminium<br />caps for injection vials. International Standard ISO 8362-3. 1989..155<br />Injection containers for injectables and accessories. Part 4: Injection<br />vials made of moulded glass. International Standard ISO 8362-4. 1989.<br />Injection containers for injectables and accessories. Part 5: Freeze–<br />drying closures for injection vials. International Standard ISO 8362-5.<br />1995.<br />Injection containers for injectables and accessories. Part 6: Caps made<br />of aluminium–plastics combinations for injection vials. International<br />Standard ISO 8362-6. 1992.<br />Injection containers for injectables and accessories. Part 7: Injection<br />caps made of aluminium–plastics combinations without overlapping<br />plastics part. International Standard ISO 8362-7. 1995.<br />Infusion equipment for medical use. Part 4: Infusion sets for single use,<br />gravity feed. International Standard ISO 8536-4. 1998.<br />Infusion equipment for medical use. Part 5: Burette-type infusion sets.<br />International Standard ISO 8536-5. 1992.<br />Infusion equipment for medical use. Part 6: Freeze–drying closures for<br />infusion bottles. International Standard ISO 8536-6. 1995.<br />Infusion equipment for medical use. Part 7: Caps made of aluminium–<br />plastics combinations for infusion bottles. International Standard ISO<br />8536-7. 1992.<br />Sterile single-use syringes, with or without needle, for insulin. Interna-tional<br />Standard ISO 8537. 1991.<br />Elastomeric parts for aqueous parenteral preparations. International<br />Standard ISO 8871. 1990.<br />Aluminium caps for transfusion, infusion and injection bottles —<br />general requirements and test methods. International Standard ISO<br />8872. 1988.<br />Injection equipment for medical use. Part 1: Ampoules for injectables.<br />International Standard ISO 9187-1. 2000.<br />Injection equipment for medical use. Part 2: One-point-cut (OPC)<br />ampoules. International Standard ISO 9187-2. 1993.<br />Dental cartridge syringes. International Standard ISO 9997. 1999.<br />Caps made of aluminium–plastics combinations for infusion bottles<br />and injection vials — requirements and test methods. International<br />Standard ISO 10985. 1999.<br />Prefilled syringes. Part 1: Glass cylinders for dental local anaesthetic<br />cartridges. International Standard ISO 11040-1. 1992..156<br />Prefilled syringes. Part 2: Plungers and discs for dental local anaes-thetic<br />cartridges. International Standard ISO 11040-2. 1994.<br />Prefilled syringes. Part 3: Aluminium caps for dental local anaesthetic<br />cartridges. International Standard ISO 11040-3. 1993.<br />Prefilled syringes. Part 4: Glass barrels for injectables. International<br />Standard ISO 11040-4. 1996.<br />Prefilled syringes. Part 5: Plungers for injectables. International Stan-dard<br />ISO 11040-5. 1996.<br />Containers and accessories for pharmaceutical preparations. Part 1:<br />Drop-dispensing bottles. International Standard ISO 11418-1. 1996.<br />Containers and accessories for pharmaceutical preparations. Part 2:<br />Screw-neck bottles for syrups. International Standard ISO 11418-2.<br />1996.<br />Containers and accessories for pharmaceutical preparations. Part 3:<br />Screw-neck bottles (vials) for solid and liquid dosage forms. Interna-tional<br />Standard ISO 11418-3. 1996.<br />Containers and accessories for pharmaceutical preparations. Part 4:<br />Tablet bottles. International Standard ISO 11418-4. 1996.<br />Containers and accessories for pharmaceutical preparations. Part 5:<br />Dropper assemblies. International Standard ISO 11418-5. 1997.<br />Containers and accessories for pharmaceutical preparations. Part 7:<br />Screw-neck vials made of glass tubing for liquid dosage forms. Interna-tional<br />Standard ISO 11418-7. 1998.<br />Pen-injectors for medical use. Part 1: Requirements and test methods.<br />International Standard ISO 11608-1. 2000.<br />Pen-injectors for medical use. Part 2: Needles — requirements and test<br />methods. International Standard ISO 11608-2. 2000.<br />Pen-injectors for medical use. Part 3: Finished cartridges — require-ments<br />and test methods. International Standard ISO 11608-3. 2000.<br />Pen systems. Part 1: Glass cylinders for pen-injectors for medical use.<br />International Standard ISO 13926-1. 1998.<br />Pen systems. Part 2: Plungers and discs for pen-injectors for medical<br />use. International Standard ISO 13926-2. 1999.<br />Disposable hanging devices for transfusion and infusion bottles —<br />requirements and test methods. International Standard ISO 15010.<br />1998..157<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 10<br />Model certificate of analysis<br />It has been recommended in various fora that WHO should establish<br />a model certificate of analysis for use in trade in starting materials<br />and by manufacturers of pharmaceutical substances, excipients<br />and medicinal products. A model of such a certificate is shown in<br />Appendix 1. The items included are based on good practices<br />for national pharmaceutical control laboratories and good manu-facturing<br />practices (GMP) for pharmaceutical products (1). The<br />certificate lists the results and includes a final evaluation and the<br />conclusions of the examination of one or more samples.<br />In accordance with GMP, the certificate can be used in lieu of testing<br />by the manufacturer (except for the identification tests as a minimum<br />requirement), provided that the reliability of the supplier’s analysis<br />is established by the periodic validation of the test results by appro-priate<br />means and, if feasible, by on-site audits of the supplier’s<br />capabilities. Certificates must be originals (not copies or duplicates)<br />or their authenticity must otherwise be assured, i.e. they must be<br />issued by the supplier of the material concerned (manufacturer, bro-ker,<br />etc.), or based on the analytical worksheet of the laboratory<br />testing the sample(s). For further details, see Annex 3.<br />The certificate should include:<br />• The name and address of the laboratory performing the tests.<br />• The registration number of the certificate of analysis.<br />• The name, description (i.e. grade, quantity received, type of<br />container) and number (used by the original manufacturer and<br />repacker/trader) of the batch for which the certificate is issued, the<br />date of manufacture, and the expiry date (or retest date).<br />• The date on which the batch for which the certificate is issued was<br />received.<br />• A reference to the test procedure used, including the acceptance<br />criteria (limits).<br />• The results of all tests performed on the batch for which the<br />certificate is issued (in numerical form, where applicable) and a<br />comparison with the established acceptance criteria (limits)..158<br />• Any additional test results obtained on samples from the batch as<br />part of a periodic statistically based testing programme.<br />• A statement indicating whether the results were found to comply<br />with the requirements.<br />• The date(s) on which the test(s) was (were) performed.<br />• The signature of the head of the laboratory or an authorized<br />person.<br />• The name, address, and telephone and fax numbers of the original<br />manufacturer. If supplied by repackers or traders, the certificate<br />should show the name, address, and telephone and fax numbers of<br />the repacker/trader and a reference to the original manufacturer.<br />• A statement of the expected conditions of shipping, packaging,<br />storage and distribution, deviation from which would invalidate the<br />certificate.<br />• A copy of the certificate generated by the original manufacturer, if<br />the sample is supplied by a repacker or trader.<br />Reference<br />1. Good manufacturing practices for pharmaceutical products. In: WHO Expert<br />Committee on Specifications for Pharmaceutical Preparations. Thirty-second<br />report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical<br />Report Series, No. 823)..159<br />Appendix 1<br />Model certificate of analysis for active<br />pharmaceutical ingredients, excipients and<br />medicinal products<br />Registration number of sample or certificate:<br />Name and address of laboratory testing the sample:<br />Sample information<br />Name of product (INN, brand name(s), etc.):<br />Dosage form (if applicable):<br />Marketing authorization number (if applicable):<br />Description (appearance of container and contents):<br />Batch number(s):<br />Required storage conditions:<br />1<br />Date received: Date of manufacture:<br />Expiry date (for medicinal products) or retest date (for starting mate-rials<br />or excipients):<br />Name and address of original manufacturer:<br />Telephone: Fax:.160<br />Name and address of repacker and/or trader (if applicable):<br />Telephone: Fax:<br />Test procedure (reference Result (numerical Acceptance criteria<br />to test procedure) result)<br />2<br />(limits)<br />(if applicable) (if applicable)<br />A. Tests performed on<br />samples from batch for<br />which certificate is issued<br />B. Tests performed as<br />part of periodic<br />statistically based testing<br />programme<br />Conclusions:<br />Compliance with acceptance criteria: yes_ no_<br />Date test performed/finalized:<br />Name and address of head of laboratory/authorized person:<br />Telephone: Fax:<br />Signature:<br />Explanatory notes<br />1<br />Statement of expected conditions of shipping, packaging, storage and distribution,<br />deviation from which could render the certificate invalid.<br />2<br />Indicate if the results were obtained from periodic statistically based testing..161<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 11<br />Guidance on the selection of comparator<br />pharmaceutical products for equivalence<br />assessment of interchangeable multisource<br />(generic) products<br />Introduction<br />This annex provides a list of comparator products for equivalence<br />assessment of interchangeable multisource (generic) products. The<br />information on comparator pharmaceutical products was collected by<br />the Secretariat from drug regulatory authorities and pharmaceutical<br />companies. The list has been drawn up to assist regulatory authorities<br />and pharmaceutical companies in deciding on appropriate compara-tor<br />products in the context of multisource (generic) marketing autho-rization.<br />The information could also be used for drug procurement<br />purposes. Where the comparator pharmaceutical product is not<br />clearly defined, criteria are suggested that are provided in a decision-tree<br />format (see Figure 1). This permits the selection of a comparator<br />pharmaceutical product.<br />The guidelines on registration requirements to establish interchange-ability<br />of multisource (generic) pharmaceutical products published by<br />WHO (1) state that multisource products must satisfy the same stand-ards<br />of quality, safety and efficacy as those applicable to the corre-sponding<br />innovator product. They recommend that quality attributes<br />of a multisource product should be tested against the innovator prod-uct<br />for which interchange is intended.<br />The innovator product is usually the most logical comparator product<br />because its quality, safety and efficacy should have been well assessed<br />in pre- and post-marketing studies and, in addition, the data on its<br />safety and efficacy are usually linked to a pharmaceutical product<br />with defined specifications for quality and performance. Despite ac-ceptance<br />of the general objective, there is no agreement on the crite-ria<br />for selecting a list of international comparator products, nor does<br />a list of such products exist. The comparator product chosen is either<br />the most widely used “leading” product on the market or the product<br />that was first introduced in that market. For this reason, among<br />others, significant differences may exist between the comparator<br />products used in different countries..162<br />In the light of the various approaches currently under scientific and<br />regulatory discussion, the feasibility of developing a system of inter-national<br />comparator products was considered. This initiative led to<br />the recommendations given here, which replace those of Part Seven<br />of the previously published WHO guidelines on multisource pharma-ceutical<br />products (1).<br />A list of international comparator pharmaceutical products for<br />equivalence assessment of interchangeable multisource (generic)<br />products<br />1<br />is given in Table 1.<br />Figure 1<br />Decision-tree for use in identifying a comparator pharmaceutical product<br />1<br />The list is based on information collected by WHO from drug regulatory authorities and<br />supplemented with that from pharmaceutical companies. It will be periodically updated.<br />Comparator pharmaceutical product (CPP)<br />of known quality, safety and efficacy<br />Innovator product known?<br />Yes No<br />Available on local market? Present on List B?<br />Yes No Yes No<br />Consider innovator<br />product as CPP<br />Consider obtaining<br />innovator product: List A<br />Follow compendial<br />standards approach<br />Consider market<br />leader product<br />Innovator product<br />available?<br />Quality of market leader product<br />known and well documented?<br />Yes No Yes No<br />Consider innovator<br />product as CPP<br />Consider market<br />leader product<br />Consider market leader<br />product as CPP<br />Conduct comparative<br />compendial tests on<br />multisource and<br />market leader products<br />Acceptable test results?<br />Yes No<br />Consider market leader<br />product as CPP<br />Consider second market<br />leader product.163<br />Instructions on the use of the list<br />1. National regulatory authorities may issue this guidance together<br />with Lists A and B, which should be available to applicants/phar-maceutical<br />companies that plan to develop multisource pharma-ceutical<br />products intended to be interchangeable with innovator or<br />other pharmaceutical products of established quality, safety and<br />efficacy.<br />2. List A provides information about pharmaceutical products<br />from the WHO Model List of Essential Drugs (2), and includes<br />the innovator products (column headed “Trademark”) and the<br />national markets where the manufacturers in question consider<br />that their products’ quality, safety and efficacy are best docu-mented<br />(column headed “Primary market”).<br />3. Pharmaceutical companies planning to develop an interchangeable<br />multisource pharmaceutical product should determine whether the<br />innovator pharmaceutical product appearing in List A is available<br />on the local market.<br />4. If the innovator pharmaceutical product is available on the local<br />market, pharmaceutical companies should use this product in<br />equivalence assessment with their multisource product.<br />5. If the innovator product is not available on the local market, phar-maceutical<br />companies should obtain from the market a product<br />that is the best representative innovator product from the point<br />of view of its quality, safety and efficacy (see column headed<br />“Primary market” of List A).<br />6. The type of equivalence assessment of the comparator pharmaceu-tical<br />product and the multisource product under investigation may<br />vary, depending on local requirements and the availability of<br />resources. Recommendations on the type of equivalence studies to<br />be carried out when such studies are necessary are given in the<br />WHO guidelines on multisource pharmaceutical products (1).<br />7. For some pharmaceutical products, an innovator product cannot<br />be identified. Examples of these products from the WHO Model<br />List of Essential Drugs (2) appear in List B. For these products,<br />a local, national or regional pharmacopoeia or The international<br />pharmacopoeia (3) for both the drug substance and, when avail-able,<br />the product, supplemented by official reference texts, may<br />provide sufficient information and requirements to allow a phar-maceutical<br />company to develop a product of the requisite quality,<br />safety and efficacy. No international comparator product for these.164<br />pharmaceutical products will be available, and no equivalence as-sessment<br />can be performed.<br />Also included in List B are pharmaceutical products for which an<br />innovator product can be identified or a marker leader product<br />may be available, but for which there is insufficient information<br />available for them to appear in List A, e.g. products for which the<br />originator no larger exists or which cannot be traced. The List A<br />approach can also be applied to these products.<br />8. When a market leader product is available on the local market but<br />no innovator product can be identified or obtained from the pri-mary<br />market, the market leader product may be used as a com-parator<br />product if its quality, safety and efficacy have been estab-lished.<br />If this is not the case, the second market leader or<br />compendial standards approach (List B) can be followed.<br />Most of the pharmaceuticals listed are included in the WHO Model<br />List of Essential Drugs (2). In the case of products for which equiva-lence<br />testing is required, it should be performed in accordance with<br />the WHO guidelines on registration requirements to establish inter-changeability<br />of multisource (generic) products (1).<br />Layout of the list<br />Pharmaceutical Section Dosage Comparator pharmaceutical<br />name (1) no. (2) forms and products (4)<br />strengths (3)<br />Trademark Primary Manufacturer<br />market<br />albendazole 6.1.1 chtab, Zentel France SmithKline<br />200 mg Beecham<br />The list is divided into two parts, as follows:<br />• List A provides information on comparator pharmaceutical prod-ucts<br />— trademark and primary market — as given by manufac-turers<br />of innovator products.<br />• List B contains products for which information has not been given<br />by manufacturers of innovator or market leader products or diffi-culties<br />in providing the information were encountered because the<br />pharmaceutical products have been marketed for a long time.<br />(1) Pharmaceutical name: International Nonproprietary Names<br />(INNs) are used to identify the active drug substance as in the<br />WHO Model List of Essential Drugs..165<br />(2) Section no.: this corresponds to the WHO Model List of Essential<br />Drugs, and indicates the therapeutic uses/pharmacological effects<br />of the pharmaceutical.<br />(3) Dosage forms and strengths: these correspond to the WHO<br />Model List of Essential Drugs. A strike-through means that no<br />products of the dosage form or strength are available on the<br />market. An entry in bold signifies that a product of the dosage<br />form or strength is available on the market instead of, or in<br />addition to, those in the WHO Model List of Essential Drugs.<br />The following abbreviations are used:<br />cap capsule<br />chcap chewable capsule<br />chtab chewable tablet<br />cre cream<br />elix elixir<br />encotab enteric-coated tablet<br />eyd eye drop<br />eyo eye ointment<br />inh inhalation<br />inj injection/injectable solution<br />lot lotion<br />loz lozenge<br />multi multiple<br />nsp nasal spray<br />oilinj injection in oil<br />oilsl oily solution<br />oilsp oil suspension<br />oilspinj oil suspension injection<br />oin ointment<br />oosl oral oily solution<br />osl oral solution<br />osp oral suspension<br />pes pessary<br />pwinj powder for injection<br />pwosp powder for oral suspension<br />pwsl powder for solution<br />respsl respirator solution<br />sbltab tablet, sublingual<br />sctab scored tablet<br />sgtab sugar-coated tablet<br />sl solution<br />sr sustained-release preparation.166<br />sup suppository<br />syr syrup<br />tab tablet<br />topsl solution, topical<br />vagtab vaginal tablet<br />wminj water-miscible injection<br />(4) Comparator pharmaceutical products: “Trademark” and “Pri-mary<br />market” for List A indicate the innovator products and<br />the national markets where the manufacturers in question con-sider<br />that their products’ quality, safety and efficacy are best<br />documented.<br />List B, which does not give this information, follows the pharma-copoeial<br />standards approach.<br />The entry ***** means that additional information on the prod-uct<br />must be provided before it can be included in List A..167<br />Table<br />1<br />International<br />comparator<br />products<br />for<br />equivalence<br />assessment<br />of<br />interchangeable<br />multisource<br />(generic)<br />productsa<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />List Aalbendazole<br />6.1.1<br />chtab,<br />200<br />mg<br />Zentel<br />France<br />SmithKline<br />Beecham<br />amiloride,<br />hydrochloride<br />16<br />tab,<br />5<br />mg<br />Midamor<br />United<br />Kingdom<br />Merck,<br />Sharp<br />&<br />Dohme<br />aminophylline<br />25.1<br />tab,<br />100<br />mg,<br />200<br />mg<br />(sr),<br />Aminophylin<br />Germany<br />BYK<br />Gulden<br />Lomberg<br />125<br />mg<br />amitriptyline,<br />24.2.1<br />tab,<br />25<br />mg<br />Elavil<br />USA<br />Zeneca<br />hydrochlorideamoxicillin<br />6.2.1<br />cap,<br />250<br />mg,<br />500<br />mg<br />Amoxil<br />United<br />Kingdom<br />SmithKline<br />Beecham<br />pwosp,<br />125<br />mg/<br />5<br />ml<br />tab,<br />250<br />mg,<br />500<br />mg<br />atenolol<br />12.1<br />tab,<br />50<br />mg,<br />100<br />mg<br />Tenormin<br />United<br />Kingdom<br />Zeneca<br />12.2<br />tab,<br />50<br />mg,<br />100<br />mg<br />12.3<br />tab,<br />50<br />mg,<br />100<br />mg<br />atropine,<br />sulfate<br />21.5<br />eyd,<br />0.1%,<br />0.5%,<br />1%<br />Atropin<br />Dispersa<br />Switzerland<br />Ciba<br />Vision<br />(Novartis)<br />benznidazole<br />6.5.5<br />tab,<br />100<br />mg<br />Radanil<br />Argentina,<br />Brazil,<br />Roche<br />Switzerland<br />biperiden,<br />hydrochloride<br />9<br />tab,<br />2<br />mg<br />Akineton<br />Germany<br />Knoll<br />captopril<br />12.3<br />sctab,<br />25<br />mg<br />Capoten<br />USA<br />Bristol-<br />Myers<br />Squibb<br />carbamazepine<br />5<br />sctab,<br />100<br />mg,<br />200<br />mg<br />(sr)<br />Tegretol<br />Switzerland<br />Novartis<br />chloramphenicol<br />6.2.2<br />cap,<br />250<br />mg<br />Chloromycetin<br />USA<br />Parke-<br />Davis<br />chloramphenicol,<br />sodium<br />6.2.2<br />oilspinj,<br />0.5<br />g/<br />2<br />ml<br />Chloromycetin<br />USA<br />Parke-<br />Davis/<br />Parkedale<br />succinate<br />sodium<br />succinate<br />chloroquine,<br />phosphate<br />6.5.3<br />tab,<br />25<br />mg,<br />100<br />mg,<br />b<br />Alaren<br />phosphate<br />USA<br />Sanofi<br />Winthrop<br />150<br />mg,<br />b,<br />c<br />500<br />mg<br />chlorphenamine,<br />3<br />tab,<br />4<br />mg<br />Chlortrimeton<br />USA<br />Schering-<br />Plough<br />hydrogen maleateciclosporin<br />8.1<br />cap,<br />25<br />mg<br />Sandimmun<br />Switzerland<br />Novartis.168<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />cimetidine<br />17.1<br />tab,<br />200<br />mg<br />Tagamet<br />France<br />SmithKline<br />Beecham<br />ciprofloxacin,<br />6.2.2<br />tab,<br />250<br />mg<br />Ciprobay<br />Germany<br />Bayer<br />hydrochloride clofazimine<br />6.2.3<br />cap,<br />50<br />mg,<br />100<br />mg<br />Lamprene<br />Switzerland<br />Novartis<br />clomifene,<br />citrate<br />18.6<br />tab,<br />50<br />mg<br />Clomid<br />USA<br />Hoechst<br />Marion<br />Roussel<br />clomipramine,<br />24.4<br />cap,<br />10<br />mg,<br />25<br />mg<br />Anafranil<br />Switzerland<br />Novartis<br />hydrochloride clonazepam<br />5<br />sctab,<br />500<br />m<br />g<br />Rivotril<br />Switzerland<br />Roche<br />cloxacillin,<br />sodium<br />6.2.1<br />cap,<br />500<br />mg<br />Penstaphon<br />Belgium<br />Bristol-<br />Myers<br />Squibb<br />pwsl,<br />125<br />mg/<br />5<br />ml<br />Tegopen<br />USA<br />cyclophosphamide<br />8.2<br />tab,<br />25<br />mg,<br />50<br />mg<br />Endoxana<br />United<br />Kingdom<br />ASTA<br />Medica<br />dapsone<br />6.2.3<br />tab,<br />25<br />mg,<br />50<br />mg,<br />100<br />mg<br />Dapsone<br />USA<br />Jacobus<br />desmopressin,<br />acetate<br />10.2<br />nsp,<br />10<br />m<br />g/<br />metered<br />dose<br />DDAVP<br />USA<br />Ferring<br />dexamethasone<br />3<br />tab,<br />500<br />m<br />g,<br />4<br />mg<br />Decadron<br />USA<br />Merck,<br />Sharp<br />&<br />Dohme<br />18.1<br />tab,<br />500<br />m<br />g,<br />4<br />mg<br />diazepam<br />24.3<br />sctab,<br />2<br />mg,<br />5<br />mg<br />Valium<br />USA<br />Roche<br />doxazosin<br />mesilate<br />12.3<br />tab,<br />1<br />mg,<br />2<br />mg,<br />4<br />mg<br />Caldura<br />Germany<br />Pfizer<br />doxycycline,<br />hyclate<br />6.2.2<br />cap,<br />100<br />mg<br />Vibramycin<br />Germany<br />Pfizer<br />tab,<br />100<br />mg<br />epinephrine,<br />21.5<br />eyd,<br />2%<br />Suprarenin<br />Germany<br />Hoechst<br />Marion<br />Roussel<br />hydrochloride ergocalciferol<br />27<br />cap,<br />1.25<br />mg<br />(50<br />000<br />IU)<br />Drisdol<br />USA<br />Sanofi<br />osl,<br />250<br />m<br />g/<br />ml<br />(10<br />000<br />IU/<br />ml)<br />tab,<br />1.25<br />mg<br />(50<br />000<br />IU)<br />ethinylestradiol<br />18.4<br />tab,<br />10<br />m<br />g,<br />20<br />m<br />g,<br />50<br />m<br />g<br />Pregynon<br />C<br />Germany<br />Schering<br />ethinylestradiol<br />+<br />18.3.1<br />tab,<br />30<br />m<br />g<br />+<br />150<br />m<br />g,<br />50<br />m<br />g<br />Nordette-<br />21<br />USA<br />Wyeth-<br />Ayerst<br />levonorgestrel<br />+<br />250<br />m<br />g.169<br />ethosuximide<br />5<br />cap,<br />250<br />mg<br />Zarontin<br />USA<br />Parke-<br />Davis<br />syr,<br />250<br />mg/<br />5<br />ml<br />etoposide<br />8.2<br />cap,<br />100<br />mg<br />Vepesid<br />Netherlands<br />Bristol-<br />Myers<br />Squibb<br />inj,<br />20<br />mg/<br />ml,<br />50<br />mg/<br />ml<br />USA<br />flucytosine<br />6.3<br />cap,<br />250<br />mg<br />Ancobon<br />USA<br />ICN<br />Pharmaceuticals<br />fludrocortisone,<br />acetate<br />18.1<br />tab,<br />100<br />m<br />g<br />Florinef<br />USA<br />Bristol-<br />Myers<br />Squibb<br />fluorouracil<br />13.5<br />oin,<br />5%<br />Efudix<br />USA<br />Roche<br />fluphenazine,<br />decanoate<br />24.1<br />depot<br />inj,<br />25<br />mg/<br />ml<br />Prolixin<br />decanoate<br />USA<br />Bristol-<br />Myers<br />Squibb<br />fluphenazine,<br />enantate<br />24.1<br />depot<br />inj,<br />25<br />mg/<br />ml<br />Prolixin<br />enanthate<br />USA<br />Bristol-<br />Myers<br />Squibb<br />furosemide<br />16<br />tab,<br />40<br />mg<br />Lasix<br />Germany<br />Hoechst<br />Marion<br />Roussel<br />glyceryl<br />trinitrate<br />12.1<br />sbltab,<br />500<br />m<br />g<br />Nitroglycerin<br />Wander<br />Switzerland<br />Novartis<br />chcap,<br />800<br />m<br />g<br />griseofulvin<br />6.3<br />cap,<br />125<br />mg,<br />250<br />mg<br />Grisactin<br />USA<br />Zeneca<br />tab,<br />125<br />mg,<br />250<br />mg<br />Fulcin<br />USA<br />haloperidol<br />24.1<br />tab,<br />2<br />mg,<br />5<br />mg<br />Haldol<br />Belgium<br />Janssen<br />hydralazine,<br />12.3<br />tab,<br />25<br />mg,<br />50<br />mg<br />Apresoline<br />Netherlands<br />Novartis<br />hydrochloride<br />pwinj,<br />20<br />mg<br />United<br />Kingdom<br />hydrochlorothiazide<br />12.3<br />tab,<br />25<br />mg<br />Hydrosaluric<br />United<br />Kingdom<br />Merck,<br />Sharp<br />&<br />Dohme<br />16<br />tab,<br />25<br />mg,<br />50<br />mg<br />ibuprofen<br />2.1<br />tab,<br />200<br />mg<br />Nurofen<br />UK<br />Boots<br />idoxuridine<br />21.1<br />eyd,<br />0.1%<br />Herplex<br />USA<br />Allergan<br />eyo,<br />0.2%<br />imipenem<br />(monohydrate)<br />6.2.1<br />pwinj,<br />250<br />mg<br />+<br />250<br />mg,<br />Tienam<br />Italy<br />Merck,<br />Sharp<br />&<br />Dohme<br />+<br />cilastin<br />(sodium)<br />500<br />mg<br />+<br />500<br />mg<br />pwinj,<br />500<br />mg<br />+<br />500<br />mg<br />insulin<br />injection<br />(soluble)<br />18.5<br />inj,<br />40<br />IU/<br />ml,<br />80<br />IU/<br />ml,<br />Actrapid<br />Germany<br />Novo<br />Nordisk<br />100<br />IU/<br />ml<br />inj,<br />40<br />IU/<br />ml,<br />80<br />IU/<br />ml,<br />Actrapid<br />Zimbabwe<br />100<br />IU/<br />ml<br />inj,<br />40<br />IU/<br />ml,<br />80<br />IU/<br />ml,<br />Novolin<br />R<br />Japan,<br />USA<br />100<br />IU/<br />ml.170<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />intermediate-<br />acting<br />18.5<br />inj,<br />40<br />IU/<br />ml,<br />80<br />IU/<br />ml,<br />Humulin<br />L<br />USA<br />Eli<br />Lilly<br />insulin<br />(as<br />compound<br />100<br />IU/<br />ml<br />insulin zincsuspension) intermediate-<br />acting<br />18.5<br />inj,<br />40<br />IU/<br />ml,<br />80<br />IU/<br />ml,<br />Humulin<br />N<br />USA<br />Eli<br />Lilly<br />insulin<br />(as<br />isophane<br />100<br />IU/<br />ml<br />insulin) ipratropium<br />bromide<br />25.1<br />inh,<br />20<br />m<br />g/<br />metered<br />dose<br />Atrovent<br />USA<br />Boehringer<br />Ingelheim<br />iron<br />dextran<br />10.1<br />inj,<br />equiv.<br />to<br />50<br />mg<br />iron/<br />ml<br />Infed<br />USA<br />Shein<br />Pharmaceuticals<br />isosorbide<br />dinitrate<br />12.1<br />sbltab,<br />5<br />mg<br />Isordil<br />USA<br />Wyeth-<br />Ayerst<br />ivermectin<br />6.1.2<br />sctab,<br />6<br />mg<br />Mectizan/<br />Stromectol<br />Netherlands<br />Merck,<br />Sharp<br />&<br />Dohme<br />ketoconazole<br />6.3<br />osp,<br />100<br />mg/<br />5<br />ml<br />Nizoral<br />Belgium<br />Janssen<br />tab,<br />200<br />mg<br />levamisole,<br />hydrochloride<br />6.1.1<br />tab,<br />50<br />mg,<br />150<br />mg<br />Ergamisol<br />Belgium<br />Janssen<br />8.2<br />tab,<br />50<br />mg<br />levodopa<br />+<br />carbidopa<br />9<br />tab,<br />100<br />mg<br />+<br />10<br />mg,<br />Sinemet<br />Italy<br />Merck,<br />Sharp<br />&<br />Dohme<br />250<br />mg<br />+<br />50<br />mg<br />levonorgestrel<br />18.3.1<br />tab,<br />30<br />m<br />g<br />Microval<br />Germany<br />Wyeth-<br />Ayerst<br />lithium<br />carbonate<br />24.2.2<br />cap,<br />300<br />mg<br />Quilonum<br />Germany<br />SmithKline<br />Beecham<br />tab,<br />300<br />mg<br />mebendazole<br />6.1.1<br />chtab,<br />100<br />mg,<br />500<br />mg<br />Vermox<br />Belgium<br />Janssen<br />medroxyprogesterone<br />18.3.1<br />depot<br />inj,<br />150<br />mg/<br />ml<br />Depo-<br />Provera<br />USA<br />Pharmacia-<br />Upjohn<br />acetate<br />18.7<br />tab,<br />5<br />mg<br />Provera<br />mefloquine,<br />6.5.3<br />tab,<br />250<br />mg<br />Lariam<br />Switzerland<br />Roche<br />hydrochloridemethyldopa<br />12.3<br />tab,<br />250<br />mg<br />Aldomet<br />Spain<br />Merck,<br />Sharp<br />&<br />Dohme<br />metoclopramide,<br />17.2<br />tab,<br />10<br />mg<br />Primperan<br />France<br />Synthlabo<br />hydrochloride.171<br />miconazole,<br />nitrate<br />13.1<br />cre,<br />2%<br />Daktarin<br />Belgium<br />Janssen<br />oin,<br />2%<br />nalidixic<br />acid<br />6.2.2<br />tab,<br />500<br />mg<br />Neggran<br />USA<br />Sanofi<br />Winthrop<br />cap,<br />500<br />mg<br />neostigmine,<br />bromide<br />20<br />tab,<br />15<br />mg<br />Prostigmin<br />Germany<br />Roche<br />niclosamide<br />6.1.1<br />chtab,<br />500<br />mg<br />Yomesan<br />Germany<br />Bayer<br />nifedipine<br />12.3<br />cap,<br />10<br />mg<br />(sr)<br />Adalat<br />10<br />Germany<br />Bayer<br />tab,<br />10<br />mg<br />(sr)<br />Adalat<br />T<br />10<br />nifurtimox<br />6.5.5<br />tab,<br />30<br />mg,<br />120<br />mg,<br />250<br />mg<br />Lampit<br />Argentina<br />Bayer<br />nitrofurantoin<br />6.2.2<br />tab,<br />100<br />mg<br />Furadantin<br />Ireland,<br />United<br />Proctor<br />&<br />Gamble<br />Kingdom<br />norethisterone<br />enantate<br />18.3.1<br />oilsl,<br />200<br />mg/<br />ml<br />Noristerat<br />Mexico,<br />South<br />Schering<br />Africa<br />nystatin<br />6.3<br />loz,<br />100<br />000<br />IU<br />Nystan<br />United<br />Kingdom<br />Bristol-<br />Myers<br />Squibb<br />pes,<br />100<br />000<br />IU<br />Mycostatine<br />France<br />tab,<br />100<br />000<br />IU<br />France<br />tab,<br />500<br />000<br />IU<br />USA<br />vagtab,<br />100<br />000<br />IU<br />France<br />oxamniquine<br />6.1.3<br />cap,<br />250<br />mg<br />Mansil/<br />Vansil<br />Brazil<br />Pfizer<br />syr,<br />250<br />mg/<br />5<br />ml<br />paracetamol<br />2.1<br />sup,<br />100<br />mg,<br />125<br />mg,<br />250<br />mg,<br />Ben-<br />U-<br />Ron<br />Germany<br />Bene<br />500<br />mg,<br />1000<br />mg<br />penicillamine<br />4.2<br />cap,<br />250<br />mg<br />Cuprimine<br />USA<br />Merck,<br />Sharp<br />&<br />Dohme<br />tab,<br />250<br />mg<br />Depen<br />Cater-<br />Wallace<br />phenobarbital<br />5<br />tab,<br />15–<br />100<br />mg<br />Luminal<br />(100<br />mg)<br />Germany<br />Desitin<br />Luminaletten<br />(15<br />mg)<br />phenoxymethylpenicillin,<br />6.2.1<br />pwosp,<br />250<br />mg/<br />5<br />ml<br />V-<br />Cillin<br />K<br />USA<br />Eli<br />Lilly<br />potassium<br />tab,<br />250<br />mg<br />phenytoin,<br />sodium<br />5<br />cap,<br />25<br />mg,<br />30<br />mg,<br />50<br />mg,<br />Dilantin<br />Kapseals<br />USA<br />Parke-<br />Davis<br />100<br />mg<br />tab,<br />25<br />mg,<br />50<br />mg,<br />100<br />mg<br />Dilantin<br />Infatabs<br />phytomenadione<br />10.2<br />tab,<br />10<br />mg<br />Konakion<br />Switzerland<br />Roche.172<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />praziquantel<br />6.1.1<br />tab,<br />150<br />mg,<br />600<br />mg<br />Biltricide<br />Germany<br />Bayer<br />6.1.3<br />tab,<br />600<br />mg<br />prednisolone<br />3<br />tab,<br />5<br />mg<br />Scherisolon<br />Colombia,<br />Uruguay<br />Schering<br />8.3<br />tab,<br />5<br />mg<br />18.1<br />tab,<br />1<br />mg,<br />5<br />mg<br />21.2<br />eyd,<br />0.5%<br />Ultracortenol<br />Germany<br />Ciba<br />Vision<br />(Novartis)<br />procainamide,<br />12.2<br />tab,<br />250<br />mg,<br />500<br />mg<br />Pronestyl<br />USA<br />Bristol-<br />Myers<br />Squibb<br />hydrochlorideprocarbazine,<br />8.2<br />cap,<br />50<br />mg<br />Natulan<br />Switzerland<br />Roche<br />hydrochlorideproguanil,<br />hydrochloride<br />6.5.3<br />tab,<br />100<br />mg<br />Paludrine<br />United<br />Kingdom<br />Zeneca<br />propranolol,<br />7.2<br />tab,<br />20<br />mg,<br />40<br />mg<br />Inderal<br />Japan<br />Zeneca<br />hydrochloride<br />—<br />tab,<br />10<br />mg,<br />40<br />mg<br />United<br />Kingdom<br />pyrantel,<br />embonate<br />6.1.1<br />chtab,<br />250<br />mg<br />Combantrin<br />Germany<br />Pfizer<br />osp,<br />50<br />mg/<br />ml<br />pyrazinamide<br />6.2.4<br />tab,<br />400<br />mg,<br />500<br />mg<br />Zinamide<br />United<br />Kingdom<br />Merck,<br />Sharp<br />&<br />Dohme<br />pyridostigmine,<br />bromide<br />20<br />tab,<br />60<br />mg<br />Mestinon<br />Switzerland<br />Roche<br />rifampicin<br />6.2.3<br />cap,<br />150<br />mg,<br />300<br />mg<br />Rifadin<br />Italy<br />Gruppo<br />Lepetit<br />tab,<br />150<br />mg,<br />300<br />mg<br />6.2.4<br />cap,<br />150<br />mg,<br />300<br />mg<br />tab,<br />150<br />mg,<br />300<br />mg<br />rifampicin<br />+<br />isoniazid<br />6.2.4<br />tab,<br />150<br />mg<br />+<br />100<br />mg,<br />300<br />mg<br />Rifinah<br />Italy<br />Gruppo<br />Lepetit<br />+<br />150<br />mg<br />rifampicin<br />+<br />isoniazid<br />6.2.4<br />tab,<br />150<br />mg<br />+<br />75<br />mg<br />Rifater<br />Italy<br />Hoechst<br />Marion<br />Roussel<br />+<br />pyrazinamide<br />+<br />400<br />mg,<br />150<br />mg<br />+<br />150<br />mg<br />+<br />500<br />mg<br />silver<br />sulfadiazine<br />13.2<br />cre,<br />1%/<br />500<br />g<br />Silvadene<br />USA<br />Hoechst<br />Marion<br />Roussel.173<br />sulfadoxine<br />+<br />6.5.3<br />tab,<br />500<br />mg<br />+<br />25<br />mg<br />Fansidar<br />Switzerland<br />Roche<br />pyrimethaminesulfamethoxazole<br />+<br />6.2.2<br />osp,<br />200<br />mg<br />+<br />40<br />mg/<br />5<br />ml<br />Bactrim<br />Switzerland<br />Roche<br />trimethoprim<br />tab,<br />100<br />mg<br />+<br />20<br />mg,<br />400<br />mg<br />+<br />80<br />mg<br />sulfasalazine<br />17.4<br />tab,<br />500<br />mg<br />Azulfidine<br />USA<br />Pharmacia-<br />Upjohn<br />tamoxifen,<br />citrate<br />8.3<br />tab,<br />10<br />mg,<br />20<br />mg<br />Nolvadex<br />United<br />Kingdom<br />Zeneca<br />testosterone,<br />enantate<br />18.2<br />inj,<br />200<br />mg/<br />ml,<br />250<br />mg/<br />ml<br />Testorion<br />depot<br />Argentina,<br />Schering<br />Germany,<br />Mexico<br />theophylline<br />25.1<br />tab,<br />100<br />mg,<br />125<br />mg,<br />20<br />0<br />mg,<br />Euphylong<br />Germany<br />BYK-<br />Gulden<br />250<br />mg,<br />375<br />mg,<br />500<br />mg<br />timolol,<br />maleate<br />21.4<br />sl<br />(eyd),<br />0.25%,<br />0.5%<br />Timoptol<br />ophthalmic<br />France<br />Merck,<br />Sharp<br />&<br />Dohme<br />solution<br />eyd,<br />0.25%,<br />0.5%<br />(unit<br />dose)<br />Timoptol<br />Ocudose<br />gel<br />(eyd),<br />0.25%,<br />0.5%<br />Timoptol<br />LP<br />tolbutamide<br />—<br />tab,<br />500<br />mg<br />Rastinon<br />Germany<br />Hoechst<br />Marion<br />Roussel<br />triclabendazole<br />6.1.3<br />tab,<br />250<br />mg<br />Egaten<br />Egypt<br />Novartis<br />tropicamide<br />14.1<br />eyd,<br />0.5%<br />Mydriacyl<br />United<br />Kingdom<br />Alcon<br />verapamil,<br />hydrochloride<br />12.1<br />tab,<br />40<br />mg,<br />80<br />mg<br />(sr)<br />Isoptin<br />Germany<br />Knoll<br />12.2<br />tab,<br />40<br />mg,<br />80<br />mg<br />(sr)<br />List Bacetazolamide<br />21.4<br />tab,<br />250<br />mg<br />*****<br />acetylsalicylic<br />acid<br />2.1<br />sup,<br />50–<br />150<br />mg<br />*****<br />tab,<br />100–<br />500<br />mg<br />*****<br />7.1<br />tab,<br />300–<br />500<br />mg<br />*****<br />12.5<br />tab,<br />100<br />mg<br />*****<br />aciclovir<br />6.4.1<br />tab,<br />200<br />mg<br />*****<br />aciclovir<br />(sodium)<br />6.4.1<br />pwinj,<br />250<br />mg<br />*****<br />allopurinol<br />2.3<br />tab,<br />100<br />mg<br />*****<br />aluminium<br />hydroxide<br />17.1<br />osp,<br />320<br />mg/<br />5<br />ml<br />tab,<br />500<br />mg.174<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />amoxicillin<br />+<br />clavulanic<br />6.2.1<br />tab,<br />500<br />mg<br />+<br />125<br />mg<br />*****<br />acidascorbic<br />acid<br />27<br />tab,<br />50<br />mg<br />atropine,<br />sulfate<br />17.5<br />tab,<br />1<br />mg<br />*****<br />azathioprine<br />8.1<br />tab,<br />50<br />mg<br />*****<br />beclometasone,<br />25.1<br />inh,<br />50<br />m<br />g/<br />dose<br />*****<br />dipropionatebenzoic<br />acid<br />+<br />salicylic<br />13.1<br />cre,<br />6%<br />+<br />3%<br />acid<br />oin,<br />6%<br />+<br />3%<br />benzoyl<br />peroxide<br />13.5<br />cre,<br />5%<br />lot,<br />5%<br />benzoyl<br />benzoate<br />13.6<br />lot,<br />25%<br />betamethasone,<br />valerate<br />13.3<br />cre,<br />0.1%<br />*****<br />oin,<br />0.1%<br />*****<br />calamine<br />lotion<br />13.3<br />lot<br />chloral<br />hydrate<br />1.3<br />syr,<br />200<br />mg/<br />5<br />ml<br />chloramphenicol,<br />6.2.2<br />osp,<br />150<br />mg/<br />5<br />ml<br />*****<br />palmitatechloroquine,<br />phosphate<br />6.5.3<br />syr,<br />50<br />mg/<br />5<br />mlb,<br />c<br />*****<br />chloroquine,<br />sulfate<br />6.5.3<br />syr,<br />50<br />mg/<br />5<br />mlb,<br />c<br />tab,<br />100<br />mg,<br />b<br />150<br />mgb,<br />c<br />chlorpromazine,<br />24.1<br />syr,<br />25<br />mg<br />/5<br />ml<br />*****<br />hydrochloride<br />tab,<br />100<br />mg<br />*****<br />coal<br />tar<br />13.5<br />topsl,<br />5%<br />codeine,<br />phosphate<br />2.2<br />tab,<br />30<br />mg<br />*****<br />17.7.2<br />tab,<br />30<br />mg<br />*****<br />colchicine<br />2.3<br />tab,<br />500<br />m<br />g<br />*****.175<br />cromoglicic<br />acid,<br />sodium<br />25.1<br />inh,<br />20<br />mg/<br />dose<br />*****<br />dextromethorphan<br />25.2<br />osl,<br />3.5<br />mg/<br />5<br />ml<br />*****<br />diethylcarbamazine,<br />6.1.2<br />tab,<br />50<br />mg<br />*****<br />dihydrogen<br />citrate<br />diethyltoluamide<br />6.6<br />topsl,<br />50%,<br />75%<br />digitoxin<br />—<br />tab,<br />50<br />m<br />g,<br />100<br />m<br />g<br />*****<br />digoxin<br />12.4<br />osl,<br />50<br />m<br />g/<br />ml<br />*****<br />tab,<br />62.5<br />m<br />g,<br />250<br />m<br />g<br />*****<br />diloxanide,<br />furoate<br />6.5.1<br />tab,<br />500<br />mg<br />*****<br />dimercaprol<br />4.2<br />oilinj,<br />50<br />mg/<br />ml<br />*****<br />dithranol<br />13.5<br />oin,<br />0.1–<br />2%<br />*****<br />ergometrine,<br />hydrogen<br />22.1<br />tab,<br />200<br />m<br />g<br />*****<br />maleate ergotamine,<br />tartrate<br />7.1<br />tab,<br />1<br />mg<br />erythromycin,<br />ethyl<br />6.2.2<br />cap,<br />250<br />mg<br />*****<br />succinate<br />pwosp,<br />125<br />mg<br />*****<br />tab,<br />250<br />mg<br />*****<br />erythromycin,<br />stearate<br />6.2.2<br />cap,<br />250<br />mg<br />*****<br />pwosp,<br />125<br />mg<br />*****<br />tab,<br />250<br />mg<br />*****<br />ethambutol,<br />6.2.4<br />tab,<br />100–<br />400<br />mg<br />*****<br />hydrochloride ethinylestradiol<br />+<br />18.3.1<br />tab,<br />35<br />m<br />g<br />+<br />1.0<br />mg<br />*****<br />norethisterone ferrous<br />salt,<br />sulfate<br />10.1<br />osl,<br />equiv.<br />to<br />25<br />mg<br />iron/<br />ml<br />tab,<br />equiv.<br />to<br />60<br />mg<br />iron<br />ferrous<br />salt<br />(sulfate)<br />+<br />10.1<br />tab,<br />equiv.<br />to<br />60<br />mg<br />iron<br />+<br />folic<br />acid<br />250<br />m<br />g<br />folic<br />acid<br />folic<br />acid<br />10.1<br />tab,<br />1<br />mg,<br />5<br />mg<br />*****<br />gentamicin,<br />sulfate<br />21.1<br />eyd,<br />0.3%<br />*****<br />glibenclamide<br />18.5<br />tab,<br />2.5<br />mg,<br />5<br />mg<br />*****.176<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />hydrocortisone,<br />acetate<br />13.3<br />cre,<br />1%<br />*****<br />oin,<br />1%<br />*****<br />17.4<br />supp,<br />25<br />mg<br />*****<br />hydrogen<br />peroxide<br />—<br />sl,<br />3%<br />iopanoic<br />acid<br />14.2<br />tab,<br />500<br />mg<br />*****<br />ipecacuanha<br />4.1<br />syr,<br />0.14%,<br />as<br />emetine<br />isoniazid<br />6.2.4<br />tab,<br />100–<br />300<br />mg<br />*****<br />isoniazid<br />+<br />ethambutol<br />6.2.4<br />tab,<br />150<br />mg<br />+<br />400<br />mg<br />*****<br />levothyroxine,<br />sodium<br />18.8<br />tab,<br />50<br />m<br />g,<br />100<br />m<br />g<br />*****<br />magnesium<br />hydroxide<br />17.1<br />osp,<br />equiv.<br />to<br />550<br />mg/<br />10<br />ml<br />mercaptopurine<br />8.2<br />tab,<br />50<br />mg<br />*****<br />metformin<br />18.5<br />tab,<br />500<br />mg<br />*****<br />DL-<br />methionine<br />4.2<br />tab,<br />250<br />mg<br />*****<br />methotrexate,<br />sodium<br />8.2<br />tab,<br />2.5<br />mg<br />*****<br />metrifonate<br />—<br />tab,<br />100<br />mg<br />*****<br />metronidazole<br />6.2.2<br />sup,<br />500<br />mg,<br />1<br />g<br />*****<br />tab,<br />200–<br />500<br />mg<br />*****<br />6.5.1<br />tab,<br />200–<br />500<br />mg<br />*****<br />metronidazole,<br />benzoate<br />6.5.1<br />osp,<br />200<br />mg/<br />5<br />ml<br />*****<br />morphine,<br />hydrochloride<br />2.2<br />osl,<br />10<br />mg/<br />5<br />ml<br />morphine,<br />sulfate<br />2.2<br />osl,<br />10<br />mg/<br />5<br />ml<br />tab,<br />10<br />mg<br />neomycin,<br />sulfate<br />+<br />13.2<br />oin,<br />5<br />mg<br />+<br />500<br />IU<br />*****<br />bacitracin<br />zinc<br />nicotinamide<br />27<br />tab,<br />50<br />mg<br />norethisterone<br />18.7<br />tab,<br />5<br />mg<br />*****<br />paracetamol<br />2.1<br />syr,<br />125<br />mg/<br />5<br />ml<br />tab,<br />100–<br />500<br />mg<br />7.1<br />tab,<br />300–<br />500<br />mg.177<br />permethrin<br />13.6<br />lot,<br />1%<br />pethidine,<br />hydrochloride<br />2.2<br />tab,<br />50<br />mg,<br />100<br />mg<br />*****<br />phenobarbital<br />5<br />elix,<br />15<br />mg/<br />5<br />ml<br />*****<br />pilocarpine,<br />21.4<br />sl<br />(eyd),<br />2%,<br />4%<br />*****<br />hydrochloride<br />or<br />nitratepodophyllum<br />resin<br />13.5<br />topsl,<br />10–<br />25%<br />potassium<br />iodide<br />18.8<br />tab,<br />60<br />mg<br />primaquine,<br />diphosphate<br />6.5.3<br />tab,<br />7.5<br />mg,<br />15<br />mg<br />*****<br />promethazine,<br />1.3<br />elix,<br />5<br />mg/<br />5<br />ml<br />*****<br />hydrochloride<br />syr,<br />5<br />mg/<br />5<br />ml<br />*****<br />17.2<br />elix,<br />5<br />mg/<br />5<br />ml<br />*****<br />syr,<br />5<br />mg/<br />5<br />ml<br />*****<br />tab,<br />10<br />mg,<br />25<br />mg<br />*****<br />propyliodone<br />14.2<br />oilsp,<br />500–<br />600<br />mg/<br />ml<br />*****<br />propylthiouracil<br />18.8<br />tab,<br />50<br />mg<br />*****<br />pyridoxine,<br />hydrochloride<br />27<br />tab,<br />25<br />mg<br />quinidine,<br />sulfate<br />12.2<br />tab,<br />200<br />mg<br />*****<br />quinine,<br />bisulfate<br />6.5.3<br />tab,<br />300<br />mg<br />quinine,<br />sulfate<br />6.5.3<br />tab,<br />300<br />mg<br />reserpine<br />12.3<br />tab,<br />100<br />m<br />g,<br />250<br />m<br />g<br />*****<br />retinol,<br />palmitate<br />27<br />cap,<br />200<br />000<br />IU<br />(110<br />mg)<br />oosl,<br />100<br />000<br />IU/<br />ml<br />sgtab,<br />10<br />000<br />IU<br />(5.5<br />mg)<br />wminj,<br />100<br />000<br />IU/<br />2<br />ml<br />(55<br />mg)<br />riboflavin<br />27<br />tab,<br />5<br />m<br />g<br />salbutamol,<br />sulfate<br />22.2<br />tab,<br />4<br />mg<br />*****<br />25.1<br />inh,<br />100<br />m<br />g/<br />dose<br />*****<br />respsl,<br />5<br />mg/<br />ml<br />*****<br />syr,<br />2<br />mg/<br />5<br />ml<br />*****<br />tab,<br />2<br />mg,<br />4<br />mg<br />*****<br />salicylic<br />acid<br />13.5<br />topsl,<br />5%.178<br />Table<br />1<br />(continued)<br />Pharmaceutical<br />name<br />Section<br />Dosage<br />forms<br />and<br />Comparator<br />pharmaceutical<br />products<br />no.<br />strengths<br />Trademark<br />Primary<br />market<br />Manufacturer<br />senna<br />(sennoside)<br />17.6<br />tab,<br />7.5<br />mg<br />silver<br />nitrate<br />21.1<br />sl<br />(eyd),<br />1%<br />sodium<br />fluoride<br />27<br />any<br />spironolactone<br />16<br />tab,<br />25<br />mg<br />*****<br />sulfadiazine<br />6.2.2<br />tab,<br />500<br />mg<br />*****<br />sulfadimidine<br />—<br />osp,<br />500<br />mg/<br />5<br />ml<br />*****<br />tab,<br />500<br />mg<br />*****<br />tetracaine,<br />hydrochloride<br />21.3<br />sl<br />(eyd),<br />0.5%<br />*****<br />tetracycline,<br />21.1<br />eyo,<br />1%<br />*****<br />hydrochloridethiamine, hydrochloride<br />27<br />tab,<br />50<br />mg<br />thioacetazone<br />+<br />isoniazid<br />6.2.4<br />tab,<br />50<br />mg<br />+<br />100<br />mg,<br />150<br />mg<br />*****<br />+<br />300<br />mg<br />trimethoprim<br />6.2.2<br />tab,<br />100<br />mg,<br />200<br />mg<br />*****<br />urea<br />13.5<br />cre,<br />10%<br />oin,<br />10%<br />valproic<br />acid,<br />sodium<br />5<br />encotab,<br />200<br />mg,<br />500<br />mg<br />*****<br />warfarin,<br />sodium<br />10.2<br />tab,<br />1<br />mg,<br />2<br />mg,<br />5<br />mg<br />*****<br />zidovudine<br />6.4.2<br />cap,<br />100<br />mg,<br />250<br />mg<br />*****<br />osl,<br />50<br />mg/<br />5<br />ml<br />*****<br />zinc<br />oxide<br />—<br />creoin<br />a<br />For<br />instructions<br />on<br />the<br />use<br />of<br />the<br />list,<br />see<br />pages<br />164–<br />167.<br />b<br />For<br />curative<br />treatment.<br />c<br />For<br />prophylaxis..179<br />Authors<br />This guidance was discussed during two meetings convened by the<br />Division of Drug Management and Policies and the Department of<br />Essential Drugs and other Medicines, World Health Organization,<br />Geneva, Switzerland, from 12 to 13 February 1996 and from 8 to 9<br />February 1999. The meetings were attended by the following people:<br />Mr M.N. Dauramanzi, Drugs Control Council, Harare, Zimbabwe<br />Dr M. Holz-Slomczyk, Federal Institute for Drugs and Medical<br />Devices, Berlin, Germany<br />Professor U. Gundert-Remy, University of Göttingen, Göttingen,<br />Germany<br />Mrs M. Ikeda, Ministry of Health and Welfare, Tokyo, Japan<br />Dr K. Morimoto, Pharmaceuticals and Medical Devices Evaluation<br />Centre, National Institute of Health Sciences, Tokyo, Japan<br />Ms A. Poompanich, Division of Drug Analysis, Ministry of Public<br />Health, Nonthaburi, Thailand<br />Dr R. Williams, Center for Drug Evaluation and Research, Food and<br />Drug Administration, Rockville, MD, USA<br />Secretariat<br />Mrs K. Bremer, Quality Assurance and Safety: Medicines, Essential<br />Drugs and other Medicines, WHO, Geneva, Switzerland<br />Dr M. Demesmaeker, Quality Assurance and Safety: Medicines,<br />Essential Drugs and other Medicines, WHO, Geneva, Switzerland<br />Dr J. Idänpään-Heikkilä, Special Adviser on Quality Assurance and<br />Safety, Health Technology and Pharmaceuticals, WHO, Geneva,<br />Switzerland<br />Dr S. Kopp-Kubel, Quality Assurance and Safety: Medicines, Essen-tial<br />Drugs and other Medicines, WHO, Geneva, Switzerland<br />Mr D. Sato, Drug Management and Policies, WHO, Geneva,<br />Switzerland<br />Miss M. Schmid, Quality Assurance and Safety: Medicines, Essential<br />Drugs and other Medicines, WHO, Geneva, Switzerland<br />Miss A. Wehrli, Regulatory Support, Drug Management and Policies,<br />WHO, Geneva, Switzerland<br />Mr Y. Yoshida, Quality Assurance and Safety: Medicines, Essential<br />Drugs and other Medicines, WHO, Geneva, Switzerland.180<br />Acknowledgements<br />Acknowledgement was made by the WHO Secretariat to the following people, for<br />their valuable contributions to the discussions: Miss M. Cone, International<br />Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva,<br />Switzerland; Dr I. Kanfer, International Generic Pharmaceutical Alliances,<br />Genpharm Inc., Etobicoke, Ontario, Canada; and Dr R. Patnaik, Deputy Director,<br />Division of Bioequivalence, Center for Drugs Evaluation and Research, Food and<br />Drug Administration, Rockville, MD, USA.<br />References<br />1. Multisource (generic) pharmaceutical products: guidelines on registration<br />requirements to establish interchangeability. In: WHO Expert Committee on<br />Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva,<br />World Health Organization, 1996, Annex 9 (WHO Technical Report Series,<br />No. 863).<br />2. The use of essential drugs. Eighth report of the WHO Expert Committee<br />(including the revised Model List of Essential Drugs). Geneva, World Health<br />Organization, 1998 (WHO Technical Report Series, No. 882).<br />3. The international pharmacopoeia, 3rd ed. Vol. 1. General methods of<br />analysis; Vol. 2. Quality specifications; Vol. 3. Quality specifications; Vol 4.<br />Tests, methods, and general requirements. Quality specifications for<br />pharmaceutical substances, excipients, and dosage forms. Geneva, World<br />Health Organization, 1979–1994..181<br />© World Health Organization<br />WHO Technical Report Series, No. 902, 2002<br />Annex 12<br />Guidelines on the use of International<br />Nonproprietary Names (INNs) for pharmaceutical<br />substances<br />1. General introduction<br />The present guidelines on the use of International Nonproprietary<br />Names (INNs) provide a general explanation of the INN selection<br />process. They should be of interest to drug regulatory authorities for<br />use in the marketing authorization/registration of products, to drug<br />manufacturers requesting new INNs, and to those using INNs, such as<br />patent authorities/offices, trademark lawyers and specialists, health<br />professionals, scientists and teachers, as well as to anyone interested<br />in nomenclature.<br />1.1 General information on the INN system<br />An INN identifies a pharmaceutical substance or active pharmaceuti-cal<br />ingredient by a unique name that is globally recognized and is<br />public property. A nonproprietary name is also known as a generic<br />name.<br />The INN system as it exists today was initiated in 1950 by World<br />Health Assembly resolution WHA3.11 (see section 5.1) and began<br />operating in 1953, when the first list of INNs for pharmaceutical<br />substances was published. The cumulative list of INNs now stands at<br />some 7000 names designated since that time, and this number is<br />growing every year by some 120–150 new INNs.<br />Since its inception, the aim of the INN system has been to provide<br />health professionals with a unique and universally available desig-nated<br />name for each pharmaceutical substance. The existence of an<br />international nomenclature for pharmaceutical substances, in the<br />form of INNs, is important for the clear identification, safe prescrip-tion<br />and dispensing of medicines to patients, and for communication<br />and the exchange of information among health professionals and<br />scientists worldwide.<br />As unique names, INNs must be distinctive in sound and spelling, and<br />not liable to confusion with other names in common use. To make<br />INNs universally available, they are formally placed by WHO in the.182<br />public domain, hence their designation as “nonproprietary”. They can<br />be used without any restriction whatsoever to identify pharmaceutical<br />substances.<br />Another important feature of the INN system is that the names of<br />pharmacologically related substances were identified by the use of<br />a common “stem” (see section 3.2). The use of common stems<br />enables the medical practitioner, the pharmacist, or anyone dealing<br />with pharmaceutical products to recognize that a particular substance<br />belongs to a group of substances of similar pharmacological activity.<br />For example, all iodine-containing contrast media are given the<br />prefix io-, while all b -adrenoreceptor antagonists have the suffix<br />-olol.<br />The extent of utilization of INNs is expanding with the increase in the<br />number of pharmaceutical names. Their wide application and global<br />recognition are also due to close collaboration in the process of INN<br />selection with numerous bodies concerned with drug nomenclature.<br />The increasing coverage of drug names by INNs has led to a situation<br />whereby the majority of pharmaceutical substances used today in<br />medical practice are designated by an INN. The use of INNs is already<br />common in research and clinical documentation, while their impor-tance<br />is growing further as a result of the expanding use of generic<br />names for pharmaceutical products.<br />The names which are given the status of an INN are selected by<br />WHO on the advice of experts from the WHO Expert Advisory<br />Panel on the International Pharmacopoeia and Pharmaceutical<br />Preparations. The process of INN selection consists of three main<br />steps:<br />1. A request/application is made by the manufacturer or inventor.<br />2. After a review of the request, a proposed INN (prop. INN) is<br />selected and published for comments.<br />3. After the period allowed for objections has lapsed, the name ob-tains<br />the status of a recommended INN (rec. INN) and is published<br />as such.<br />The procedures relating to each of these steps are described in detail<br />in sections 2.1 and 2.2.<br />INNs are selected in principle only for single, well-defined substances<br />that can be unequivocally characterized by a chemical name (or for-mula).<br />It is the policy of the INN programme not to select names for<br />mixtures of substances, while substances that are not fully character-ized<br />are included in the INN system in exceptional cases only.<br />INNs are not selected for herbal substances (vegetable drugs) or for.183<br />homeopathic products. It is also the policy of the INN programme not<br />to select names for those substances that have a long history of use for<br />medical purposes under well-established names, such as alkaloids<br />(e.g. morphine, codeine), or that have well-known trivial chemical<br />names (e.g. acetic acid).<br />An INN is usually assigned to the active part of the molecule only, to<br />avoid the multiplication of entries in cases where several salts, esters,<br />etc., are actually used. In such cases, the user of the INN can create a<br />modified INN (INNM) (see section 2.4), e.g. mepyramine maleate<br />for the mepyramine salt of maleic acid. When the creation of an<br />INNM would require the use of a long or inconvenient name for the<br />radical (or group) part of the INNM, the INN programme will select<br />a short name for such a radical (or group) (e.g. mesilate for<br />methanesulfonate; see section 2.3).<br />Names of pharmaceutical preparations, such as those used in titles of<br />pharmacopoeial monographs, usually consist of two elements, the<br />first designating the active substance (for which an INN is used), and<br />the second designating the dosage form of the product. Rules for<br />creating such names fall outside the scope of the INN programme and<br />are not discussed here.<br />In the process of INN selection, the rights of existing trademark<br />owners are fully protected. If, in a period of 4 months following the<br />publication of a proposed INN, a formal objection is filed by an<br />interested person who considers that the proposed INN is in conflict<br />with an existing trademark, WHO will make every effort to persuade<br />the person concerned to withdraw their objection or will reconsider<br />the proposed name. As long as the objection to the name exists,<br />WHO will not publish it as a recommended INN.<br />With the growing number of INNs and trademarks, the possibility of<br />conflicts between the two has gradually increased, even though the<br />rights of existing trademarks are fully protected. The main source of<br />conflict is usually an attempt by a manufacturer to propose a new<br />trademark containing stems established in the INN programme. If<br />protection were granted to such a name, that might limit the freedom<br />of the INN programme in selecting further INNs for the same group<br />of substances. To prevent such occurrences, the matter was taken<br />up in resolution WHA46.19 of the World Health Assembly (see<br />section 4).<br />1.2 Use of INNs<br />Nonproprietary names are intended for use in pharmacopoeias,<br />labelling, product information, advertising and other promotional.184<br />material, drug regulation and scientific literature, and as a basis for<br />product names, e.g. for generics. Their use is normally required by<br />national or, as in the case of the European Community, by interna-tional<br />legislation. As a result of ongoing collaboration, national<br />names such as British Approved Names (BAN), Dénominations<br />Communes Françaises (DCF), Japanese Adopted Names (JAN) and<br />United States Accepted Names (USAN) are nowadays, with rare<br />exceptions, identical to the corresponding INNs.<br />Some countries have defined the minimum size of characters in which<br />the generic nonproprietary name must be printed under the trade-mark<br />labelling and advertising. In several countries the generic name<br />must appear prominently in type at least half the size of that used for<br />the proprietary or brand name. In some countries it must be in larger<br />type than the trademark name. Certain countries have even gone so<br />far as to abolish trademarks within the public sector.<br />To avoid confusion, which could jeopardize the safety of patients,<br />trademarks cannot be derived from INNs and, in particular, must not<br />include their common stems. As already mentioned, the selection of<br />further names within a group of substances would be seriously<br />hindered by the use of a common stem in a brand name.<br />2. Elements in the INN system<br />2.1 Proposed INNs<br />The selection of a new INN follows a strict procedure. On receipt<br />of an INN request form, the INN Secretariat examines the sug-gested<br />names for conformity with the general rules, and for similari-ties<br />with published INNs and potential conflicts with existing<br />names, including published INNs and trademarks. A note summariz-ing<br />the result of this examination is added, and the request is then<br />forwarded to the INN experts for comments. As soon as all the<br />experts agree on a name, the applicant is informed of the selected<br />name.<br />Newly selected, proposed INNs are then published in WHO Drug<br />Information, after which a period of 4 months is allowed for com-ments<br />on and/or objections to them to be made. The reasons for any<br />objection must be clearly stated and will be evaluated by the experts.<br />Users are requested to refrain from using the proposed name until it<br />becomes a recommended INN, in order to avoid confusion should the<br />name be modified.<br />Two lists of proposed INNs are published yearly. An example is<br />shown in Figure 1..185<br />2.2 Recommended INNs<br />The final stage of the selection process is the recommended INN.<br />Once a name has been published as a recommended INN it will not<br />normally be modified further and is ready for use in labelling, and in<br />publications and drug information. It will serve to identify the active<br />pharmaceutical substance during its lifetime worldwide. Since the<br />name is available in the public domain it may be freely used. It should<br />not be registered as a trademark, since this would prevent its use by<br />other parties (see also section 4).<br />Recommended INNs are published in WHO Drug Information after<br />the completion of the procedure for dealing with proposed INNs (see<br />section 2.1). As from 1997, two lists of proposed INNs are published<br />yearly, and as from list 37 of recommended INNs, graphic formulae<br />are also included to facilitate identification of the substances.<br />An example of an entry in the list is shown in Figure 2.<br />2.3 Names for radicals and groups<br />During the twentieth meeting of the WHO Expert Committee on<br />Nonproprietary Names for Pharmaceutical Substances (1), the ex-perts<br />discussed the issue of INNs for salts and esters and noted that<br />requests had frequently been received for INNs for salts, esters, or<br />combination products of substances for which INNs already existed.<br />At that time, the experts decided that INNs for simple salts and esters<br />should be derived from the INNs in conformity with normal chemical<br />practice.<br />Figure 1<br />A proposed INN<br />acidum iocanlidicum (<br />123<br />I)<br />iocanlidic (<br />123<br />I) acid 15-( p-[<br />123<br />I]iodophenyl)pentadecanoic acid<br />radiodiagnostic agent<br />acide iocanlidique (<br />123<br />I) acide 15-(4-[<br />123<br />I]iodophényl)pentadécanoïque<br />produit à usage radiodiagnostique<br />ácido iocanlídico (<br />123<br />I) ácido 15-( p-[<br />123<br />I]iodofenil)pentadecanoico<br />agente de radiodiagnóstico<br />C21 H33<br />123<br />IO2 74855-17-7<br />CO2 H<br />123 I.186<br />Some of the radicals and groups involved are, however, so complex<br />that it is inconvenient to use the chemical nomenclature. It was there-fore<br />decided that, in such cases, shorter nonproprietary names should<br />be selected for these active moieties and published in the list of<br />proposed INNs under the title “Names for radicals and groups”.<br />Separate names for salts and esters derived from this procedure are<br />not published. If a “radical and group name” is used in conjunction<br />with an INN, it is referred to as an International Nonproprietary<br />Name (Modified) or INNM (see section 2.4).<br />A comprehensive list of radicals and groups, which is regularly up-dated,<br />may be obtained from Marketing and Dissemination<br />1<br />or the<br />INN Secretariat (2).<br />2.4 Modified INNs (INNMs)<br />As previously mentioned, INNs are usually selected only for the<br />active part of the molecule, which is usually the base, acid or alcohol.<br />In some cases, however, the active part needs to be extended for<br />various reasons, e.g. for formulation purposes, or to increase the<br />bioavailability or absorption rate of the substance. At its twentieth<br />meeting in 1975, the WHO Expert Committee on Nonproprietary<br />Names for Pharmaceutical Substances (1) decided to adopt a new<br />policy for naming such molecules. As a result, names for different<br />N H3 C<br />OCH3<br />O<br />H<br />Figure 2<br />A recommended INN<br />agomelatinum<br />agomelatine N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide<br />agomélatine N-[2-(7-méthoxynaphtalén-1-yl)éthyl]acétamide<br />agomelatina N-[2-(7-metoxi-1-naftil)etil]acetamida<br />C15 H17 NO2<br />1<br />Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211<br />Geneva 27, Switzerland..187<br />salts or esters of the same active substance should differ only with<br />regard to the inactive moiety of the molecule. For example, oxacillin<br />and ibufenac are INNs and their salts are named oxacillin sodium and<br />ibufenac sodium. The latter are called modified INNs (INNMs).<br />Before the introduction of this rule, some INNs were published for<br />salts. In such cases, the term “modified INN” may also be used for a<br />base or acid. For example, levothyroxine sodium was published as an<br />INN and levothyroxine may thus be referred to as an INNM.<br />2.5 Cumulative list<br />All names selected as proposed and recommended INNs are pub-lished<br />in a cumulative list (3), which is updated periodically. The<br />generic names are listed in alphabetical order by Latin name. Each<br />entry includes:<br />— the equivalent nonproprietary names in Latin, English, French,<br />Russian and Spanish;<br />— a reference to the INN list in which the name was originally<br />proposed or recommended, or last amended;<br />— a reference to names of substances that have been abandoned or<br />never marketed;<br />— a reference to national nonproprietary names;<br />— a reference to pharmacopoeial monographs or similar official<br />publications;<br />— a reference to names established by the International Organiza-tion<br />for Standardization (ISO);<br />— a reference to the Convention on Psychotropic Substances (4), if<br />applicable;<br />— a reference to the List of Narcotic Drugs under International<br />Control (5), if applicable;<br />— the molecular formula;<br />— the Chemical Abstracts Service (CAS) number.<br />The information contained in the cumulative list of INNs (3) is pre-sented<br />as shown in Figure 3.<br />3. Principles for selection of INNs<br />3.1 General rules<br />General rules were established at the beginning of the INN<br />programme in order to guide the members of the INN committee and<br />to allow health professionals to understand the rationale for a number<br />of new names. At first, some countries used shortened chemical<br />names as generic names, but this system was found to be of very<br />limited use, since many molecules contain similar elements and.188<br />Figure 3<br />Example of an entry from the Cumulative list<br />* An asterisk in place of a recommended list number signifies that an objection has been raised to the<br />proposed name.<br />Note: Cross-references are provided for entries corresponding to (a) English, French and Spanish<br />INN that appear in different alphabetical positions from the Latin INN and (b) national names<br />that differ from the INN. Entries for (a) are printed in lower-case letters (as in the example of<br />aceburic acid, below) while entries for (b) are printed in capitals (as in the examples of<br />ACEBUTOLOL HYDROCHLORIDE and ACEBUTOLOLO).<br />English INN Cross-reference to Latin INN<br />3377 aceburic acid — acidum aceburicum<br />3295 ACEBUTOLOL HYDROCHLORIDE — acebutololum<br />3295 ACEBUTOLOLO — acebutololum<br />National name(s)<br />differing from the INN<br />Request number<br />List of proposed INN Abbreviations for national<br />names identical to the INN List of<br />recommended*<br />INN INN in English INN in French<br />INN in Latin<br />0626 0804 paracetamol<br />apaueTaMo<br />paracétamol<br />paracetamol<br />paracetamolum<br />BAN BPC CHP CSP DCF EP INDP<br />IP MXP USSRP YP<br />ACETAMINOPHEN<br />ACETAMINOPHENUM<br />PARACETAMOLO<br />USP<br />JP<br />DCIT<br />103-90-2 C8 H9 NO2<br />INN in Spanish INN in Russian<br />CAS registry number<br />Molecular formula National name(s)<br />differing from the INN<br />(abbreviation for source of name (left),<br />and name (right)).189<br />groups (e.g. phenol, chlor, methyl or benzene rings) in their chemical<br />structures. In addition, a name that indicates a relationship to a group<br />of substances having similar pharmacological effects is more mean-ingful<br />to users.<br />The general principles for devising INNs and the procedures for<br />selecting them were reviewed by the WHO Expert Committee<br />on Nonproprietary Names for Pharmaceutical Substances at its<br />twentieth meeting (1).<br />3.2 Use of stems<br />An INN usually consists of a randomly chosen prefix and a common<br />stem (see Appendix 1); the latter shows that the substance concerned<br />belongs to a group of pharmacologically related substances. Substems<br />are sometimes established to differentiate between different related<br />groups of substances, e.g. -teplase for tissue-plasminogen activators<br />and -uplase for urokinase-type plasminogen activators.<br />It should be noted that a number of stems have been discontinued<br />(see Appendix 2).<br />3.3 Stereoisomers<br />An INN for a new chemical entity does not routinely specify the<br />stereoisomeric state of the molecule in the nonproprietary name. If<br />the stereochemistry has been determined, this information is included<br />in the chemical name(s) used to identify the substance. An INN can<br />therefore identify the racemic mixture (e.g. ibuprofen, tetramisole),<br />the ()-isomer (e.g. amifostine, lofentanil, prenalterol, remoxipride,<br />quadazocine), or the (“´¬–”²ª› )-form (e.g. butopamine). Subsequently, if an<br />INN is needed for a different enantiomer or for the racemic form, the<br />following prefixes should be added to the existing INN:<br />— for the ()-form, the lev-/levo- prefix is used, e.g. levocarnitine,<br />levamisole;<br />— for the (“´¬–”²ª› )-form, the dex- prefix is used, e.g. dexamisole, dexi-buprofen;<br />— for the racemic form, the rac-/race- prefix is used, e.g.<br />racepinefrine.<br />3.4 Radioactive compounds<br />A name for a drug substance containing a radioactive atom should<br />list, in the following order:<br />— the name of the substance containing the radioactive atom;<br />— the isotope number;.190<br />— the element symbol; and<br />— the name of the carrier agent, if any.<br />Examples include cyanocobalamin (<br />60<br />Co), technetium (<br />99m<br />Tc) bicisate<br />and technetium (<br />99m<br />Tc) sestamibi.<br />3.5 Specific groups of biological compounds<br />Because of the complexity of certain new types of pharmaceutical<br />products, such as those produced by biotechnology, general rules are<br />not always easily formulated (6). Some of these substances may al-ready<br />have descriptive names assigned by other institutions such as<br />the International Union of Biochemistry (IUB), the International<br />Union of Pure and Applied Chemistry (IUPAC), and the Joint Com-mission<br />on Biochemical Nomenclature (JCBN). These names may<br />not be suitable as INNs.<br />4. Protection of INNs<br />Lists of both proposed and recommended INNs are sent together<br />with a note verbale by WHO to its Member States (of which there<br />are at present 191), to national pharmacopoeia commissions and to<br />other bodies designated by Member States. The note verbale requests<br />Member States to take such steps as are necessary to prevent the<br />acquisition of proprietary rights in the names, including prohibiting<br />their registration as tradenames or trademarks.<br />Over the years, the need to maintain the integrity of the INN system<br />has become urgent. This is reflected in the following extract from the<br />fifth report of the WHO Expert Committee on the Use of Essential<br />Drugs (7), which met in November 1991:<br />The procedure for selecting INNs allows manufacturers to contest names that<br />are either identical or similar to their licensed trademarks. In contrast,<br />trademark applications are disallowed, in accordance with the present<br />procedure, only when they are identical to an INN. A case for increased<br />protection of INNs is now apparent as a result of competitive promotion of<br />products no longer protected by patents. Rather than marketing these<br />products under the generic name, many companies apply for a trademark<br />derived from an INN and, in particular, including the INN common stem. This<br />practice endangers the principle that INNs are public property; it can frustrate<br />the rational selection of further INNs for related substances, and it will<br />ultimately compromise the safety of patients by promoting confusion in drug<br />nomenclature.<br />These concerns were debated during the Sixth International Confer-ence<br />of Drug Regulatory Authorities (ICDRA) in Ottawa in October<br />1991..191<br />On the basis of the recommendations made by the WHO Expert<br />Committee on the use of Essential Drugs, a resolution on nonpropri-etary<br />names for pharmaceuticals (WHA46.19) was adopted by the<br />World Health Assembly in 1993 (8). This requested Member States:<br />• to enact rules or regulations, as necessary, to ensure that international<br />nonproprietary names (or the equivalent nationally approved generic<br />names) used in the labelling and advertising of pharmaceutical products are<br />always displayed prominently;<br />• to encourage manufacturers to rely on their corporate name and the<br />international nonproprietary names, rather than on trademarks, to pro-mote<br />and market multisource products introduced after the expiry of a<br />patent;<br />• to develop policy guidelines on the use and protection of international<br />nonproprietary names, and to discourage the use of names derived from<br />them, and particularly names including established stems as trademarks.<br />Attention is drawn to this resolution concerning the use and protec-tion<br />of INNs in the note verbale.<br />As a matter of principle, it may thus be recommended that trade-marks<br />should not be derived from INNs. In particular, the intentional<br />incorporation of meaningful INN stems in trademarks should be<br />avoided.<br />Similarly, the inclusion of elements from biochemical nomenclature<br />(e.g. -feron from interferon, or -leukin from interleukin) in trade-marks<br />is discouraged since these elements are likely to be used as<br />stems within the INN nomenclature. Their inclusion in trademarks<br />could thus prevent the logical development of the INN nomenclature.<br />In accordance with resolution WHA46.19, the registration of an INN<br />together with a firm’s name is perfectly acceptable as long as it does<br />not prevent another manufacturer from adopting the same approach.<br />5. How to apply for an INN<br />5.1 Procedure for selection of INNs<br />The selection of INNs is based on the resolution on the procedure for<br />the selection of INNs for pharmaceutical substances (WHA3.11)<br />adopted by the World Health Assembly in 1950 (9), and subsequently<br />adopted and amended by the Executive Board in 1955 (10) and 1969<br />(11).<br />In countries with national nomenclature commissions, applications<br />for INNs can be made through these commissions. In countries<br />without a national nomenclature commission, requests for INNs may<br />be forwarded directly to WHO. Applications for INNs should be<br />addressed to:.192<br />Secretary of the INN Programme<br />Quality Assurance and Safety: Medicines<br />Essential Drugs and Medicines Policy<br />World Health Organization<br />20 avenue Appia<br />1211 Geneva 27<br />Switzerland<br />Tel: +41 22 791 0746<br />Fax: +41 22 791 3636/3660<br />5.2 INN request form<br />Before a suggested name can be evaluated by the INN Secretariat,<br />complete information must be provided on a request form to facilitate<br />handling of the data and to ensure that pertinent items have not been<br />omitted. It is important that the information is as comprehensive as<br />possible. If some of the information is missing or explanations are<br />unclear or incomplete, the INN Secretariat will request the applicant<br />to provide the missing data or further explanation. This can result in<br />delays, because an INN cannot be selected until all the relevant<br />information is available to the INN experts.<br />The following explanations will help applicants to complete the INN<br />form. If additional information is needed, an applicant can contact the<br />INN Secretariat at the above-mentioned address.<br />Suggested names in order of preference<br />An applicant can suggest three names for an INN relating to the acid,<br />base or alcohol of the chemical entity concerned. The suggested name<br />should be a single word and not inconveniently long.<br />Since a nonproprietary name is intended to show the group of phar-macologically<br />related substances to which the substance concerned<br />belongs, whenever justified, the suggested name must incorporate the<br />established common stem. A list of stems (12) is available on request<br />from Marketing and Dissemination<br />1<br />or the INN Secretariat.<br />Occasionally stems require modification. For example, some drugs<br />inhibit a -adrenoreceptors as well as b -adrenoreceptors and differ in<br />structure from the “-olol” prototype. Accordingly, for this type of<br />drug, one letter in the stem was changed to give “-alol”. The signifi-cance<br />of this change in the naming of related groups of drugs might<br />1<br />Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211<br />Geneva 27, Switzerland..193<br />not be apparent to everyone, but would be understood by someone<br />familiar with the naming conventions of the b -adrenoreceptor antago-nists<br />and related compounds.<br />It is imperative that the newly suggested name does not conflict with<br />existing chemical names, other nonproprietary names or trademarks.<br />The INN Secretariat therefore requests the applicant to verify the<br />absence of conflicts with existing chemical names, common names for<br />insecticides, other nonproprietary names and trademarks. Some firms<br />routinely perform exhaustive searches for possible conflicts with a<br />suggested INN and for pharmacologically and chemically related<br />compounds with already assigned INNs. It would be helpful if the<br />INN Secretariat could be informed when such searches have been<br />carried out and be given a summary of the results.<br />Chemical name and description<br />The chemical information provided on the request form should be<br />as complete and as up to date as possible. Information on stereo-chemistry<br />should be included, if known. The chemical names should<br />be in accordance with the IUPAC rules of nomenclature, as inter-preted<br />by the Chemical Abstracts Service (CAS) (8th collective<br />period); the Chemical Abstracts Index names in their current style<br />may also be included as additional information. The chemical name<br />provided by the manufacturer is reviewed for accuracy and to<br />confirm that its construction follows the accepted rules of chemical<br />nomenclature.<br />A description can be used to identify a substance that is insufficiently<br />defined to be assigned a IUPAC and CAS chemical name. This de-scription<br />will be superseded by the chemical name when the drug<br />substance has been fully characterized.<br />Precautions are taken to ensure confidentiality of the material sub-mitted<br />to WHO, but an applicant should not attempt to obtain an<br />INN before all patent procedures are completed and until full chemi-cal<br />information can be made available to WHO.<br />Graphic formula<br />Without a graphic formula, it may be difficult to determine whether<br />an INN already exists. In addition, a graphic formula is necessary to<br />relate the new drug to existing compounds in the same chemical<br />family. Guidelines for drawing structures are available on request<br />from the INN Secretariat (13).<br />Molecular formula<br />A one-line molecular formula constructed in accordance with<br />accepted chemical practices should be supplied, e.g. C21 H28 N2 ..194<br />CAS registry number<br />If a CAS registry number has been assigned to a new compound<br />before it is submitted to the INN Secretariat, the number should be<br />included on the request form. If no number has yet been assigned, the<br />manufacturer should obtain the CAS registry number from the<br />Chemical Abstracts Services for publication in the INN lists. Proof of<br />the entry will be required.<br />Trademarks (known or contemplated)<br />If a trademark has been issued for the drug, it should be entered on<br />the form. Any national or international trademarks (and manufactur-ers)<br />and the name of the country where the trademark is registered<br />should be listed.<br />Any other name or code<br />Sometimes, long before a nonproprietary name or a trademark has<br />been selected for a new compound, it may have acquired a trivial<br />name that has been used both in the laboratory and in the scientific<br />literature. The INN Secretariat would like to be made aware of such<br />names but requests manufacturers not to create, use or in any way<br />encourage the creation of trivial names for new drugs. The fact that a<br />trivial name has become accepted in the literature will not ensure its<br />adoption as a nonproprietary name and may only cause confusion<br />when an official nonproprietary name is selected. It is therefore rec-ommended<br />that codes should be used before a recommended nonpro-prietary<br />name is published, and that these should be indicated on the<br />request form sent to the INN Secretariat as an additional reference.<br />Principal therapeutic use(s) and posology<br />It is important to know the therapeutic category to which the new<br />compound belongs as such information may determine the stem se-lected<br />for the nonproprietary name. Reprints presenting evidence of<br />the claimed therapeutic use should be included with the application.<br />A list of terms for the pharmacological action and therapeutic use of<br />drugs is available from WHO in English, French and Spanish (14).<br />Pharmacological action<br />The pharmacological action should be explained in as much detail as<br />possible, since it may also influence the stem selected for the com-pound.<br />Again, reprints must be included to support the claimed action<br />(for terminology, see above).<br />Date of clinical trial<br />As a general guide, the development of a drug should have reached<br />the stage of phase II clinical trials before an application is submitted.195<br />to the INN Secretariat. The approximate date when clinical trials<br />began should be indicated as proof that such trials are under way. It<br />is the belief that if a drug has entered clinical trials, there is a reason-able<br />expectation that it will be marketed, and thus the name selected<br />will have been developed for that purpose. If, however, the develop-ment<br />of the drug is stopped, the manufacturer should inform the INN<br />Secretariat as soon as possible, in order to halt the selection process.<br />Availability of suggested names<br />The originator of the INN request should confirm with his or her<br />signature that the names are suggested on the understanding that, so<br />far as is known, none of them have been registered or are awaiting<br />registration.<br />Permission to publish the CAS registry number<br />The applicant must confirm that the CAS registry number sent to the<br />INN Secretariat is correct and may be used in the INN lists.<br />Additional comments<br />This section allows the applicant to make additional comments and/or<br />provide further information.<br />References<br />1. Nonproprietary names for pharmaceutical substances. Twentieth report of<br />the WHO Expert Committee. Geneva, World Health Organization, 1975<br />(WHO Technical Report Series, No. 581).<br />2. INNs: names for radicals and groups, combined summary list.<br />1<br />Geneva,<br />World Health Organization (unpublished document WHO/PHARM S/<br />NOM1506; available from INN Secretariat, Essential Drugs and Medicines<br />Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />3. International nonproprietary names (INN) for pharmaceutical substances.<br />Cumulative list no. 9. Geneva World Health Organization, 1996.<br />4. Convention on Psychotropic Substances, 1971. Vienna, United Nations,<br />1978.<br />5. List of narcotic drugs under international control, 41st ed. Vienna, United<br />Nations, 1999.<br />6. Definition of INNs for substances prepared by biotechnology.<br />1<br />Geneva,<br />World Health Organization (unpublished document WHO/PHARM S/<br />NOM1348; available from INN Secretariat, Essential Drugs and Medicines<br />Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />7. The use of essential drugs. Fifth report of the WHO Expert Committee.<br />Geneva, World Health Organization, 1992 (WHO Technical Report Series,<br />No. 825).<br />1<br />Updated regularly..196<br />8. Nonproprietary names for pharmaceutical substances. In: Forty-sixth World<br />Health Assembly, Geneva, 3–14 May 1993. Volume 1. Resolutions and<br />decisions, annexes. Geneva, World Health Organization, 1993 (unpublished<br />document WHA46/1993/REC/1):20–21.<br />9. Nonproprietary names for pharmaceutical substances. In: Handbook of<br />resolutions and decisions of the World Health Assembly and the Executive<br />Board. Volume I, 1948–1972. Geneva, World Health Organization, 1973:128.<br />10. EB15.R1. In: Handbook of resolutions and decisions of the World Health<br />Assembly and the Executive Board. Volume I, 1948–1972. Geneva, World<br />Health Organization, 1973:129.<br />11. EB43.R9. In: Handbook of resolutions and decisions of the World Health<br />Assembly and the Executive Board. Volume I, 1948–1972. Geneva, World<br />Health Organization, 1973:130.<br />12. The use of common stems in the selection of international nonproprietary<br />names (INNs) for pharmaceutical substances. Geneva, World Health<br />Organization (unpublished document updated annually; available from INN<br />Secretariat, Essential Drugs and Medicines Policy, World Health<br />Organization, 1211 Geneva 27, Switzerland).<br />13. The graphic representation of chemical formulae in the publications of<br />international nonproprietary names (INNs) for pharmaceutical substances.<br />Geneva, World Health Organization, 1995 (unpublished document WHO/<br />PHARM/95.579; available from INN Secretariat, Essential Drugs and<br />Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).<br />14. Pharmacological action and therapeutic use of drugs: a list of terms.<br />Geneva, World Health Organization, 1996 (unpublished document WHO/<br />PHARM/96.320; available from Essential Drugs and Medicines Policy, World<br />Health Organization, 1211 Geneva 27, Switzerland)..197<br />Appendix 1<br />List of common stems used in the selection<br />of INNs<br />Stem<br />a<br />Substem, Definition<br />if available<br />-abine see -arabine, -citabine<br />-ac anti-inflammatory agents, ibufenac derivatives<br />-acetam see -racetam<br />-actide synthetic polypeptides with corticotropin-like<br />action<br />-adol or -adol- analgesics<br />-adom analgesics, tifluadom derivatives<br />-afenone antiarrhythmics, propafenone derivatives<br />-aj- antiarrhythmics, ajmaline derivatives<br />-aldrate antacids, aluminium salts<br />-alol see -olol<br />-alox see -ox<br />-amab see -mab<br />-amivir see vir<br />andr steroids, androgens ( see also -stan- or -ster-)<br />-anide<br />-etanide diuretics, piretanide derivatives<br />-oxanide antiparasitic, salicylanilides and analogues<br />-anserin serotonin receptor antagonists (mostly 5-HT2 )<br />-antel anthelminthics (undefined group)<br />-apine see -pin(e)<br />-a(ra)bine arabinofuranosyl derivatives<br />-arit antiarthritic substances, with a similar<br />mechanism of action to clobuzarit and<br />lobenzarit (mechanism different from anti-inflammatory-<br />type substances, e.g.<br />-fenamates or -profens)<br />-arol anticoagulants, dicoumarol derivatives<br />-arone antiarrhythmics, calcium channel blockers,<br />uricosurics<br />-arte- antimalarial agents, artemisinin-related<br />compounds<br />-ase enzymes:<br />-diplase — plasminogen activator combined with<br />another enzyme<br />-dismase — with superoxide dismutase activity<br />-lipase — with lipase activity<br />-teplase — tissue-type plasminogen activators<br />-uplase — urokinase-type plasminogen activators<br />-ast antiasthmatics, antiallergics, not acting<br />primarily as antihistamines:<br />-lukast — leukotriene receptor antagonists ( see also<br />-lubant).198<br />Stem<br />a<br />Substem, Definition<br />if available<br />-trodast — thromboxane A2 receptor antagonists,<br />antiasthmatics<br />-asteride see -ster<br />-astine antihistamines<br />-azam see -azepam<br />-azenil benzodiazepine receptor antagonists/agonists<br />(benzodiazepine derivatives):<br />-carnil — benzodiazepine receptor antagonists/<br />agonists (carboline derivatives)<br />-quinil — benzodiazepine receptor partial agonists<br />(quinoline derivatives)<br />-azepam diazepam derivatives<br />-azepide cholecystokinin receptor antagonists<br />-azocine narcotic antagonists/agonists related to<br />6,7-benzomorphan<br />-azolam see -azepam<br />-azoline antihistamines or local vasoconstrictors,<br />antazoline derivatives<br />-azone see -buzone<br />-azosin antihypertensive substances, prazosin<br />derivatives<br />-bactam b -lactamase inhibitors<br />-bamate tranquillizers, propanediol and pentanediol<br />derivatives<br />barb hypnotics, barbituric acid derivatives<br />-benakin see -kin<br />-bendan see -dan<br />-bendazole anthelminthics, tiabendazole derivatives<br />-betasol see pred<br />bol anabolic steroids<br />-bradine bradycardic agents<br />-brate see -fibrate<br />-butazone see -buzone<br />-buzone anti-inflammatory analgesics, phenylbutazone<br />derivatives<br />-cain- class I antiarrhythmics, procainamide and<br />lidocaine derivatives (antifibrillants with local<br />anaesthetic activity)<br />-caine local anaesthetics<br />calci vitamin D analogues/derivatives<br />-carbef antibiotics, carbacephem derivatives<br />-carnil see -azenil<br />-castat see -stat<br />-cavir see vir<br />cef- antibiotics, cefalosporanic acid derivatives:<br />-oxef — antibiotics, oxacefalosporanic acid<br />derivatives<br />cell-, -cell- or cellulose derivatives:<br />cel-.199<br />Stem<br />a<br />Substem, Definition<br />if available<br />cell-ate — cellulose ester derivatives for substances<br />containing acidic residues<br />-cellose — cellulose ether derivatives<br />cell-ate see cell--<br />cellose see cell--<br />cic hepatoprotective substances with a carboxylic<br />acid group<br />-cidin naturally occurring antibiotics (undefined<br />group)<br />-cillide see -cillin<br />-cillin antibiotics, 6-aminopenicillanic acid derivatives<br />-cillinam see -cillin<br />-cilpine see -pin(e)<br />-cisteine see -steine<br />-citabine nucleoside antiviral or antineoplastic agents,<br />cytarabine or azarabine derivatives<br />-clone hypnotic tranquillizers<br />-cog blood coagulation factors:<br />(-)eptacog — blood coagulation factor VII<br />(-)nonacog — blood coagulation factor IX<br />(-)octacog — blood coagulation factor VIII<br />-conazole systemic antifungal agents, miconazole<br />derivatives<br />cort corticosteroids, except prednisolone derivatives<br />-crinat diuretics, etacrynic acid derivatives<br />-crine acridine derivatives<br />-cromil antiallergics, cromoglicic acid derivatives<br />-curium see -ium<br />-cycline antibiotics, tetracycline derivatives<br />-dan cardiac stimulants, pimobendan derivatives<br />-dapsone antimycobacterials, diaminodiphenylsulfone<br />derivatives<br />-decakin see -kin<br />-dermin see -ermin<br />-dil vasodilators<br />-dilol see -dil<br />-dipine calcium channel blockers, nifedipine derivatives<br />-dismase see -ase<br />-distim see -stim<br />-dodekin see -kin<br />-dopa dopamine receptor agonists, dopamine<br />derivatives, used as antiparkinsonism<br />drugs/prolactin inhibitors:<br />-opamine — dopaminergic agents, dopamine derivatives<br />used as cardiac stimulants/antihypertensives/<br />diuretics<br />-dox see -ox<br />-dralazine antihypertensives, hydrazinephthalazine<br />derivatives.200<br />Stem<br />a<br />Substem, Definition<br />if available<br />-drine sympathomimetics:<br />-frine — phenethyl derivatives<br />-dronic acid calcium metabolism regulator, pharmaceutical<br />adjunct<br />-dutant see -tant<br />-dyl see -dil<br />-ectin antiparasitics, ivermectin derivatives<br />-elestat see -stat<br />-elvekin see -kin<br />-emab see -mab<br />-entan endothelin receptor antagonists<br />-eptacog see -cog<br />erg ergot alkaloid derivatives<br />-eridine analgesics, pethidine derivatives<br />-ermin growth factors:<br />-dermin — epidermal growth factors<br />-fermin — fibrinoblast growth factors<br />-filermin — leukaemia-inhibiting factor<br />-nermin — tumour necrosis factor<br />-plermin — platelet-derived growth factor<br />-sermin — insulin-like growth factors<br />-termin — transforming growth factor<br />estr- estrogens<br />-etanide see -anide<br />-ethidine see -eridine<br />-exakin see -kin<br />-exine mucolytic, bromhexine derivatives<br />-fenamic acid anti-inflammatory, anthranilic acid derivatives<br />-fenamate — fenamic acid derivatives<br />-fenin diagnostic aids, (phenylcarbamoyl)methyl<br />iminodiacetic acid derivatives<br />-fenine analgesics, glafenine derivatives (subgroup of<br />-fenamic acid group)<br />-fentanil narcotic analgesics, fentanyl derivatives<br />-fermin see -ermin<br />-fiban fibrinogen receptor antagonists (glycoprotein<br />IIb/IIIa receptor antagonists)<br />-fibrate clofibrate derivatives<br />-filermin see -ermin<br />-flapon 5-lipoxygenase-activating protein (FLAP)<br />inhibitor<br />-flurane halogenated compounds used as general<br />inhalation anaesthetics<br />-formin antihyperglycaemics, phenformin derivatives<br />-fos, -fos- or fos- insecticides, anthelminthics, pesticides, etc.,<br />phosphorus derivatives<br />-fradil calcium channel blockers acting as vasodilators<br />-frine see -drine<br />-fungin antifungal antibiotics.201<br />Stem<br />a<br />Substem, Definition<br />if available<br />-fylline N-methylated xanthine derivatives<br />gab gabamimetic agents<br />gado- diagnostic agents, gadolinium derivatives<br />-gatran thrombin inhibitors, antithrombotic agents<br />gest steroids, progestogens<br />-gesterone see -ster<br />-giline monoamine oxidase inhibitors, type B<br />-gillin antibiotics produced by Aspergillus spp.<br />gli antihyperglycaemics, sulfonamide derivatives<br />-golide dopamine receptor agonists, ergoline<br />derivatives<br />-gosivir see vir<br />-gramostim see -stim<br />-grastim see -stim<br />-grel- or -grel platelet aggregation inhibitors<br />guan- antihypertensives, guanidine derivatives<br />-ibine see -ribine<br />-icam anti-inflammatory, isoxicam derivatives<br />-ifene antiestrogens, clomifene and tamoxifen<br />derivatives<br />-igetide see -tide<br />-ilide class III antiarrhythmics, sematilide derivatives<br />-imab see -mab<br />imex immunostimulants<br />-imod immunomodulators, both stimulant/suppressive<br />and stimulant<br />-imus immunosuppressants (other than<br />antineoplastics)<br />-ine alkaloids and organic bases<br />io- iodine-containing contrast media<br />-io- or iod- iodine-containing compounds other than<br />contrast media<br />-iptan serotonin (5HT1 ) receptor agonists, sumatriptan<br />derivatives<br />-irudin hirudin derivatives<br />-isomide antiarrhythmics, disopyramide derivatives<br />-ium quaternary ammonium compounds:<br />-curium — curare-like substances<br />-izine diphenylmethyl piperazine derivatives:<br />-rizine — antihistamines/cerebral (or peripheral)<br />vasodilators<br />-kacin antibiotics, kanamycin and bekanamycin<br />derivatives (obtained from Streptomyces<br />kanamyceticus)<br />-kalant potassium channel blockers<br />-kalim potassium channel activators, antihypertensive<br />-kef- enkephalin agonists<br />-kin interleukin (IL)-type substances ( see also -stim):<br />-benakin — IL-1 analogues and derivatives.202<br />Stem<br />a<br />Substem, Definition<br />if available<br />-decakin — IL-10 analogues and derivatives<br />-dodekin — IL-12 analogues and derivatives<br />-elvekin — IL-11 analogues and derivatives<br />-exakin — IL-6 analogues and derivatives<br />-kinra — IL receptor antagonists<br />-leukin — IL-2 analogues and derivatives<br />-nakin — IL-1 analogues and derivatives<br />-nakinra — IL-1 receptor antagonists<br />-octakin — IL-8 analogues and derivatives<br />-onakin — IL-1 analogues and derivatives<br />-trakin — Il-4 analogues and derivatives<br />-kinra see -kin<br />-kiren renin inhibitors<br />-leukin see -kin<br />-listat see -stat<br />-lubant leukotriene B4 receptor antagonist ( see also -ast)<br />-lukast see -ast<br />-mab monoclonal antibodies:<br />-amab — of rat origin<br />-emab — of hamster origin<br />-imab — of primate origin<br />-omab — of mouse origin<br />-umab — of human origin<br />-ximab — of chimeric origin<br />-zumab — of humanized origin<br />-mantadine, adamantane derivatives<br />-mantine or<br />-mantone<br />-meline cholinergic agents, muscarinic receptor<br />agonists/partial antagonists used in the<br />treatment of Alzheimer disease<br />-mer polymers<br />-mesine sigma receptor ligands<br />-mestane aromatase inhibitors<br />-metacin anti-inflammatory, indometacin derivatives<br />-met(h)asone see pred<br />-micin antibiotics obtained from various<br />Micromonospora spp.<br />-mifene see -ifene<br />-monam monobactam antibiotics<br />-morelin see -relin<br />-mostim see -stim<br />-motine antivirals, quinoline derivatives<br />-moxin monoamine oxidase inhibitors, hydrazine<br />derivatives<br />-mustine antineoplastic, alkylating agents, (-chloroethyl)<br />amine derivatives<br />-mycin antibiotics obtained from various Streptomyces<br />spp. ( see also -kacin).203<br />Stem<br />a<br />Substem, Definition<br />if available<br />nab cannabinol derivatives<br />-nakin see -kin<br />-nakinra see -kin<br />nal- narcotic antagonists/agonists related to<br />normorphine<br />-naritide see -tide<br />-navir see vir<br />-nercept tumour necrosis factor antagonist<br />-nermin see -ermin<br />-netant see -tant<br />-nicate see nico-nico-,<br />nic- or ni- nicotinic acid or nicotinoyl alcohol derivatives:<br />-nicate — antihypercholesterolaemic and/or<br />vasodilating nicotinic acid esters<br />-nidazole antiprotozoals, metronidazole derivatives<br />-nidine see -onidine<br />nifur- 5-nitrofuran derivatives<br />-nil see -azenil<br />nitro-, nitr-, nit-, NO2 -derivatives<br />ni- or -ni--<br />nixin anti-inflammatory, anilinonicotinic acid<br />derivatives<br />-nonacog see -cog<br />-octacog see -cog<br />-octakin see -kin<br />-olol b -adrenoreceptor antagonists:<br />-alol — aromatic ring –CHOH–CH2 –NH–R related to<br />-olols<br />-olone see pred<br />-omab see -mab<br />-onakin see -kin<br />-one ketones<br />-onide steroids for topical use, acetal derivatives<br />-onidine antihypertensives, clonidine derivatives<br />-onium see -ium<br />-opamine see -dopa<br />-orex anorectics<br />-orph- see orphan<br />orphan narcotic antagonists/agonists, morphinan<br />derivatives<br />-ox antacids, aluminium derivatives:<br />-pirox — antimycotic pyridone derivatives<br />-xanox — antiallergics, tixanox group<br />-oxacin antibacterials, nalidixic acid derivatives<br />-oxan(e) benzodioxane derivatives<br />-oxanide see -anide<br />-oxef see cef--<br />oxepine see -pine<br />-oxetine antidepressants, fluoxetine derivatives.204<br />Stem<br />a<br />Substem, Definition<br />if available<br />-oxicam see -icam<br />-oxifene see -ifene<br />-oxopine see -pine<br />-pafant platelet-activating factor antagonists<br />-pamide diuretics, sulfamoylbenzoic acid derivatives<br />-pamil coronary vasodilators, verapamil derivatives<br />-parcin glycopeptide antibiotics<br />-parin heparin derivatives including those of low<br />relative molecular mass:<br />-parinux — synthetic heparinoids<br />-parinux see -parin<br />-pase see -ase<br />-pendyl see -dil<br />-penem analogues of penicillanic acid antibiotics<br />modified in the five-membered ring<br />perfl(u)- perfluorinated compounds used as blood<br />substrates and/or diagnostic agents<br />-peridol see -perone<br />-peridone see -perone<br />-perone tranquillizers, neuroleptics, 4¼ñêô-fluoro-4-<br />piperidinobutyrophenone derivatives:<br />-peridol — antipsychotics, haloperidol derivatives<br />-peridone — antipsychotics, risperidone derivatives<br />-phenine see -fenine<br />-pidem hypnotics/sedatives, zolpidem derivatives<br />-pin(e) tricyclic compounds:<br />-apine — psychoactive<br />-cilpine — antiepileptic<br />-zepine — antidepressant/neuroleptic<br />-piprazole see -prazole<br />-pirone see -spirone<br />-pirox see -ox<br />-pitant see -tant<br />-plact platelet factor 4 analogues and derivatives<br />-planin antibacterials obtained from various<br />Actinoplanes spp.<br />-plase see -ase<br />-platin antineoplastic agents, platinum derivatives<br />-plermin see -ermin<br />-plestim see -stim<br />-plon pyrazolo[.]pyrimidine derivatives, used as<br />anxiolytics, sedatives, hypnotics<br />-poetin erythropoietin-type blood factors<br />-porfin benzoporphyrin derivatives<br />-poride Na + /H + antiport inhibitor<br />-pramine substances of the imipramine group<br />-prazole antiulcer, benzimidazole derivatives:<br />-piprazole — psychotropics, phenylpiperazine derivatives<br />pred prednisone and prednisolone derivatives:.205<br />Stem<br />a<br />Substem, Definition<br />if available<br />-olone — steroids other than prednisolone derivatives<br />-prenaline see -terol<br />-pressin vasoconstrictors, vasopressin derivatives<br />-pride sulpiride derivatives<br />-pril(at) angiotensin-converting enzyme inhibitors<br />-prim antibacterials, trimethoprim derivatives<br />-profen anti-inflammatory agents, ibuprofen derivatives<br />prost prostaglandins:<br />-prostil — anti-ulcer<br />-prostil see prost<br />-quinil see -azenil<br />-racetam amide-type nootrope agents, piracetam<br />derivatives<br />-relin prehormones or hormone release-stimulating<br />peptides:<br />-morelin — growth hormone release-stimulating<br />peptides<br />-tirelin — thyrotropin-releasing hormone analogues<br />-relix hormone release-inhibiting peptides<br />-renone aldosterone antagonists, spironolactone<br />derivatives<br />-restat or -restat- see -stat<br />retin retinol derivatives<br />-ribine ribofuranyl derivatives of the “pyrazofurin” type<br />rifa- antibiotics, rifamycin derivatives<br />-rinone cardiac stimulants, amrinone derivatives<br />-rizine see -izine<br />-rozole aromatase inhibitors, imidazole–triazole<br />derivatives<br />-rubicin antineoplastic antibiotics, daunorubicin<br />derivatives<br />sal-, -sal or -sal- analgesic, anti-inflammatory salicylic acid<br />derivatives:<br />-salan — brominated salicylamide derivatives,<br />disinfectant<br />-salazo — phenylazosalicylic acid derivatives,<br />antibacterial<br />-salan see sal--<br />salazine or see sal--<br />salazide<br />-salazo see sal--<br />sartan angiotensin II receptor antagonists,<br />antihypertensive (non-peptidic)<br />-semide diuretics, furosemide derivatives<br />-sermin see -ermin<br />-serpine derivatives of Rauwolfia alkaloids<br />-setron serotonin receptor antagonists (5-HT3 ) not<br />fitting into other established groups of<br />serotonin receptor antagonists.206<br />Stem<br />a<br />Substem, Definition<br />if available<br />som- growth hormone derivatives<br />-sopine see -pin(e)<br />-spirone anxiolytics, buspirone derivatives<br />-stat or -stat- enzyme inhibitors:<br />-castat — dopamine b -hydroxylase inhibitors<br />-elestat — elastase inhibitors<br />-listat — pancreatic lipase inhibitors<br />-mastat — matrix metalloproteinase inhibitors<br />-restat or -restat- — aldose reductase inhibitors<br />-vastatin — antilipidaemic substances, HMG CoA<br />reductase inhibitors<br />-steine mucolytics, other than bromhexine derivatives<br />-ster- androgens/anabolic steroids:<br />-(a)steride — antineoplastics<br />-stigmine acetylcholinesterase inhibitors<br />-stim colony-stimulating factors:<br />-distim — combination of two different types of<br />colony-stimulating factor<br />-gramostim — granulocyte macrophage colony-stimulating<br />factor (GM-CSF)-type substances<br />-grastim — granulocyte colony-stimulating factor<br />(G-CSF)-type substances<br />-mostim — macrophage colony-stimulating factor<br />(M-CSF)-type substances<br />-plestim — IL-3 analogues and derivatives<br />sulfa- anti-infectives, sulfonamides<br />-sulfan antineoplastics, alkylating agents,<br />methanesulfonates<br />-tant neurokinin (tachykinin) receptor antagonists:<br />-dutant — neurokinin NK2 receptor antagonist<br />-netant — neurokinin NK3 receptor antagonist<br />-pitant — neurokinin NK1 (substance P) receptor<br />antagonist<br />-tecan antineoplastics, topoisomerase I inhibitors<br />-tepa antineoplastics, thiotepa derivatives<br />-tepine see -pin(e)<br />-teplase see -ase<br />-terenol see -terol<br />-termin see -ermin<br />-terol bronchodilators, phenylethylamine derivatives<br />-terone antiandrogens<br />-tiazem calcium channel blockers, diltiazem derivatives<br />-tide peptides and glycopeptides (for specific groups<br />of peptides, see -actide, -pressin, -relin and<br />-tocin)<br />-tidine histamine H2 receptor antagonists, cimetidine<br />derivatives<br />-tiline see -triptyline<br />-tirelin see -relin.207<br />Stem<br />a<br />Substem, Definition<br />if available<br />-tizide diuretics, chlorothiazide derivatives<br />-tocin oxytocin derivatives<br />-toin antiepileptics, hydrantoin derivatives<br />-trakin see -kin<br />-trexate folic acid analogues<br />-tricin antibiotics, polyene derivatives<br />-triptan serotonin (5HT1 ) receptor agonists, sumatriptan<br />derivatives<br />-triptyline antidepressants, dibenzo[ a, d]cycloheptane or<br />cycloheptene derivatives<br />-troban thromboxane A2 receptor antagonists,<br />antithrombotic agents<br />-trodast see -ast<br />trop atropine derivatives<br />-umab see -mab<br />-uplase see -ase<br />-ur see -uridine<br />-uracil uracil derivatives used as thyroid antagonists<br />and as antineoplastics<br />-uridine uridine derivatives used as antiviral agents and<br />as antineoplastics:<br />-vudine — zidovudine-type antivirals and<br />antineoplastics<br />-vastatin see -stat<br />-verine spasmolytics with a papaverine-like action<br />vin- or -vin- vinca alkaloids<br />vir antivirals (undefined group):<br />-amivir — neuraminidase inhibitors<br />-cavir — carbocyclic nucleosides<br />-gosivir — glucoside inhibitors<br />-navir — HIV protease inhibitors<br />-virsen antisense oligonucleotides<br />-vos see -fos<br />-vudine see -uridine<br />-xanox see -ox<br />-ximab see -mab<br />-yzine see -izine<br />-zafone alozafone derivatives<br />-zepine see -pin(e)<br />-zone see -buzone<br />-zumab see -mab<br />a<br />The hyphens indicate the position of the stem (prefix, infix or suffix) within the INN. If the<br />hyphen is absent, the stem may be used in any position within the name..208<br />Appendix 2<br />Common stems that have been discontinued<br />Stem<br />a<br />Definition<br />-al(d) aldehydes (deleted from General Principles in 14th report of the<br />WHO Subcommittee on Nonproprietary Names (1968))<br />mer- or -mer- mercury-containing drugs, antimicrobial or diuretic (deleted from<br />General Principles in List 28 of proposed INNs)<br />mito- antineoplastics, nucleotoxic agents (deleted from General Principles<br />in List 24 of proposed INNs)<br />-ol alcohols and phenols (deleted from General Principles in 14th report<br />of the WHO Subcommittee on Nonproprietary Names (1968))<br />-quine or quin quinoline derivatives (deleted from General Principles in List 28 of<br />proposed INNs)<br />a<br />The hyphens indicate the position of the stem (prefix, infix or suffix) within the INN. If the<br />hyphen is absent, the stem may be used in any position within the name..i<br />Further information on these and other WHO publications can be obtained from<br />Marketing and Dissemination, World Health Organization, 1211 Geneva 27, Switzerland<br />S E L E C T E D WHO P U B L I C A T I O N S OF R E L A T E D I N T E R E S T<br />The international pharmacopoeia, third edition.<br />Volume 1: general methods of analysis. 1979 (223 pages)<br />Volume 2: quality specifications. 1981 (342 pages)<br />Volume 3: quality specifications. 1988 (407 pages)<br />Volume 4: tests, methods, and general requirements: quality specifications for<br />pharmaceutical substances, excipients and dosage forms. 1994 (358 pages)<br />Basic tests for drugs: pharmaceutical substances, medicinal plant materials and<br />dosage forms.<br />1998 (94 pages)<br />Basic tests for pharmaceutical dosage forms.<br />1991 (134 pages)<br />Quality assurance of pharmaceuticals: a compendium of guidelines and related<br />materials.<br />Volume 1: 1997 (244 pages)<br />Volume 2: good manufacturing practices and inspection. 1999 (201 pages)<br />Quality control methods for medicinal plant materials.<br />1998 (123 pages)<br />WHO Expert Committee on Specifications for Pharmaceutical Preparations.<br />Thirty-fifth report.<br />WHO Technical Report Series, No. 885, 1999 (162 pages)<br />International nonproprietary names (INN) for pharmaceutical substances.<br />Cumulative list no. 9.<br />1996 (898 pages)<br />The use of essential drugs.<br />Ninth report of the WHO Expert Committee (including the revised Model<br />List of Essential Drugs).<br />WHO Technical Report Series, No. 895, 2000 (66 pages)<br />WHO Expert Committee on Biological Standardization.<br />Forty-eighth report.<br />WHO Technical Report Series, No. 889, 1999 (117 pages).ii<br />ISBN 92 4 120902 X<br />This report presents the recommendations of an international<br />group of experts convened by the World Health Organization to<br />consider matters concerning the quality assurance of pharma-ceuticals<br />and specifications for drug substances and dosage<br />forms. Of particular relevance to drug regulatory authorities and<br />pharmaceutical manufacturers, the report discusses activities<br />related to the development of The international pharmacopoeia<br />and basic tests for pharmaceutical substances and dosage<br />forms, as well as quality control of reference materials, good<br />manufacturing practices (GMP), packaging and other aspects of<br />quality assurance of pharmaceuticals, nomenclature and regula-tory<br />issues.<br />The report is complemented by numerous annexes, including<br />lists of available International Chemical Reference Substances<br />and International Infrared Reference Spectra, considerations for<br />requesting analysis of drug samples, guidelines on pre-approval<br />inspections of pharmaceutical manufacturers, and guidelines for<br />packaging of pharmaceutical products. Guidance is provided on<br />the basic elements of GMP and the requirements for sterile<br />products and for national GMP inspectorates of pharmaceutical<br />manufacturers. The final annexes provide guidance on the<br />selection of comparator pharmaceutical products for equiva-lence<br />assessment of interchangeable multisource (generic)<br />products and the use of International Nonproprietary Names<br />(INNs).pharmaceuticalformulationhttp://www.blogger.com/profile/15915251551551692435noreply@blogger.com1