Monday, April 14, 2008

WHO EXPERT COMMITTEE
ON SPECIFICATIONS FOR
PHARMACEUTICAL PREPARATIONS





Contents
1. Introduction 1
2. Quality control — specifications and tests 2
2.1 The international pharmacopoeia — 50 years on 2
2.2 Monographs for The international pharmacopoeia 3
2.3 Dissolution test requirements for individual monographs 3
2.4 Basic tests for pharmaceutical substances and dosage forms 3
3. Quality control — reference materials 4
3.1 International Chemical Reference Substances 4
3.2 International Infrared Reference Spectra 4
3.3 Biological reference materials 5
3.4 Information on reference materials for pharmacopoeial analysis 5
4. Quality control — pharmaceutical control laboratories 5
4.1 Good practices for national pharmaceutical control laboratories 5
4.2 Equipment for drug control laboratories 6
4.3 Requests for analysis of drug samples 6
4.4 External quality assessment 6
5. Quality assurance — good manufacturing practices 6
5.1 Good manufacturing practices in pharmaceutical production 6
5.2 Good manufacturing practices for sterile pharmaceutical
products 7
5.3 Guidelines for good storage practices 7
5.4 Hazard analysis and critical control point system 7
6. Quality assurance — inspection 7
6.1 Pre-approval inspections 7
6.2 Quality systems for national GMP inspectorates 8
7. Quality assurance — packaging 8
7.1 General aspects of packaging 8
7.2 Glass containers for pharmaceutical use and rubber closures
for containers of pharmaceuticals 8
8. Quality assurance — general topics 8
8.1 Starting materials for pharmaceutical products: control and
safe trade 8
8.2 Model certificate of analysis for use in trade and procurement 9
8.3 Screening tests for antimalarials and antituberculosis drugs 9
8.4 Tuberculosis programme — fixed-dose combinations 9
8.5 Comparator products for equivalence assessment of
interchangeable multisource (generic) products 10
8.6 Measures to combat counterfeit drugs 10
8.7 Information on general publications 11
9. Nomenclature and computerized systems 11
9.1 International Nonproprietary Names for pharmaceutical
substances 11.iv
9.2 Regulatory information systems 12
9.3 Drug quality assurance terminology 12
10. Regulatory issues 12
10.1 Harmonization of regulatory requirements 12
Acknowledgements 13
References 15
Annex 1
List of available International Chemical Reference Substances 18
Annex 2
List of available International Infrared Reference Spectra 25
Annex 3
Good practices for national pharmaceutical control laboratories 27
Annex 4
Considerations for requesting analysis of drug samples 69
Annex 5
Basic elements of good manufacturing practices in pharmaceutical
production 73
Annex 6
Good manufacturing practices for sterile products 76
Annex 7
Guidelines on pre-approval inspections 94
Annex 8
Quality systems requirements for national good manufacturing practice
inspectorates 101
Annex 9
Guidelines on packaging for pharmaceutical products 119
Annex 10
Model certificate of analysis 157
Annex 11
Guidance on the selection of comparator pharmaceutical products for
equivalence assessment of interchangeable multisource (generic) products 161
Annex 12
Guidelines on the use of International Nonproprietary Names (INNs) for
pharmaceutical substances 181.v

1. Introduction
The WHO Expert Committee on Specifications for Pharmaceutical
Preparations met in Geneva from 31 May to 4 June 1999. The meeting
was opened on behalf of the Director-General by Dr M. Scholtz,
Executive Director of Health Technology and Pharmaceuticals, who
stressed that it was of the utmost importance that WHO should vigor-ously
maintain and strengthen its constitutional responsibility for
setting clear and practical norms if it was to meet the needs and
expectations of its 191 Member States. Essential drugs were recog-nized
as a high priority, but WHO also needed to maintain all its
activities concerned with drugs, including innovative products. A cru-cial
part of the quality assurance programme was the network of 13
WHO collaborating centres, whose activities included the verifica-tion
of test methods, the establishment of reference materials, and
training. During the World Health Assembly in May 1999, concern
had been expressed about persistent problems in ensuring the quality
of medicines and their starting materials. Member States were urged
to establish and enforce regulations to ensure quality assurance of
pharmaceuticals, and WHO was called on to extend guidelines in-corporated
in the WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International Commerce (1) to
cover pharmaceutical starting materials. WHO was also called on to
develop further training tools for inspectors to ensure compliance
with good manufacturing practices (GMP) published by WHO.
Dr Scholtz also emphasized the importance of the links between the
setting and the implementation of normative standards, and urged
the Expert Committee to keep those links in mind throughout its
discussions.
The Ninth International Conference of Drug Regulatory Authorities
(ICDRA), held in Berlin in April 1999, had reviewed progress made
in the international harmonization of regulatory requirements, and
the collaboration between WHO and the International Conference
on Harmonisation (ICH). WHO’s role was to ensure that the advan-tages
of harmonization were of benefit to all concerned (as endorsed
by the World Health Assembly in resolution WHA45.28; 2).
Dr J.D. Quick, Director, Essential Drugs and other Medicines,
briefed the Committee on the new headquarters structure of WHO,
and outlined new challenges for WHO in the area of pharmaceuticals
and biologicals. These included, inter alia, increased internationaliza-tion
of the trade in, and production of, starting materials, intermedi-ates
and finished products. A matter of serious concern was that drugs.2
of poor quality that were ineffective and harmful remained on sale.
Only one-sixth of the 191 WHO Member States had well-developed
capacities for drug regulation. WHO’s strategies to meet these chal-lenges
included the provision of global guidance by means of interna-tionally
applicable norms and standards, and the strengthening of
national drug regulation (through, for example, guidelines, manuals
and training on GMP, laboratory practices, inspection and registra-tion).
WHO facilitated communication and information exchange
through newsletters and bodies such as the Association of South-East
Asian Nations (ASEAN) and the African Drug Regulatory Authori-ties
Network (AFDRAN), and provided a forum for regulators.
Dr J. Idänpään-Heikkilä, Special Adviser on Quality Assurance and
Safety within Health Technology and Pharmaceuticals, informed the
Committee of the progress made in drug quality assurance since its
last meeting. Because of the concern that exists regarding the control
of starting materials, a meeting was held in 1998 at which proposals
were made for a model certificate of analysis, and for expansion of the
WHO Certification Scheme on the Quality of Pharmaceutical Prod-ucts
Moving in International Commerce to include starting materials,
as well as brokers and traders in such materials (3). Efforts to enhance
the implementation of GMP and to create an awareness of the need
to produce good quality products, as well as the preparation of train-ing
modules for GMP inspectors, were also proposed.
A list of international comparator products, together with guidance
on how best to choose such a product for the purpose of assessing
interchangeability, had been drafted in collaboration with drug regu-latory
authorities and the pharmaceutical industry. This list was pre-sented
to the Committee, which was asked to consider its adoption.
Collaboration with the World Intellectual Property Organization
(WIPO) for the protection of International Nonproprietary Names
(INNs) had also been strengthened. The Committee was further in-formed
that WHO retained its observer status in ICH and continued
its role in ICDRA.
2. Quality control — specifications and tests
2.1 The international pharmacopoeia — 50 years on
The Committee confirmed that publication of The international phar-macopoeia
(4) continued to fulfil a need in developing countries by
providing less technically advanced tests for specific substances and
preparations. The usefulness of monographs for finished products was
also confirmed..3
The Committee discussed the merits of introducing modern analytical
techniques. It was recognized that such new techniques could some-times
be more sensitive, rapid and robust, as well as potentially less
expensive. However, there was still a need for less advanced methods.
It was proposed that information on both types of methods might
be provided in parallel, with the newer techniques indicated as the
first choice and the less advanced methods as alternatives. Thus,
where resources permitted, the more technically advanced methods
should be used. However, the possibility of using the less advanced
alternative methods to check compliance with pharmacopoeial
specifications, where necessary, would increase the usefulness of The
international pharmacopoeia. In making these proposals, the Com-mittee
emphasized the importance of compliance with pharmacopoe-ial
requirements as part of the overall strategy for detecting
counterfeit and substandard products (5). The introduction of alter-native
methods would require careful presentation, and it was recom-mended
that a statement should be inserted in Volume 5 of The
international pharmacopoeia to introduce the concept, together with
the use of appropriate headings. This would reiterate that implemen-tation
of The international pharmacopoeia was the responsibility of
national drug authorities.
2.2 Monographs for The international pharmacopoeia
The Committee was pleased to note that a number of additional
monographs for drug substances, pharmaceutical preparations (e.g.
tablets) and excipients are nearing completion for inclusion in The
international pharmacopoeia. It approved the inclusion of mono-graphs
for antimalarials in Volume 5 of The international pharmaco-poeia,
which is currently in press.
2.3 Dissolution test requirements for individual monographs
The Committee was informed that the WHO collaborating centres
were assisting with proposals on work in establishing dissolution re-quirements,
test conditions and acceptance criteria (limits) for certain
monographs. The Committee supported the concept of cooperation
with the International Pharmaceutical Federation (FIP) in hands-on
courses on dissolution testing. It is envisaged that WHO collaborating
centres might provide a venue for such courses and that attendance
would be open to participants from national control laboratories and
the pharmaceutical industry.
2.4 Basic tests for pharmaceutical substances and dosage forms
The Committee was informed of progress in the development of basic
tests, and verification by the collaborating laboratories. So far, three.4
volumes (Basic tests for pharmaceutical substances, Basic tests for
pharmaceutical dosage forms and Basic tests for drugs: pharmaceutical
substances, medicinal plant materials and dosage forms (6–8)) have
been published. These volumes now include 345 basic tests for sub-stances,
208 for dosage forms and four for medicinal plant materials.
The next volume will be made available once a sufficient number of
tests have been developed and verified.
The need for four verifications of each test for dosage forms as
currently applied according to Annex 6 of the Committee’s twenty-ninth
report (9) was discussed. The possibility of accepting three
verifications was suggested, provided that there were no significant
differences between the results. The use of additional laboratories,
and encouraging feedback from those using the tests, was advocated.
3. Quality control — reference materials
3.1 International Chemical Reference Substances
The 1997 and 1998 reports of the WHO Collaborating Centre for
Chemical Reference Substances were presented to the Committee.
Nine new International Chemical Reference Substances (ICRS)
1
were adopted by the Committee according to the procedure de-scribed
in its thirty-second report (10). The recommendation to with-draw
the reference substance for tubocurarine hydrochloride was
endorsed since it is no longer required. The total collection now
comprises 205 chemical reference substances and 12 melting-point
reference substances (Annex 1).
The Committee adopted the reports and expressed its appreciation to
the WHO Collaborating Centre for Chemical Reference Substances
for its work, and to the National Corporation of Swedish Pharmacies
for its continued financial support to the WHO programme on ICRS.
3.2 International Infrared Reference Spectra
A total of 69 International Infrared Reference Spectra (IIRS) are
currently available from the WHO Collaborating Centre for Chemi-cal
Reference Substances, Kungens Kurva, Sweden (Annex 2). The
Committee acknowledged the contribution of the WHO Collaborat-ing
Centre for International Infrared Reference Spectra, Zurich,
1
Captopril, captopril disulfide, ciprofloxacin hydrochloride, cisplatin, kanamycin
monosulfate, piperazine adipate, piperazine citrate, sodium amidotrizoate and
streptomycin sulfate..5
Switzerland, which prepares the spectra. It was agreed that in future
the infrared reference spectra would be recorded on a Fourier trans-form
infrared spectroscopy instrument and that they should be pub-lished
in reduced size, either in The international pharmacopoeia or as
a separate publication.
3.3 Biological reference materials
The Committee noted that the WHO Expert Committee on Biologi-cal
Standardization was carrying out a review of biological reference
materials. Any such materials proposed for discontinuation as a
biological reference material would be assessed by the WHO Col-laborating
Centre for Chemical Reference Substances for its potential
suitability for use as an ICRS.
3.4 Information on reference materials for pharmacopoeial
analysis
The Committee noted that the comprehensive list of reference
substances and infrared reference spectra is regularly updated and
available on the Internet at http://www.who.int/medicines.
4. Quality control — pharmaceutical control
laboratories
4.1 Good practices for national pharmaceutical control
laboratories
The Committee adopted the revised guidelines (11) on good practices
for national pharmaceutical control laboratories (GPCL) (Annex 3).
The new title was chosen to emphasize that these guidelines were
intended primarily for national control laboratories. They take into
account other existing guidance on the subject, including that pro-vided
by the International Organization for Standardization (12),
the Organisation for Economic Co-operation and Development (13)
and the Swiss Association for Standardization (14), as well as the
recommendations on a quality system for official medicines control
laboratories, published by the Pharmaceutical Inspection Convention
(PIC) (15).
The importance of these guidelines should be drawn to the attention
of the national drug control authorities that would be responsible for
their implementation. It should be noted that a model test report for
active pharmaceutical ingredients, excipients and medicinal products
is appended to the guidelines..6
4.2 Equipment for drug control laboratories
The Committee adopted a revised list of equipment for pharmaceuti-cal
control laboratories to be appended to the GPCL (see Annex 3).
National control laboratories may contact the WHO Secretariat for
detailed information on costs.
4.3 Requests for analysis of drug samples
The Committee adopted recommendations to countries which need
to request the analysis of drug samples, e.g. where a national control
laboratory does not exist, or where it lacks competence in a particular
technique. These recommendations (Annex 4) are applicable to drug
regulatory authorities but may also be suitable for the independent
analysis of pharmaceuticals in trade.
4.4 External quality assessment
The Committee was informed that, since its previous meeting, 12
national quality control laboratories had been identified and had
agreed to participate in a pilot external quality assessment pro-gramme.
Progress would be reported at its next meeting.
5. Quality assurance — good manufacturing
practices
5.1 Good manufacturing practices in pharmaceutical production
The Committee acknowledged the importance of putting norms and
standards into practice. If GMP are to be implemented in countries,
decision-makers at all levels in the national public health sector must
be properly informed about them and convinced of their importance.
Information on the progress made with the project on the implemen-tation
of GMP in Member States was reported. Training material on
basic GMP principles had been prepared and training modules for
advanced GMP topics were planned. It was anticipated that the
project would include initial consultation, review and planning; the
preparation of training modules; country visits and training in
the performance of GMP inspections; the preparation of advanced
training modules in validation, water supply and sterile product
manufacture; and follow-up workshops. The possibility of establish-ing
training networks was considered, in order to establish a training
cascade, i.e. to train trainers, who in turn would train others.
The objective of the project was to improve the implementation of
GMP in countries. The selection criteria to be met by the countries.7
involved included their willingness and commitment to partici-pate,
and the presence of local and multinational pharmaceutical
manufacturers.
The Committee endorsed the project and encouraged the Secretariat
to continue work in this area.
Information on the basic elements of GMP in pharmaceutical produc-tion
is needed by interested parties and decision-makers at all levels,
and the provision of such information is encouraged. A brief sum-mary,
intended mainly for non-specialists, is given in Annex 5.
5.2 Good manufacturing practices for sterile pharmaceutical
products
A revised text for the section of the GMP guidelines dealing with
sterile products (16, section 17) was adopted (Annex 6). This took
account of the European and other guidelines (17, 18) and comments
received, which supported harmonization.
5.3 Guidelines for good storage practices
The Committee encouraged the Secretariat to collaborate with FIP
on guidelines for good storage practices. It was noted that a draft
prepared by FIP was already available.
5.4 Hazard analysis and critical control point system
A system known as the hazard analysis and critical control point
system (HACCP) was brought to the attention of the Committee.
While to date HACCP has been used primarily to assess hazards
associated with the production of food, it was recognized that the
identification of risks and critical processes is part of GMP. The
Secretariat was encouraged to explore and make use of appropriate
HACCP documentation that might be useful to illustrate the concepts
of GMP.
6. Quality assurance — inspection
6.1 Pre-approval inspections
The Committee adopted the guidelines on pre-approval inspections
(Annex 7) which extend the advice provided in the provisional guide-lines
on the inspection of pharmaceutical manufacturers in Annex 2
of its thirty-second report (19). Conducting inspections before grant-ing
marketing authorization could avoid problems at a later stage in
the evaluation process. This should assist both regulatory authorities
and manufacturers..8
6.2 Quality systems for national GMP inspectorates
The Committee adopted the guidelines given in Annex 8, which are
based on PIC recommendations for PIC Contracting States (20).
Recommendations and requirements for quality systems for the
operation of inspection services within a competent authority con-cerned
with GMP inspections are given, relating to administrative
structure, organization, personnel, records, inspection procedures,
confidentiality and internal audits. These guidelines are intended for
use by inspection services as the basis for developing their own quality
systems.
7. Quality assurance — packaging
7.1 General aspects of packaging
The Committee adopted a text relating to packaging material which is
addressed mainly to those involved in the supply of pharmaceuticals,
but also contains important information and references for their de-velopment,
manufacture and quality control (Annex 9). It focuses on
the role of packaging in relation to the stability of pharmaceuticals
and the potential for counterfeiting. The objective is to ensure that
medicines arrive safely in the hands of the patients for whom they are
intended.
7.2 Glass containers for pharmaceutical use and rubber closures
for containers of pharmaceuticals
The Committee approved two texts for inclusion in The international
pharmacopoeia. They provide information on the types and use of
glass containers and rubber closures for pharmaceutical purposes.
8. Quality assurance — general topics
8.1 Starting materials for pharmaceutical products: control and
safe trade
Further to the discussion during the thirty-fifth meeting of the Com-mittee
(21) on pharmaceuticals contaminated with diethylene glycol,
several activities aimed at ensuring the control of, and safe trade in,
starting materials for pharmaceutical products have been identified.
The Committee was informed of the report and recommendations of
a meeting on this subject that had been held in Geneva in May 1998
(3). The Committee noted that the World Health Assembly had
adopted the proposed resolution on the revised drug strategy.9
(WHA52.19) in May 1999 (22). Efforts were needed to promote
increased awareness of existing guidelines. The Committee noted that
several recommendations were made in the report for action by gov-ernments,
manufacturers, traders and brokers, as well as by WHO,
which would need to collaborate with all the parties involved. It was
suggested that the above-mentioned recommendations should be
consolidated and priorities assigned, and the resulting document cir-culated
widely among associations and representative bodies.
8.2 Model certificate of analysis for use in trade and procurement
A model certificate of analysis was adopted (Annex 10) for use in
trade in starting materials and for manufacturers of pharmaceutical
substances, excipients and medicinal products, as recommended by
World Health Assembly resolution WHA52.19 (22).
8.3 Screening tests for antimalarials and antituberculosis drugs
In view of the high priority of WHO’s Roll Back Malaria and Stop TB
programmes, the Committee emphasized the importance of the dif-ferent
projects being conducted in a number of Member States aimed
at developing methods for the rapid detection of counterfeit and
substandard drugs. These would be a useful supplement to the WHO
basic tests (6–8). In particular, it was agreed that thin-layer chroma-tography
(TLC) was a useful method for the rapid screening of
pharmaceuticals.
In line with established practice in The international pharmacopoeia
and the basic tests, the use of hazardous solvents such as chloroform
and ether should be avoided, and an effort should be made to mini-mize
the quantities of any solvents used. This is consistent with cur-rent
safety and environmental considerations.
For both the malaria and tuberculosis programmes, the Committee
encouraged the preparation of test manuals to incorporate all rel-evant
tests focused on the particular drug groups concerned. Such
manuals should reflect the stepwise approach of progressing first from
basic tests to screening methods and then to full pharmacopoeial
analysis.
8.4 Tuberculosis programme — fixed-dose combinations
The Committee was informed of WHO treatment policies for tuber-culosis
aimed at preventing acquired drug resistance and taking into
account the most efficient use of limited resources for combating
the disease. The key element is the development and promotion of.10
fixed-dose combination (FDC) tablets to replace single drug tablets
for the treatment of tuberculosis. FDC tablets simplify drug manage-ment,
treatment (increased patient and doctor compliance) and distri-bution.
Problems possibly associated with FDC tablets include the
management of side-effects, stability, the lack of standardization and
the poor bioavailability of rifampicin.
It was recommended that the Secretariat should take advantage of the
expertise of the Committee to provide advice on the quality assurance
aspects of FDC tablets. While appreciating the urgency with which an
adequate supply of FDC tablets is required, the Committee empha-sized
that quality assurance should not be compromised. Attention
should be paid to the pharmaceutical aspects of such tablets, particu-larly
their stability and in vitro dissolution. The development of
monographs on FDC tablets for The international pharmacopoeia was
recommended.
8.5 Comparator products for equivalence assessment of
interchangeable multisource (generic) products
In line with the recommendations made at its previous meeting (21),
the Committee adopted the document on “comparator products”
(Annex 11). This contains a list of international comparator phar-maceutical
products for the equivalence testing and assessment of
interchangeable multisource (generic) products and includes a
decision-tree for use in identifying comparator pharmaceutical pro-ducts.
It was emphasized that the list was intended to serve as an
information tool for drug regulatory authorities and pharmaceutical
manufacturers. The suggested use of comparator products is not in
any way intended to be binding on those responsible for choosing a
reference product. The final decision must be made at the national
level. The list and the guidance provided will need to be updated
periodically.
8.6 Measures to combat counterfeit drugs
The Committee noted that the guidelines for the development of
measures to combat counterfeit and substandard products are ap-proaching
finalization. It emphasized the importance of communica-tion
among all the bodies involved.
Vigilance and the reporting of counterfeit drugs were necessary at all
times, rather than only in response to isolated incidents or when
special requests for information were made. The Committee encour-aged
the sharing of information by national regulatory authorities
through the network of liaison officers established to combat counter-feit
pharmaceuticals..11
8.7 Information on general publications
The Committee noted that the Secretariat maintains a number of
useful information resources and databases, including WHO drug
quality control data, an index of pharmacopoeias, a list of GMP,
monographs of national and regional pharmacopoeias, and official
compendia. It was suggested that the Secretariat should explore the
feasibility of making these more widely available, possibly in elec-tronic
form.
Publications (in English, French and Spanish) are available, inter alia,
on basic tests for pharmaceutical substances, dosage forms and me-dicinal
plant materials (6–8). It was noted that the texts on some basic
tests have also been translated into Chinese.
The Committee noted that Volume 1 of a compilation of various
guidelines from previous WHO technical reports has been published
under the title Quality assurance of pharmaceuticals: a compendium
of guidelines and related materials (23), and that Volume 2, which
contains GMP reports and inspection guidelines, is expected to be
published shortly.
1
However, Volume 3 has not yet been planned as
compilation will depend on the approval and adoption of reports.
Continuation of this work is encouraged to ensure that any changes
and additional information will be widely available.
The Committee also noted that the tenth cumulative list of INNs for
pharmaceutical substances, which includes all INNs published to date,
is being prepared.
9. Nomenclature and computerized systems
9.1 International Nonproprietary Names for pharmaceutical
substances
The Committee endorsed the guidelines on the use of INNs for phar-maceutical
substances (Annex 12).
The Committee was informed of the current activities of the
programme on INNs for pharmaceutical substances. Since it last met,
245 new names have been published as proposed INNs, and 275
names have reached recommended INN status. The Committee was
1
Quality assurance of pharmaceuticals: a compendium of guidelines and related
materials. Vol. 2. Good manufacturing practices and inspection. Geneva, World Health
Organization, 1999..12
pleased with the progress made with regard to the use of INNs in
Chinese and Russian.
The revision of the procedure for the selection of INNs will attempt to
cover aspects such as objections raised to a proposed INN and the
replacement of a recommended INN. New developments in naming
biotechnology-derived products are also receiving attention. The
Committee endorsed the close collaboration with the WHO Expert
Committee on Biological Standardization.
Closer collaboration with WIPO in the field of protection of INNs has
been initiated. WIPO’s Standing Committee on the Law of Trade-marks,
Industrial Designs and Geographic Indications has discussed
the issue of trademarks and INNs and agreed to conduct a survey to
enquire to what extent national patent offices examine trademarks for
potential conflict with INNs. Another area of collaboration is with the
Internet Corporation for Assigned Names and Numbers (ICANN) in
the protection of INNs against misuse in Internet domain names.
9.2 Regulatory information systems
The Committee supported the investigation undertaken to assess the
feasibility of establishing information systems linking drug regulatory
authorities with WHO, and considered that such systems would be a
useful asset. National drug regulatory authorities should be alerted to
the possibility that a global information system may be established by
WHO in order to avoid problems of duplication or incompatibility.
9.3 Drug quality assurance terminology
As a first step towards greater harmonization, the establishment of a
glossary of existing terminology was suggested. While maintaining an
awareness of other harmonization initiatives is necessary, the first
priority should be to ensure consistency within WHO documents.
Many of the basic terms and concepts used in quality assurance are
the same for biologicals and pharmaceuticals.
10. Regulatory issues
10.1 Harmonization of regulatory requirements
The Committee noted the accelerating pace of regional and interre-gional
harmonization activities, particularly those under the auspices
of ICH. Recognizing WHO’s international normative responsibilities,
the Committee strongly supported WHO’s active participation in
such activities. This would facilitate the wider dissemination of.13
harmonization proposals and consideration of their applicability to
the regulatory situations in Member States at different stages of de-velopment.
While WHO was encouraged to take account of interre-gional
guidelines, the Committee emphasized the need to use these
flexibly when formulating WHO recommendations. The latter should
be appropriate for use in the context of the broader constituency of
WHO’s 191 Member States.
The Committee endorsed the recent ICDRA recommendation of
April 1999 that WHO should focus, in particular, on the quality and
regulation of multisource (generic) medicinal products. It urged the
Secretariat to take measures to make its international normative
function more widely known and understood, and to provide informa-tion
on its participation in other harmonization activities.
Acknowledgements
Special acknowledgement was made by the Committee to the following WHO staff
members, who assisted in the preparation and proceedings of the meeting: Mrs K.
Bremer, Quality Assurance and Safety: Medicines, Essential Drugs and other
Medicines; Dr M. Demesmaeker, Quality Assurance and Safety: Medicines,
Essential Drugs and other Medicines; Mr P. Graaff, Essential Drugs Programme,
WHO Regional Office for the Eastern Mediterranean, Alexandria, Egypt; Dr
E. Griffiths, Quality Assurance and Safety: Biologicals, Vaccines and other
Biologicals; Dr C.-C. Heuck, Blood Safety and Technology; Dr K. Kimura, Quality
Assurance and Safety: Medicines, Essential Drugs and other Medicines; Dr
Y. Motarjemi, Protection of the Human Environment; Dr M. Sesay, Policy, Access
and Rational Use, Essential Drugs and other Medicines; Dr S. Spinaci, Country
Support, Communicable Disease Prevention and Control; Dr G. Szalay, Informatics
and Infrastructure Services; Dr M. ten Ham, Drug Safety, Drug Management and
Policies; Dr P. Trigg, Communicable Disease Prevention and Control; Mr E.
Wondemagegnehu, Quality Assurance and Safety: Medicines, Essential Drugs
and other Medicines; Mr T. Yoshida, Quality Assurance and Safety: Medicines,
Essential Drugs and other Medicines.
The Committee also acknowledged with thanks the valuable contributions made to
its work by the following institutions and individuals: WHO Collaborating Centre
for Drug Quality Control, Woden, Australian Capital Territory, Australia; WHO
Collaborating Centre for Drug Quality Assurance, Beijing, China; WHO
Collaborating Centre for Biopharmaceutical Aspects of Drug Quality Control,
Clermont-Ferrand, France; WHO Collaborating Centre for Stability Studies of
Drugs, Nantes, France; WHO Collaborating Centre for Drug Information and
Quality Control, Budapest, Hungary; WHO Collaborating Centre for Drug
Information and Quality Assurance of Essential Drugs, Calcutta, India; WHO
Collaborating Centre for Quality Assurance of Essential Drugs, Jakarta, Indonesia;
WHO Collaborating Centre for Regulatory Control of Pharmaceuticals, Petaling
Jaya, Malaysia; WHO Collaborating Centre for Drug Quality Assurance, Singapore;
WHO Collaborating Centre for the Quality Assurance of Drugs, Potchefstroom,
South Africa; WHO Collaborating Centre for Chemical Reference Substances,
Kungens Kurva, Sweden; WHO Collaborating Centre for International Infrared
Reference Spectra, Zurich, Switzerland; WHO Collaborating Centre for Quality
Assurance of Essential Drugs, Nonthaburi, Thailand..14
Professor R.I. Akubue, University of Nigeria, Nsukka, Nigeria; Mr O. Andriollo,
Pharmaciens sans Frontières, Clermont-Ferrand, France; Dr H.E. Bale, Jr,
International Federation of Pharmaceutical Manufacturers Associations (IFPMA),
Geneva, Switzerland; Professor F. Ballereau, Faculty of Pharmacy, Epidemiology
and Public Health, Nantes, France; Dr D. Beck, Basel, Switzerland; Professor R.
Boudet-Dalbin, René Descartes University, Paris, France; Mr D.R. Buckley,
Therapeutic Goods Administration, Woden, Australian Capital Territory, Australia;
Dr Y. Chiu, Office of New Drug Chemistry, Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, MD, USA; Miss M. Cone,
IFPMA, Geneva, Switzerland; Mr T. Corquaye, Food and Drugs Board, Accra,
Ghana; Mrs E.M. Cortes Montejano, Ministry of Health and Consumer Affairs,
Madrid, Spain; Dr R. Dabbah, The United States pharmacopeia, Rockville, MD,
USA; Mrs E.F. Damas, Direction de Pharmacie, Ministry of Health, Port-au-Prince,
Haiti; Dr G. Détári, National Institute of Pharmacy, Budapest, Hungary; Dr D.
Doelcher, West Pharmaceutical Services Deutschland GmbH, Eschweiler,
Germany; Mr P. Duneton, Drugs Agency, Saint-Denis, France; Dr R. Freimanis,
United States Adopted Names Council, American Medical Association, Chicago,
IL, USA; Dr H. Fukuda, Society of Japanese Pharmacopoeia, Tokyo, Japan; Mrs E.
Fuller, Geneva, Switzerland; Dr G. Gernez, Villemoisson-sur-Orge, France; Ms E.
Gómez, Baxter Laboratories, Cali, Colombia; Dr T. Godschan, Intercantonal Office
for the Control of Medicines, Berne, Switzerland; Mr J. Gouws, Medicines Control
Council, Cape Town, South Africa; Professor A. Haggag, Alexandria, Egypt; Mr H.
Ikäläinen, National Agency for Medicines, Helsinki, Finland; Dr H.J. de Jong,
International Regulatory Affairs, Leiden University, Leiden, Netherlands; Dr K.
Kawamura, Otsuka Pharmaceutical Co., Tokyo, Japan; Dr M. Keller, Intercantonal
Office for the Control of Medicines, Berne, Switzerland; Professor Kil-Soo Kim,
Ewha Women’s University, Seoul, Republic of Korea; Mr R. Kuwana, Medicines
Control Authority, Harare, Zimbabwe; Mr J. Lanet, Qualassur, Paris, France; Ms K.
Lang, Shell Chemicals Ltd, London, England; Dr H. Leblanc, European Chemical
Industry Council, Brussels, Belgium; Dr H. Letterman, New Providence, NJ, USA;
Mrs V. Li-Frankenstein, UNICEF Supply Division, Copenhagen, Denmark; Dr R.
Lindauer, The United States pharmacopeia, Rockville, MD, USA; Professor J.
Lipták, National Public Health Service, Budapest, Hungary; Mr J.A. Lisman,
Ministry of Health, Welfare and Sport, Rijswijk, Netherlands; Dr K.L. Loening,
Topterm, North American Division, Columbus, OH, USA; Dr M.K. Majumdar,
Calcutta, India; Mr R.F. Mantik, Bogor, Indonesia; Mrs J. Maritoux, Réseau
Médicaments et Développement, Paris, France; Professor L. Martinec, State
Institute for the Control of Drugs, Bratislava, Slovakia; Dr N. Miyata, National
Institute of Health Sciences, Tokyo, Japan; Mr M.G. Moester, Ministry of Health,
Welfare and Sport, Rijswijk, Netherlands; Mrs D. Monk, Australian Pharmaceutical
Manufacturers Association, North Sydney, New South Wales, Australia; Mrs Z.J.
Montbrun de Reinfeld, National Institute of Hygiene, Caracas, Venezuela; Dr A.B.
Moraes da Silva, National Health Institute of Quality Control, Rio de Janeiro, Brazil;
Professor R.C. Moreau, Paris, France; Dr M. Negwer, FIZ Chemie, Berlin, Germany;
Dr E. Njau, Arusha, United Republic of Tanzania; Professor T.L. Paál, National
Institute of Pharmacy, Budapest, Hungary; Dr P.R. Pabrai, Ranbaxy Laboratories
Ltd, New Delhi, India; Mrs E. Pelkonen, National Agency for Medicines, Helsinki,
Finland; Mr G. Pierce, Division of Emergency and Investigational Operations, Food
and Drug Administration, Rockville, MD, USA; Dr S. Raicu, State Institute for Drug
Control and Pharmaceutical Research, Bucharest, Romania; Dr M. Raijmakers,
Wemos Foundation, Amsterdam, Netherlands; Dr J. Reinstein, World Self-Medication
Industry, London, England; Mrs N. Ridolphi, Réseau Médicaments
et Développement, Strasbourg, France; Mr N. Sasidharan, World Customs
Organization, Brussels, Belgium; Dr K. Satiadarma, Bandung, Indonesia; Mr A.
Schijveschuurder, Avrachem AG, Zurich, Switzerland; Dr D. Schnädelbach,
Federal Institute for Drugs and Medical Devices, Berlin, Germany; Dr J. Schrank,
Interpharma, Basel, Switzerland; Dr M.A. Siewert, Hoechst Marion Roussel,.15
Frankfurt am Main, Germany; Dr E. Spingler-Kloess, Schönenbuch, Switzerland;
Mrs L. Stefanini-Oresic, Croatian Institute for Medicines Control, Zagreb, Croatia;
Dr S. Sur, Central Laboratory for Quality Control of Medicines, Kiev, Ukraine; Dr R.
Szyszkowsky, Latin American Pharmaceutical Industries Association, Buenos
Aires, Argentina; Mrs Tan Shook Fong, Ministry of Health, Singapore; Dr R. Tengler,
Intercantonal Office for the Control of Medicines, Berne, Switzerland; Dr A. Thépot,
Roche, Paris, France; Dr S. Throm, German Association of Research-based
Pharmaceutical Companies (VFA) e.V., Bonn, Germany; Mr P. Thummel,
Interpharma, Basel, Switzerland; Mr R.B. Trigg, British Pharmacopoeia
Commission, London, England; Professor Tu Guoshi, National Institute for the
Control of Pharmaceutical and Biological Products, Ministry of Public Health,
Beijing, China; Mrs E. Uramis, BioCen National Centre for Bio-Preparations,
Havana, Cuba; Dr W. van de Poel, Helvoet S.A., Alken, Belgium; Dr T. van Quy,
National Institute of Drug Quality Control, Hanoi, Viet Nam; Mr J.-Y. Videau,
Pharmaciens sans Frontières, Clermont-Ferrand, France; Mr P.H. Vree, Ministry of
Health, Welfare and Sport, Rijswijk, Netherlands; Mrs M.C. de Vries, Ministry of
Health, Welfare and Sport, Rijswijk, Netherlands; Mrs M. Westermark, Apoteket AB,
Central Laboratory, Kungens Kurva, Sweden; Professor W. Wieniawski, Polish
Pharmacopoeia Commission, Warsaw, Poland; Dr H. Woerder, Bünder Glass
GmbH, Bünde, Germany; Dr Woo Soo On, Department of Scientific Services,
Institute of Science and Forensic Medicine, Singapore; Mr D.R. Work, North
Carolina Board of Pharmacy, Carrboro, NC, USA; Mrs C. Yzer, VFA e.V., Bonn,
Germany.
References
1. Guidelines for implementation of the WHO Certification Scheme on the
Quality of Pharmaceutical Products Moving in International Commerce. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 10
(WHO Technical Report Series, No. 863).
2. Handbook of resolutions and decisions of the World Health Assembly and
the Executive Board, Volume III, 1985–1992, 3rd ed. Geneva, World Health
Organization, 1993:94.
3. Starting materials for pharmaceutical products: control and safe trade.
Geneva, World Health Organization, 1998 (unpublished document WHO/
PHARM/98.605; available from Essential Drugs and Medicines Policy, World
Health Organization, 1211 Geneva 27, Switzerland).
4. The international pharmacopoeia, 3rd ed. Vol. 1. General methods of
analysis; Vol. 2. Quality specifications; Vol. 3. Quality specifications; Vol. 4.
Tests, methods, and general requirements. Quality specifications for
pharmaceutical substances, excipients, and dosage forms. Geneva, World
Health Organization, 1979–1994.
5. Counterfeit drugs. Guidelines for the development of measures to combat
counterfeit drugs. Geneva, World Health Organization, 1999 (unpublished
document WHO/EDM/QSM/99.1; available from Essential Drugs and
Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).
6. Basic tests for pharmaceutical substances. Geneva, World Health
Organization, 1986..16
7. Basic tests for pharmaceutical dosage forms. Geneva, World Health
Organization, 1991.
8. Basic tests for drugs: pharmaceutical substances, medicinal plant materials
and dosage forms. Geneva, World Health Organization, 1998.
9. Collaboration within the basic test programme. In: WHO Expert Committee
on Specifications for Pharmaceutical Preparations. Twenty-ninth report.
Geneva, World Health Organization, 1984, Annex 6 (WHO Technical Report
Series, No. 704).
10. WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-second report. Geneva, World Health Organization, 1992 (WHO
Technical Report Series, No. 823).
11. National laboratories for drug quality surveillance and control. In: WHO
Expert Committee on Specifications for Pharmaceutical Preparations.
Twenty-ninth report. Geneva, World Health Organization, 1984, Annex 1
(WHO Technical Report Series, No. 704).
12. General requirements for the competence of testing and calibration
laboratories. International Standard ISO/IEC 17025. Geneva, International
Organization for Standardization, 1999.
13. OECD series on principles of good laboratory practice and compliance
monitoring. No. 1. OECD principles of good laboratory practice. Paris,
Organisation for Economic Co-operation and Development, 1997 (available
from Head of Publications Service, OECD, 2 rue André-Pascal, 75775 Paris
Cédex 16, France).
14. General criteria for the operation of testing laboratories. SN EN 45001.
1
Zurich, Swiss Association for Standardization, 1989 (available from the
Swiss Association for Standardization, Kirchweg 4, Postfach, 8032 Zurich,
Switzerland).
15. Recommendations on a quality system for official medicines control
laboratories. Geneva, Pharmaceutical Inspection Convention, 1995
(unpublished document PH 2/95; available from EFTA Secretariat, 9–11 rue
de Varembé, 1211 Geneva 20, Switzerland).
16. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823).
17. Manufacture of sterile medicinal products. Brussels, European Commission,
1997 (available from Directorate-General for Internal Market and Industrial
Affairs, 200 rue de la Loi, B-1049 Brussels, Belgium).
18. Clean rooms and associated controlled environments. International standard
ISO/TC 209. Geneva, International Organization for Standardization, 1999.
1
Superseded by General requirements for the competence of testing and calibration
laboratories. SN EN 17025. Zurich, Swiss Association for Standardization, 2000
(available from the Swiss Association for Standardization, Kirchweg 4, Postfach, 8032
Zurich, Switzerland)..17
19. Provisional guidelines on the inspection of pharmaceutical manufacturers.
In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-second report. Geneva, World Health Organization,
1992, Annex 2 (WHO Technical Report Series, No. 823).
20. Quality system requirements for GMP inspectorates. Geneva, Pharma-ceutical
Inspection Convention, 1995 (unpublished document PH 7/94;
available from EFTA Secretariat, 9–11 rue de Varembé, 1211 Geneva 20,
Switzerland).
21. WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-fifth report. Geneva, World Health Organization, 1999 (WHO Technical
Report Series, No. 885).
22. The revised drug strategy. In: Fifty-second World Health Assembly, Geneva,
17–25 May 1999. Volume 1. Resolutions and decisions, and list of
participants. Geneva, World Health Organization, 1999 (unpublished
document WHA52/1999/REC/1).
23. Quality assurance of pharmaceuticals: a compendium of guidelines and
related materials. Vol. 1. Geneva, World Health Organization, 1997..18
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 1
List of available International Chemical Reference
Substances
1
International Chemical Reference Substances (ICRS) are established
on the advice of the WHO Expert Committee on Specifications for
Pharmaceutical Preparations. They are supplied primarily for use in
physical and chemical tests and assays described in the specifica-tions
for quality control of drugs published in The international phar-macopoeia
or proposed in draft monographs. The ICRS are mainly
intended to be used as primary standards to calibrate secondary
standards.
Directions for use, and the analytical data required for the use de-scribed
in the relevant specifications of The international pharmaco-poeia,
are given in the certificates enclosed with the substances when
distributed. More detailed analytical reports on the substances may
be obtained from the WHO Collaborating Centre for Chemical
Reference Substances.
ICRS may also be used in tests and assays not described in The
international pharmacopoeia. However, the responsibility for assess-ing
the suitability of the substances then rests with the user or with the
pharmacopoeia commission or other authority that has prescribed
this use.
It is generally recommended that the substances should be stored
protected from light and moisture and preferably at a temperature of
about 5°C. When special storage conditions are required, this is
stated on the label or in the accompanying leaflet. It is recommended
that the user purchase only an amount sufficient for immediate use.
The stability of the ICRS kept at the Collaborating Centre is moni-tored
by regular re-examination, and any material that has deterio-rated
is replaced by new batches as necessary. Lists giving control
numbers for the current batches are issued in the annual reports from
the Centre and new yearly lists may be obtained on request.
1
As updated at the thirty-sixth meeting of the WHO Expert Committee on Specifications
for Pharmaceutical Preparations, 31 May–4 June 1999..19
Orders for the ICRS should be sent to:
WHO Collaborating Centre for Chemical Reference Substances
Apoteket AB
Produktion & Laboratorier Centrallaboratoriet, ACL
Prismavägen 2
S-141 75 Kungens Kurva
Sweden
Tel.: +46 8 466 1000
Fax: +46 8 740 6040
Email: who.apl@apoteket.se
The ICRS are supplied only in the standard packages indicated in
Table 1.
Table 1
Available International Chemical Reference Substances
Reference substance Package size Control number
aceclidine salicylate 100mg 172048
p-acetamidobenzalazine 25mg 290042
acetazolamide 100mg 186128
allopurinol 100mg 287049
amidotrizoic acid 100mg 196205
2-amino-5-nitrothiazole 25mg 186131
3-aminopyrazole-4-carboxamide hemisulfate 100mg 172050
3-amino-2,4,6-triiodobenzoic acid 100mg 196206
amitriptyline hydrochloride 100mg 181101
amodiaquine hydrochloride 200mg 192160
amphotericin B 400mg 191153
ampicillin (anhydrous) 200mg 390001
ampicillin sodium 200mg 388002
ampicillin trihydrate 200mg 274003
anhydrotetracycline hydrochloride 25mg 180096
atropine sulfate 100mg 183111
azathioprine 100mg 172060
bacitracin zinc 200mg 192174
beclometasone dipropionate 200mg 192175
bendazol hydrochloride 100mg 173066
benzobarbital 100mg 172051
benzylamine sulfate 100mg 172052
benzylpenicillin potassium 200mg 180099
benzylpenicillin sodium 200mg 280047
bephenium hydroxynaphthoate 100mg 183112
betamethasone 100mg 183113
betamethasone sodium phosphate 100mg 196203
betamethasone valerate 100mg 190145
betanidine sulfate 100mg 172053
bupivacaine hydrochloride 100mg 289054.20
Table 1 ( continued)
Reference substance Package size Control number
caffeine 100mg 181102
calcium folinate (leucovorin calcium) 100mg 194188
captopril 100mg 197214
captopril disulfide 25mg 198216
carbamazepine 100mg 189143
carbenicillin monosodium 200mg 383043
chloramphenicol 200mg 486004
chloramphenicol palmitate 1g 286072
chloramphenicol palmitate (polymorph A) 200mg 175073
5-chloro-2-methylaminobenzophenone 100mg 172061
chloroquine sulfate 200mg 195201
2-(4-chloro-3-sulfamoylbenzoyl)benzoic acid 50mg 181106
chlorphenamine hydrogen maleate 100mg 182109
chlorpromazine hydrochloride 100mg 178080
chlortalidone 100mg 183114
chlortetracycline hydrochloride 200mg 187138
cimetidine 100mg 190150
ciprofloxacin hydrochloride 400mg 197210
ciprofloxacin by-compound A 20mg 198220
ciprofloxacin desfluoro-compound 20mg 198219
ciprofloxacin ethylenediamine-compound 20mg 198218
ciprofloxacin fluoroquinolonic acid 20mg 198217
cisplatin 100mg 197207
clomifene citrate 100mg 187136
clomifene citrate Z-isomer see zuclomifene
cloxacillin sodium 200mg 274005
colecalciferol (vitamin D3 ) 500mg 190146
cortisone acetate 100mg 167006
dapsone 100mg 183115
desoxycortone acetate 100mg 167007
dexamethasone 100mg 388008
dexamethasone acetate 100mg 288009
dexamethasone phosphoric acid 100mg 192161
dexamethasone sodium phosphate 100mg 192158
diazepam 100mg 172062
diazoxide 100mg 181103
dicloxacillin sodium 200mg 174071
dicolinium iodide 100mg 172055
dicoumarol 100mg 178077
diethylcarbamazine dihydrogen citrate 100mg 181100
digitoxin 100mg 277010
digoxin 100mg 587011
N, N¼ñêô-di-(2,3-xylyl)anthranilamide 50mg 173067
dopamine hydrochloride 100mg 192159
doxorubicin hydrochloride 100mg 196202
emetine hydrochloride 100mg 187134
4-epianhydrotetracycline hydrochloride 25mg 288097.21
Table 1 ( continued)
Reference substance Package size Control number
4-epitetracycline hydrochloride 25mg 293098
ergocalciferol (vitamin D2 ) 500mg 190147
ergometrine hydrogen maleate 50mg 277012
ergotamine tartrate 50mg 385013
erythromycin 250mg 191154
erythromycin B 150mg 194186
erythromycin C 25mg 194187
estradiol benzoate 100mg 167014
estrone 100mg 279015
etacrynic acid 100mg 281056
ethambutol hydrochloride 100mg 179081
ethinylestradiol 100mg 291016
ethisterone 100mg 167017
ethosuximide 100mg 179088
etocarlide 100mg 172057
flucloxacillin sodium 200mg 195194
flucytosine 100mg 184121
fludrocortisone acetate 200mg 195199
fluorouracil 100mg 184122
fluphenazine decanoate dihydrochloride 100mg 182107
fluphenazine enantate dihydrochloride 100mg 182108
fluphenazine hydrochloride 100mg 176076
folic acid 100mg 388019
3-formylrifamycin 200mg 190149
framycetin sulfate (neomycin B sulfate) 200mg 193178
furosemide 100mg 171044
gentamicin sulfate 100mg 194183
griseofulvin 200mg 280040
haloperidol 100mg 172063
hydrochlorothiazide 100mg 179087
hydrocortisone 100mg 283020
hydrocortisone acetate 100mg 280021
hydrocortisone sodium succinate 200mg 194184
()-3-(4-hydroxy-3-methoxyphenyl)-2-hydrazino-2-
methylalanine (3- O-methylcarbidopa) 25mg 193180
()-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine
(3- O-methylmethyldopa) 25mg 179085
ibuprofen 100mg 183117
imipramine hydrochloride 100mg 172064
indometacin 100mg 178078
o-iodohippuric acid 100mg 171045
isoniazid 100mg 185124
kanamycin monosulfate 12mg 197211
lanatoside C 100mg 281022
levodopa 100mg 295065.22
Table 1 ( continued)
Reference substance Package size Control number
levonorgestrel 200mg 194182
levothyroxine sodium 100mg 189144
lidocaine 100mg 181104
lidocaine hydrochloride 100mg 181105
liothyronine sodium 50mg 193179
loperamide hydrochloride 100mg 194185
mebendazole 200mg 195195
mefenamic acid 100mg 173068
melting-point reference substances
azobenzene (69°C) 4g 192168
vanillin (83 °C) 4g 192169
benzil (96 °C) 4g 294170
acetanilide (116 °C) 4g 297171
phenacetin (136°C) 4g 297172
benzanilide (165 °C) 4g 192173
sulfanilamide (166 °C) 4g 192162
sulfapyridine (193 °C) 4g 192163
dicyanodiamide (210°C) 4g 192164
saccharin (229 °C) 4g 192165
caffeine (237 °C) 4g 192166
phenolphthalein (263 °C) 4g 192167
metazide 100mg 172058
methaqualone 100mg 173069
methotrexate 100mg 194193
methyldopa 100mg 179084
methyltestosterone 100mg 167023
meticillin sodium 200mg 274024
metronidazole 100mg 183118
nafcillin sodium 200mg 272025
neamine hydrochloride (neomycin A hydrochloride) 0.5 mg 193177
neomycin B sulfate see framycetin sulfate
neostigmine metilsulfate 100mg 187135
nicotinamide 100mg 179090
nicotinic acid 100mg 179091
nifurtimox 100mg 194189
niridazole 200mg 186129
niridazole-chlorethylcarboxamide 25mg 186130
norethisterone 100mg 186132
norethisterone acetate 100mg 185123
nystatin 200mg 191152
oubain 100mg 283026
oxacillin sodium 200mg 382027
oxytetracycline dihydrate 200mg 189142
oxytetracycline hydrochloride 200mg 189141
papaverine hydrochloride 100mg 185127
paracetamol 100mg 195198.23
Table 1 ( continued)
Reference substance Package size Control number
paromomycin sulfate 75mg 195197
pheneticillin potassium 200mg 167028
phenoxymethylpenicillin 200mg 179082
phenoxymethylpenicillin calcium 200mg 179083
phenoxymethylpenicillin potassium 200mg 176075
phenytoin 100mg 179089
piperazine adipate 100mg 197212
piperazine citrate 100mg 197213
praziquantel 100mg 194191
prednisolone 100mg 389029
prednisolone acetate 100mg 289030
prednisolone hemisuccinate 200mg 195196
prednisolone sodium phosphate 200mg 194190
prednisone 100mg 167031
prednisone acetate 100mg 169032
probenecid 100mg 192156
procaine hydrochloride 100mg 183119
procarbazine hydrochloride 100mg 184120
progesterone 100mg 167033
propicillin potassium 200mg 274034
propranolol hydrochloride 100mg 187139
propylthiouracil 100mg 185126
pyrantel embonate (pyrantel pamoate) 500mg 192157
pyridostigmine bromide 100mg 182110
reserpine 100mg 186133
retinol acetate (solution) 5 capsules
a
898038
riboflavin 250mg 382035
rifampicin 200mg 191151
rifampicin quinone 200mg 190148
sodium amidotrizoate 100mg 198221
sodium cromoglicate 100mg 188140
spectinomycin hydrochloride 200mg 193176
streptomycin sulfate 100mg 197215
sulfacetamide 100mg 196200
sulfamethoxazole 100mg 179092
sulfamethoxypyridazine 100mg 178079
sulfanilamide 100mg 179094
sulfasalazine 100mg 191155
tamoxifen citrate 100mg 196208
tamoxifen citrate E-isomer 10mg 196209
testosterone enantate 200mg 194192
testosterone propionate 100mg 167036
tetracycline hydrochloride 200mg 180095
thioacetazone 100mg 171046
4,4¼ñêô-thiodianiline 50mg 183116.24
Table 1 ( continued)
Reference substance Package size Control number
thyroxine sodium see levothyroxine sodium
tolbutamide 100mg 179086
tolnaftate 100mg 176074
toluene-2-sulfonamide 100mg 196204
trimethadione 200mg 185125
trimethoprim 100mg 179093
trimethylguanidine sulfate 100mg 172059
vincristine sulfate 9.7 mg/vial 193181
vitamine A acetate (solution) see retinol acetate
(solution)
warfarin 100mg 168041
zuclomifene 50mg 187137
a
Each containing about 8 mg in 230 mg of oil..25
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 2
List of available International Infrared Reference
Spectra
International Infrared Reference Spectra are established on the
advice of the WHO Expert Committee on Specifications for Pharma-ceutical
Preparations. Full-scale reproductions of spectra produced
from authenticated material on a suitable instrument are supplied for
use in identification tests described in the specifications for quality
control of drugs, published in The international pharmacopoeia or
proposed in draft monographs.
Precise instructions for the preparation of spectra are given on the
label of each reference spectrum. All International Infrared
Reference Spectra are distributed together with a document giving
further details on the use of such spectra, entitled “General recom-mendations
for the preparation and use of infrared spectra in
pharmaceutical analysis”.
1
Orders for International Infrared Reference Spectra should be sent
to:
WHO Collaborating Centre for Chemical Reference Substances
Apoteket AB
Produktion & Laboratorier Centrallaboratoriet, ACL
Prismavägen 2
S-141 75 Kungens Kurva
Sweden
Tel.: +46 8 466 1000
Fax: +46 8 740 6040
Email: who.apl@apoteket.se
The following International Infrared Reference Spectra are currently
available from the Centre:
1
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth
report. Geneva, World Health Organization, 1996, Annex 4 (WHO Technical Report
Series, No. 863).
amiloride hydrochloride
amitriptyline hydrochloride
ampicillin trihydrate
aceclidine salicylate
acetazolamide
allopurinol.26
beclometasone dipropionate
benzylpenicillin potassium
biperiden
biperiden hydrochloride
bupivacaine hydrochloride
caffeine (anhydrous)
calcium folinate
carbidopa
chlorphenamine hydrogen
maleate
clofazimine
cloxacillin sodium
colchicine
cytarabine
dexamethasone
dexamethasone acetate,
monohydrate
dextromethorphan
hydrobromide
diazepam
dicolinium iodide
dicoumarol
diethylcarbamazine dihydrogen
citrate
diphenoxylate hydrochloride
erythromycin ethylsuccinate
erythromycin stearate
etacrynic acid
ethionamide
ethosuximide
furosemide
gallamine triethiodide
glibenclamide
haloperidol
hydrochlorothiazide
ibuprofen
imipramine hydrochloride
indometacin
isoniazid
lidocaine
lidocaine hydrochloride
lindane
metronidazole
miconazole nitrate
niclosamide
nicotinamide
noscapine
oxamniquine
papaverine hydrochloride
phenobarbital
phenoxymethylpenicillin
calcium
phenytoin
primaquine phosphate
propylthiouracil
protionamide
pyrimethamine
salbutamol
salbutamol sulfate
sulfadimidine
sulfadoxine
sulfamethoxazole
sulfamethoxypyridazine
tiabendazole
trihexyphenidyl hydrochloride
trimethoprim
valproic acid
verapamil hydrochloride.27
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 3
Good practices for national pharmaceutical
control laboratories
General considerations 28
Glossary 29
Part One. Management and infrastructure 33
1. Organization and management 33
2. Quality system 34
3. Control of documentation 35
4. Records 36
5. Data-processing equipment 37
6. Personnel 37
7. Premises 40
8. Equipment, instruments and other devices 41
Part Two. Materials and setting-up of equipment, instruments and
other devices 42
9. Specifications archive 42
10. Reagents 43
11. Reference materials 45
12. Calibration, validation and verification of equipment, instruments
and other devices 46
13. Traceability 49
Part Three. Working procedures 52
14. Incoming samples 52
15. Analytical worksheet 54
16. Testing 57
17. Evaluation of test results 57
18. Retained samples 58
Part Four. Safety 59
19. General rules 59
References 60
Appendix 1
Model analytical test report for active pharmaceutical ingredients,
excipients and pharmaceutical products 62
Appendix 2
Equipment for a first-stage and medium-size pharmaceutical control
laboratory 64.28
General considerations
The government, normally through the drug regulatory authority,
establishes and maintains a pharmaceutical control laboratory to
carry out the required tests and assays to ensure that active pharma-ceutical
ingredients, excipients and pharmaceutical products meet
quality specifications. Throughout the process of marketing authori-zation,
the laboratory works closely with the national drug regulatory
authority. The review of test methods for newly registered drugs plays
an important role in ensuring their suitability for the control of quality
and safety, and requires a major effort, especially since routine drug
testing must also be carried out. Some countries maintain larger
establishments called “drug control centres” or “drug control
institutes”.
The importance of a pharmaceutical control laboratory to a national
drug control system has already been outlined in three guidelines on
quality assessment (1–3).
In most countries the laboratory is responsible for analytical services
only, and not for the inspection of pharmaceuticals. However, some
aspects of inspection are included in these guidelines.
A governmental pharmaceutical control laboratory provides effective
support for a drug regulatory authority acting together with its inspec-tion
services. The analytical results obtained should accurately
describe the properties of the samples assessed, permitting correct
conclusions to be drawn about the quality of each drug, and also
serving as an adequate basis for any subsequent administrative regu-lations
and legal action.
To ensure patient safety, the role of the control laboratory must be
defined in the general drug legislation of the country in such a way
that the results provided by it can, if necessary, lead to enforcement of
the law and legal action.
For the quality of a drug sample to be correctly assessed:
— the submission of a sample to the laboratory, selected in accor-dance
with national requirements, must be accompanied by a
statement of the reason why the analysis has been requested;
— the analysis must be correctly planned and meticulously executed;
— the results must be competently evaluated to determine whether
the sample complies with the quality specifications or other
relevant criteria.
Precise documentation is required to make each operation simple and
unambiguous as far as possible (see also Part One, section 2.1)..29
These guidelines provide advice on the analysis of active pharmaceu-tical
ingredients, excipients and pharmaceutical products. Particular
consideration is given to countries with limited resources wishing to
establish a governmental pharmaceutical control laboratory, having
recently done so, or planning to modernize the existing laboratory.
Many of the recommendations are also relevant to drug quality con-trol
testing by the pharmaceutical manufacturer. This is usually a
matter of repetitive testing of samples of active pharmaceutical ingre-dients
or of a limited number of pharmaceutical products, whereas,
theoretically, governmental control laboratories have to deal with all
the drugs on the market and therefore have to use a wider variety of
test methods.
Special attention must be given to ensuring the correct and efficient
functioning of the laboratory. Planning and future budgets must
ensure that the necessary resources are available, inter alia, for the
maintenance of the laboratory, as well as for an adequate infrastruc-ture
and energy supply. Means and procedures must be in place (in
case of anticipated supply problems) to ensure that the laboratory can
continue its activities.
The laboratory should be appropriately equipped to respond to all
reasonable demands.
Glossary
The definitions given below apply to the terms as used in these guide-lines.
They may have different meanings in other contexts.
active pharmaceutical ingredient
A substance or compound that is intended to be used in the manufac-ture
of a pharmaceutical product as a pharmacologically active com-pound
(ingredient) (4).
analytical worksheet
A printed form for recording information about the sample, test
procedure and results of testing (see Part Three, section 15).
batch (or lot)
A defined quantity of starting material, packaging material, or product
processed in a single process or series of processes so that it could be
expected to be homogeneous. In the case of continuous manufacture,
the batch must correspond to a defined fraction of the production,
characterized by its intended homogeneity. It may sometimes be nec-essary
to divide a batch into a number of sub-batches, which are later
brought together to form a final homogeneous batch (4)..30
batch number (or lot number)
A distinctive combination of numbers and/or letters which specifically
identifies a batch on the labels, the batch records, the certificate of
analysis, etc. (4).
calibration
The set of operations that establish, under specified conditions, the
relationship between values indicated by an instrument or system for
measuring (especially weighing), recording and controlling, or the
values represented by a material measure, and the corresponding
known values of a reference standard. Limits for acceptance of the
results of measuring should be established (4).
calibration of equipment
The documented act of proving that the equipment is performing to
predefined tolerances or criteria.
certificate of analysis
Report of the results obtained, including the final conclusion of the
examination of a sample issued by the manufacturer and repacker/
trader (see Annex 10).
drug
An active pharmaceutical ingredient or a pharmaceutical product
(see also pharmaceutical excipient and pharmaceutical product).
good manufacturing practice(s) (GMP)
That part of quality assurance which ensures that pharmaceutical
products are consistently produced and controlled to the quality
standards appropriate to their intended use and as required by the
marketing authorization (4).
manufacturer
A company that carries out at least one step of manufacture (4).
marketing authorization (product licence, registration certificate)
A legal document issued by the competent drug regulatory authority
that establishes the detailed composition and formulation of the
pharmaceutical product and the pharmacopoeial or other recognized
specifications of its ingredients and of the final product itself, and
includes details of packaging, labelling and shelf-life.
pharmaceutical excipient
A substance, other than the active pharmaceutical ingredient, which
has been appropriately evaluated for safety and is included in a drug
delivery system to:.31
— aid in the processing of the drug delivery system during its
manufacture;
— protect, support or enhance stability, bioavailability or patient
acceptability;
— assist in pharmaceutical product identification; or
— enhance any other attribute of the overall safety and effectiveness
of the drug during its storage or use (5, 6).
pharmaceutical product
Any medicine intended for human or veterinary use, presented in its
finished dosage form, that is subject to control by pharmaceutical
legislation in both the exporting state and the importing state.
qualification of equipment
The act of planning, carrying out and recording the results of the
tests on equipment to demonstrate that it will perform as intended.
Measuring instruments and systems must be calibrated (see Part Two,
section 12).
quality assurance
A wide-ranging concept covering all matters that individually or col-lectively
influence the quality of a product. It is the totality of the
arrangements made with the object of ensuring that pharmaceutical
products are of the quality required for their intended use (4).
quality control
All measures taken, including the setting of specifications, sampling,
testing and analytical clearance, to ensure that raw materials, inter-mediates,
packaging materials and finished pharmaceutical products
conform with established specifications for identity, strength, purity
and other characteristics (4).
quality manual
A handbook that describes the various elements of the system for
assuring the quality of the test results generated by a laboratory (see
Part One, section 2.1).
quality specification
Explicit written test procedures and requirements that must be met.
quality system
An appropriate infrastructure, encompassing the organizational
structure, procedures, processes and resources, and systematic actions
necessary to ensure adequate confidence that a product (or services).32
will satisfy given requirements for quality (see Part One, sections 2.1
and 3.1).
specification
A document describing in detail the requirements with which the
pharmaceutical products or materials used or obtained during manu-facture
have to conform. Specifications serve as a basis for quality
evaluation.
specifications archive
An up-to-date collection of all quality specifications and related docu-ments
(see Part Two, section 9).
standard operating procedure (SOP)
An authorized written procedure giving instructions for performing
operations not necessarily specific to a given product or material
but of a more general nature (e.g. equipment operation, maintenance
and cleaning; validation; cleaning of premises and environmental con-trol;
sampling and inspection). Certain SOPs may be used to supple-ment
product-specific master and batch production documentation
(4).
test report
The report of the results, including the final conclusion of the analysis
of a sample which has been submitted by a laboratory in another
country or in the field not having appropriate facilities to perform
certain tests, and issued by the official pharmaceutical control labora-tory
that performed the test. This is often in the same style as a
certificate of analysis (see Part Three, section 17.3).
traceability
Traceability aims at ensuring that the results of laboratory measure-ments
using procedures of lower metrological order are reproducible
and scientifically acceptable by referring to an internationally agreed
denominator by means of a reference procedure of highest metrologi-cal
order and/or a primary reference material (see Part Two, section
13).
validation of analytical procedures/methods
The documented evidence that analytical procedures or methods are
suitable for their intended purpose (7).
verification of methods
Verification is conducted where the methods are compendial to con-firm
whether the pharmaceutical product as compounded can be
analysed satisfactorily by the official method..33
Part One. Management and infrastructure
1. Organization and management
1.1 The laboratory, or the organization of which it is part, must be an
entity that is legally authorized to function and can be held legally
responsible.
1.2 The laboratory must be organized and operate so as to meet the
requirements laid down in these guidelines.
1.3 The laboratory must:
(a) have managerial and technical personnel with the authority and
resources needed to carry out their duties and to identify the
occurrence of departures from the quality system or the proce-dures
for performing tests and/or calibrations, validation and
verification, and to initiate actions to prevent or minimize such
departures;
(b) have arrangements to ensure that its management and personnel
are not subject to commercial, political, financial and other pres-sures
or conflicts of interest that may adversely affect the quality
of their work;
(c) define, with the aid of organizational charts, the organization and
management structure of the laboratory, its place in any parent
organization, such as the ministry or the drug regulatory author-ity,
and the relationships between management, technical opera-tions,
support services and the quality system;
(d) specify the responsibility, authority and interrelationships of all
personnel who manage, perform or verify work which affects
the quality of the tests and/or calibrations, validations and
verifications;
(e) provide adequate supervision of staff, including trainees, by
persons familiar with the test and/or calibration, validation and
verification methods and procedures, as well as their purpose and
the assessment of the results;
(f) have a technical manager who has overall responsibility for the
technical operations and the provision of resources needed to
ensure the required quality of laboratory operations; and
(g) have appropriate safety procedures (see Part Four).
1.4 The laboratory, regardless of whether it is small (without sub-units)
or large (and possibly divided into subunits), must have a
central registry with the following functions:.34
(a) receiving, distributing and supervising the consignment of the
samples to the specific units;
(b) keeping records on all incoming samples and accompanying
documents;
(c) ensuring the precise allocation of responsibilities, particularly
in the designation of specific units for particular types of drugs;
and
(d) maintaining a specifications archive (see Part Two, section 9)
containing an up-to-date collection of all quality specifications
and related documents.
1.5 In a large laboratory, communication and coordination must be
guaranteed between the staff involved in the testing of the same
sample in different units.
2. Quality system
2.1 The laboratory management establishes, implements and main-tains
a quality system appropriate to the scope of its activities,
including the type, range and volume of testing and/or calibration,
validation and verification activities it undertakes. The laboratory
management must describe its policies, systems, programmes, proce-dures
and instructions to the extent necessary to enable the labora-tory
to assure the quality of the test results that it generates. The
documentation used in this quality system must be communicated and
available to, and understood and implemented by, the appropriate
personnel. The elements of this system must be documented in a
quality manual, available to the laboratory personnel, which must
be maintained and updated by a nominated responsible member
of the laboratory personnel. The quality manual must contain as a
minimum:
(a) the structure of the laboratory (organizational chart);
(b) the operational and functional activities pertaining to quality, so
that each person concerned will know the extent and the limits of
his or her responsibilities;
(c) the general internal quality assurance procedures;
(d) references to specific quality assurance procedures for each test;
(e) information on participation in appropriate proficiency testing
schemes, use of reference materials, etc.;
(f) details of satisfactory arrangements for feedback and corrective
action when testing discrepancies are detected;.35
(g) a procedure for dealing with complaints;
(h) a flow-chart for samples;
(i) details of audit and quality system review;
(j) information on the appropriate qualifications that personnel are
required to possess;
(k) information on initial and in-service training of staff;
(l) a quality policy statement, including at least the following:
(i) a statement of the laboratory management’s intentions with
respect to the standard of service it will provide;
(ii) the purpose of the quality system;
(iii) the laboratory management’s commitment to good profes-sional
practice and quality of testing, calibration, validation
and verification, as a service to its clients;
(iv) the laboratory management’s commitment to compliance
with the content of these guidelines;
(v) a requirement that all personnel concerned with testing
and calibration activities within the laboratory familiarize
themselves with the documentation concerning quality and
the implementation of the policies and procedures in their
work.
2.2 The quality system must be reviewed systematically and periodi-cally
(internal and external audits) by, or on behalf of, the manage-ment
to ensure the continued effectiveness of the arrangements and
apply any necessary corrective measures. Such reviews must be re-corded,
together with details of any corrective action taken.
2.3 The laboratory management must appoint a member of the staff
as quality manager, who, irrespective of other duties and responsi-bilities,
should have defined responsibilities and authority for ensur-ing
that the quality system is implemented and followed at all times.
The quality manager must have direct access to the highest level of
management at which decisions are taken on laboratory policies or
resources.
3. Control of documentation
3.1 Documentation is an essential part of the quality system. The
laboratory must establish and maintain procedures to control and
review all documents (both internally generated and from external
sources) that form part of the quality documentation..36
4. Records
4.1 The laboratory must establish and maintain procedures for the
identification, collection, indexing, retrieval, storage, maintenance
and disposal of, and access to, all quality documentation and technical
records.
4.2 All original observations, calculations and derived data, calibra-tion,
validation and verification records, etc., and final results must be
retained on record for an appropriate period of time in accordance
with national regulations. Ideally, they should be kept for the whole
length of time that the drug concerned is on the market. The records
for each test must contain sufficient information to permit the tests to
be repeated. The records must include the identity of the personnel
involved in the sampling, preparation and testing of the samples. The
records of samples to be used in legal proceedings should be kept
according to the legal requirements applicable to them.
4.3 All records must be legible, readily retrievable, stored and
retained, using facilities that provide a suitable environment that will
prevent modification, damage or deterioration and/or loss. The condi-tions
under which all original records are stored must be such as to
ensure their security and confidentiality. Quality records must include
reports from internal (and external, if performed) audits and manage-ment
reviews, including records of possible corrective and preventive
actions.
4.4 Authorized written standardized operating procedures (SOPs)
are required, including, but not limited to, instructions for administra-tive
and technical operations, such as:
(a) the purchase and receipt of consignments of materials (e.g.
samples, reference materials, reagents);
(b) the internal labelling, quarantine and storage of materials;
(c) the appropriate installation of each instrument and item of
equipment;
(d) sampling and inspection;
(e) the testing of materials, with descriptions of the methods and
equipment used;
(f) the qualification of equipment;
(g) the calibration of analytical apparatus;
(h) maintenance, cleaning and sanitation;
(i) safety measures;.37
( j) actions relating to personnel matters, including qualifications,
training, clothing and hygiene;
(k) environmental monitoring;
(l) the preparation and control of reference materials.
5. Data-processing equipment
5.1 For computers, automated tests or calibration equipment, and the
collection, processing, recording, reporting, storage or retrieval of test
and/or calibration data, the laboratory must ensure that:
(a) calculations and data transfers are systematically subject to
appropriate verifications;
(b) computer software developed by the user is documented in
sufficient detail and appropriately validated or verified as being
adequate for use;
(c) procedures are established and implemented for protecting the
integrity of data. Such procedures must include, but are not
limited to, measures to ensure the integrity and confidentiality of
data entry or collection, and the storage, transmission and pro-cessing
of data;
(d) computers and automated equipment are maintained so as to
function properly, and are provided with the environmental and
operating conditions necessary to ensure the integrity of test and
calibration data;
(e) procedures are established and implemented for making, docu-menting
and controlling for changes to information maintained in
computerized systems; and
(f) procedures exist to protect and keep back-up data on computers
or other means (e.g. magnetic tapes, diskettes and CD-ROMs) at
all times, and to prevent unauthorized access or amendments to
the data.
6. Personnel
6.1 The laboratory must have sufficient personnel with the necessary
education, training, technical knowledge and experience for their
assigned functions. They should be free from any conflict of interest
and not subject to any pressure that would interfere with the quality
of the results.
6.2 The laboratory management must ensure the competence of all
persons operating specific equipment, instruments or other devices,.38
who are performing tests and/or calibrations, validations or veri-fications.
Their duties also involve the evaluation of results as well as
signing test reports (see Appendix 1) and calibration certificates.
6.3 Staff undergoing training must be appropriately supervised, and
a formal assessment after training is recommended. Personnel per-forming
specific tasks must be appropriately qualified in terms of
their education, training, experience and/or demonstrated skills, as
required.
6.4 The laboratory personnel must be permanently employed or
under contract. The laboratory must ensure that additional technical
and key support personnel who are under contract are supervised
and sufficiently competent and motivated, and that their work is in
accordance with the good practice of the laboratory.
6.5 The laboratory must maintain current job descriptions for mana-gerial,
technical and key support personnel involved in tests and/or
calibrations, validations and verifications. The laboratory must also
maintain records of all technical personnel, including those under
contract, describing their areas of competence, educational and pro-fessional
qualifications, training, skills and experience. This informa-tion
must be readily available and must include the date on which
authorization and/or competence was confirmed. The criteria on
which the authorization is based must also be given, together with the
name of the confirming authority.
6.6 The laboratory must have the following managerial and technical
personnel:
(a) a head of laboratory (supervisor), who must be of high profes-sional
standing with extensive experience in drug analysis and
laboratory management in a pharmaceutical control laboratory in
the regulatory sector or in industry. The head of laboratory also
takes final responsibility for recommending any regulatory action
in the event of non-compliance of a tested sample. The person’s
function is to ensure that:
(i) all key members of the laboratory staff have the requisite
competence and are given grades matching their
responsibilities;
(ii) standard samples are analysed periodically;
(iii) the adequacy of existing staffing, management and training
procedures is reviewed periodically;
(iv) “self-checking” procedures for instrument operators are
devised;.39
(v) regular in-service training programmes to update and extend
the skills of both professionals and technicians are arranged;
(vi) the safe keeping of any narcotics (see Part One, sections
7.10–7.12) kept in the workplace is under the supervision of
an authorized person;
(b) a head of central registry, who must have wide experience in drug
analysis and be responsible for:
(i) receiving and keeping records of all incoming samples and
accompanying documents;
(ii) supervising their consignment to the specific units con-cerned;
(iii) monitoring the progress of analyses and the dispatch of
completed reports (see also Part One, section 1.4);
(iv) if required, collating and evaluating the test results for each
analysis;
(c) analysts, who must be graduates in pharmacy, analytical chemis-try,
microbiology or other relevant subjects with the requisite
knowledge, skills and ability to adequately perform the tasks
assigned to them by management and to supervise technical staff;
(d) technical staff, who should hold diplomas in their subjects
awarded by technical or vocational schools;
(e) a storekeeper (see Part Two, section 10.13), who is responsible
for keeping the central store and must have appropriate compe-tence
and be trained to handle reagents and materials with the
necessary care and safety;
(f) a quality manager (see Part One, section 2.3).
6.7 In large laboratories with subunits, the following additional per-sonnel
are necessary:
(a) heads of various subunits;
(b) a reference material coordinator (see Part Two, section 11.8).
6.8 The more routine analyses performed, the greater the propor-tion
of technicians required. Non-routine work, and particularly the
review of test methods for newly registered drugs, requires a higher
proportion of fully qualified specialists. In general, the ratio of techni-cians
to analysts in a routine testing environment has been shown to
be 3: 1 in a chemical or physicochemical unit, and 5 : 2 in a biological
or microbiological laboratory..40
7. Premises
7.1 The laboratory should be of a suitable size, construction and
location. Safety requirements should be taken into consideration in
the design (see Part Four).
7.2 The design of the laboratory should be such as to provide an
adequate degree of separation of any activity which may interfere
with the proper conduct of each study.
7.3 The laboratory should have a sufficient number of rooms or areas
to ensure that test systems are isolated from one another.
7.4 The premises must have suitable testing and safety equipment.
The necessary energy sources should be available; if the line voltage
is variable, suitable voltage stabilizers should be installed.
7.5 Storage rooms or areas should be available, as needed, for sup-plies
and materials, and should be conveniently located. These rooms
should be separated from those areas housing the test systems and
should provide adequate protection against infestation, contamina-tion
and/or deterioration.
7.6 To prevent contamination or mix-ups, separate rooms or areas
for the receipt and storage of test and reference items should be
available, as well as for the mixing of test items with a vehicle.
7.7 Storage rooms or areas for test items should be separate from
those containing the test systems. They should be constructed in such
a way as to preserve the identity, concentration, purity and stability of
the test item, and ensure safe storage of hazardous substances. All
storage areas must be located and equipped in accordance with fire
regulations. For safety reasons, and to reduce contamination of the
laboratory environment, flammable reagents, fuming and concen-trated
acids and bases, volatile amines, etc., must never be kept in the
laboratory without good reason.
Central store
7.8 Separate central storage facilities must be maintained for the
secure storage of samples, retained samples (see Part Three, section
18), and reagents, laboratory accessories (see Part Two, sections
10.12–10.14) and reference materials (see Part Two, section 11).
Storage facilities must be equipped to store material, if necessary,
under refrigeration and securely locked. Access must be restricted to
designated personnel.
7.9 The central store should be organized in such a way so as to
accommodate incoming and outgoing samples, reagents, equipment,
instruments and other devices..41
7.10 Appropriate safety regulations must be drawn up and rigorously
implemented wherever toxic or flammable reagents are stored or
used.
7.11 Reagents subject to poison regulations or to the controls applied
to narcotic and psychotropic substances must be clearly marked as
“Poison”. They must be kept separately from other reagents in locked
cabinets.
7.12 The designated responsible member of staff must maintain a
register of these substances. The head of each unit must accept per-sonal
responsibility for the safe keeping of any of these reagents kept
in the workplace (see Part One, section 6.6).
7.13 Archive facilities should be provided to ensure the secure
storage and retrieval of all documents (internally generated or from
external sources), samples of test items and specimens. The design
and condition of the archives should be such as to protect the
contents from untimely deterioration. Access to the archives must be
restricted to designated personnel.
7.14 The handling and disposal of wastes should be carried out in
such a way as not to jeopardize the integrity of studies and the
environment. Appropriate facilities for the collection, storage and
disposal of wastes should be available, as well as a means of decon-tamination,
where applicable, and transportation.
7.15 The environment in which the tests are undertaken must not be
such as to invalidate the test results or adversely affect the required
accuracy of measurements. This applies particularly to sites other
than permanent laboratory premises. Testing premises must be pro-tected,
as required, from conditions such as heat, cold, dust, moisture,
steam, noise, vibration and electromagnetic disturbance or interfer-ence.
Devices to monitor the environmental conditions must be in-stalled,
if required by the nature of the testing. Access to, and use of,
all test areas must be controlled and limited to the minimum neces-sary
for their designated purpose. Persons external to the laboratory
must satisfy the specified conditions of entry. Adequate measures
must be taken to ensure good housekeeping in the test laboratory.
8. Equipment, instruments and other devices
8.1 Equipment, instruments and other devices must be designed, con-structed,
adapted, located, calibrated, qualified, verified and main-tained
as required by the operations to be carried out in the local
environment. The user should purchase the equipment from an
agent capable of providing full technical support and maintenance.42
when necessary. Documentation should be written in the language
employed in the laboratory.
8.2 To ensure proper sampling and measurement, the laboratory
must have the required test equipment, instruments and other devices
for the correct performance of the tests and/or calibrations, valida-tions
and verifications (including the preparation of test and/or
calibration items, and the processing and analysis of test and/or
calibration data). As a guide, a list of basic equipment, instruments
and other devices is given in Appendix 2.
8.3 Equipment, instruments and other devices, including those used
for sampling, must meet the laboratory’s requirements, and comply
with the relevant standard specifications, as well as be verified and/or
calibrated (see Part Two, section 12).
Part Two. Materials and setting-up of equipment,
instruments and other devices
9. Specifications archive
9.1 It is recommended that every pharmaceutical control labora-tory
should have a specifications archive. Current versions of all
necessary specifications should be kept in accordance with the
national legislation, as described in pharmacopoeial compendia or in
manufacturers’ registration documents. All updates and corrections
must be noted in the principal volumes of pharmacopoeias to prevent
the use of obsolete sections. Additional or replacement pages for
loose-leaf publications must be inserted immediately upon receipt,
and pages no longer valid must be removed. Adequate numbers of
supplements and addenda must be available.
Content
9.2 The specifications archive must contain:
(a) a list of all the pharmacopoeias in the laboratory;
(b) a file of non-pharmacopoeial quality specifications for drugs
tested to specifications established either by the manufacturer or
by the laboratory itself and approved by the authority responsible
for drug control. In this file, each entry must be numbered and
dated so that the latest version can easily be recognized. In ad-dition,
the version in the archive file (master copy) must bear
the date of approval by the national registration authority or the
specific unit and contain any other information relevant to the
status of the quality specifications. All subsequent corrections or.43
changes must be entered in the master copy and endorsed with
the name and signature of the person responsible and the date. A
revised document should be produced as soon as possible.
9.3 Master copies of documents should not be released from the
archive; photocopies must be accounted for and controlled for labora-tory
use.
9.4 Manufacturers’ specifications are the property of the company
concerned. They are often made available to governments strictly for
the purpose of assessing applications for marketing authorization.
The pharmaceutical control laboratory may need to negotiate their
release with manufacturers or even, in some cases, to develop inde-pendent
specifications. National laboratories may be asked routinely
to give their opinion on the specifications for each newly introduced
pharmaceutical product before it is authorized for marketing by the
drug regulatory authority.
9.5 In a large laboratory the specifications archive supervisor will
provide a documentation service and will be responsible for:
(a) updating all pharmacopoeias, including the insertion of supple-ments,
addenda and descriptions of corrective measures used in
the laboratory;
(b) maintaining a specifications file for all drugs authorized for mar-keting
within the country concerned.
10. Reagents
10.1 All reagents and chemicals, including solvents and materials
used in tests and assays, must be of appropriate quality.
10.2 Reagents must be purchased from reputable manufacturers or
dealers, and be accompanied by the certificate of analysis. In some
cases, a list of pre-qualified suppliers will have to be established.
10.3 In the preparation of reagents in the laboratory:
(a) responsibility for this task must be clearly specified in the job
description of the person assigned to carry it out;
(b) prescribed procedures must be used which are in accordance with
published pharmacopoeial or other standards, where available.
Records should be kept of the preparation and standardization of
volumetric solutions.
10.4 The labels of all reagents must clearly specify:
(a) the contents, the manufacturer, the date received and, as appro-priate,
the concentration, standardization factor, shelf-life and.44
storage conditions. Labels for reagents prepared in the laboratory
must state the date of preparation, and give the name and initials
of the responsible technician;
(b) for volumetric solutions prepared by dilution, the name of the
manufacturer of the original reagent, the date of preparation,
the date of standardization, the dilution factor, and the name of
the responsible technician.
10.5 In the transportation and subdivision of reagents:
(a) they must not be moved unnecessarily from unit to unit;
(b) whenever possible, they must be transported in the original
containers;
(c) when subdivision is necessary, scrupulously clean, fully labelled
containers must always be used.
Inspection
10.6 All reagent containers must be inspected to ensure that the seals
are intact both when they are delivered to the central store and when
they are distributed to the units.
10.7 These inspections must be recorded on the label, together with
the date, and the name and initials of the person responsible.
10.8 Reagents appearing to have been tampered with should be
rejected; however, this requirement may exceptionally be waived if
the identity and purity of the reagent concerned can be confirmed
by testing.
Distilled water and deionized water
10.9 Water should be considered as a reagent.
10.10 Precautions must be taken to avoid contamination during its
supply, storage and distribution.
10.11 Stocks must be verified regularly to ensure that pharmaco-poeial
and other official quality requirements are met.
Storage
10.12 Stocks of reagents must be maintained in a central store under
the appropriate storage conditions. The store must contain a supply
of clean bottles, vials, spoons, funnels and labels, as required, for
dispensing reagents from larger to smaller containers. Special equip-ment
may be needed for the transfer of larger volumes of corrosive
liquids..45
10.13 The storekeeper is responsible for looking after the central
store and its inventory, and for noting the expiry date of chemicals
and reagents. Training may be needed in handling chemicals with the
necessary care and safety.
10.14 The laboratory must provide separate rooms or areas for stor-ing
flammable substances, fuming and concentrated acids and bases,
volatile amines and other reagents, such as hydrochloric acid, nitric
acid, ammonia and bromine. Self-igniting materials, such as metallic
sodium and potassium, must also be stored separately.
11. Reference materials
11.1 Reference materials (8, 9) (e.g. official reference substances
and reference preparations, secondary reference materials and non-official
materials prepared in the laboratory as working standards) are
necessary for the testing and/or calibration, validation or verification
of a sample or of equipment, instruments or other devices.
Registration and labelling
11.2 An identification number must be assigned to all reference
materials, whether newly delivered or prepared in the laboratory.
11.3 A new identification number must be assigned to each new
batch.
11.4 This number must be marked on each vial of the material.
11.5 The identification number must be quoted on the analytical
worksheet every time the material is used (see Part Three, section
15.5).
Central register
11.6 Details concerning all reference materials required are compiled
in a central register, which may be a record book, a card file, or data-processing
equipment.
11.7 The central register must provide the following information:
(a) the identification number of the material;
(b) a precise description of the material;
(c) the source;
(d) the date of receipt;
(e) the batch designation or other identification code;.46
(f) the intended use of the material (e.g. as an infrared reference
material, as an impurity reference material for thin-layer chroma-tography,
etc.);
(g) the location of storage in the laboratory, and any special storage
conditions;
(h) any further necessary information (e.g. the results of inspections).
11.8 The functions of a person serving as a reference material co-ordinator
in a large laboratory (see Part One, section 6.7) must be
specified. This person is responsible for keeping the central register
for reference materials.
11.9 If a national drug laboratory is required to establish reference
materials for use by other institutions or by drug manufacturers, a
separate reference materials unit, which would perform all the duties
of the reference material coordinator, may be required.
Information file
11.10 In addition to the central register, a file must be kept in which
all information on the properties of each reference material is
entered.
11.11 For working standards prepared in the laboratory, the file must
include the results of all tests and verifications used to establish the
standard; these must be initialled by the responsible analyst.
Inspection
11.12 All reference materials must be inspected at regular intervals to
ensure that deterioration has not occurred and that the storage condi-tions
are appropriate for the materials concerned.
11.13 The results of these inspections must be recorded in the central
register and/or the information file, and initialled by the responsible
analyst.
11.14 Further details on the handling and storage of reference mate-rials
are given in the general guidelines on the establishment, mainte-nance
and distribution of reference materials (8). A compilation of
national, regional and international reference substances, which is
kept up to date, is available from the Secretariat (9).
12. Calibration, validation and verification of equipment,
instruments and other devices
12.1 All equipment, instruments and other devices used to measure
the physical properties of substances must be regularly calibrated,
validated and verified..47
12.2 Specific procedures must be established for each type of equip-ment,
instrument and other device, having regard to the extent to
which they are used, verified and calibrated at regular intervals ac-cording
to the SOP.
For example:
(a) pH meters are verified with standard certified buffer solutions at
least once a day;
(b) infrared spectrophotometers require verification at least once a
day and calibration at regular intervals.
12.3 Only authorized personnel should operate equipment, instru-ments
and devices. Up-to-date instructions on the use, maintenance,
verification and calibration of equipment, instruments and devices
(including any relevant manuals provided by the manufacturer) must
be readily available for use by the appropriate laboratory personnel
(e.g. a copy of these instructions should be placed beside each appa-ratus,
together with a schedule of the dates on which it is due for
verification and/or calibration). The results of the verification must
be recorded on a control chart, forming the basis for the timing of
calibration.
12.4 Each item of equipment, instrument or other device used for
testing, verification and calibration must, when practicable, be uni-quely
identified.
12.5 Records must be kept of each item of equipment, instrument or
other device used to perform testing, verification and/or calibration.
The records must include at least the following:
(a) the identity of the equipment, instrument or other device;
(b) the manufacturer’s name, the type identification, serial number
or other unique identification;
(c) the verification and/or calibration required to comply with the
specifications;
(d) the current location, where appropriate;
(e) the manufacturer’s instructions, if available, or an indication of
their location;
(f) the dates, results and copies of reports, verifications and certifi-cates
of all calibrations, adjustments, acceptance criteria, and the
due date of the next verification and/or calibration;
(g) the maintenance carried out to date and the maintenance plan;
(h) a history of any damage, malfunction, modification or repair..48
It is also recommended that records should be kept and additional
observations made of the time for which the equipment, instruments
or devices were used.
12.6 To prevent contamination or deterioration, the laboratory must
perform systematic verifications, specify procedures and have an es-tablished
plan for the safe handling, transport, storage, use and main-tenance
of measuring equipment so as to ensure that it functions
properly.
12.7 Maintenance procedures must be established (regular servicing
must be performed by a team of maintenance specialists, whether
internal or external, whenever possible).
12.8 Equipment, instruments and other devices, either subjected
to overloading or mishandling, giving suspect results, shown to be
defective or outside specified limits, must be taken out of service
and clearly labelled or marked. Wherever possible, they must not be
used until they have been repaired and shown by calibration or testing
to perform correctly.
12.9 All equipment, instruments and other devices under the control
of the laboratory and requiring calibration must be labelled, coded or
otherwise identified to indicate the status of calibration and the date
when recalibration is due.
12.10 When the equipment, instruments and other devices are out-side
the direct control of the laboratory for a certain period of time,
the laboratory must ensure that their function and calibration status
are verified and shown to be satisfactory before they are returned to
service.
12.11 Depending on the types of analytical equipment, instruments
and other devices used, their fragility, the extent to which they are
used, and the skills required to operate them, they can be:
(a) grouped together;
(b) dispersed between the various units;
(c) protected from extreme states of humidity or temperature in a
specially designed area;
(d) adequately protected so as to be resistant to corrosion;
(e) protected against mould and fungal growth.
12.12 Further guidance:
(a) Procedures for verifying and calibrating refractometers, ther-mometers
used in determinations of melting temperatures, and.49
potentiometers for pH determinations are given in The inter-national
pharmacopoeia (10), together with methods for verifying
the reliability of scales for ultraviolet and infrared spectropho-tometers
and spectrofluorometers.
(b) Guidelines for the validation of analytical procedures used in the
examination of chemical and physicochemical attributes of phar-maceutical
materials are provided in Annex 5 of the thirty-second
report of the WHO Expert Committee on Specifications for Phar-maceutical
Preparations (11). Other guidelines are also available
(12).
13. Traceability
13.1 Traceability aims at ensuring that the results of laboratory mea-surements
using procedures of lower metrological order are repro-ducible
and scientifically acceptable by referring to an internationally
agreed denominator by means of a reference procedure of highest
metrological order and/or a primary reference material. The analyti-cal
specificities of each measurement procedure and reference mate-rial
that is used to ascertain traceability must therefore be known.
A transfer protocol, together with a detailed description of the trace-ability
chain, including measurement procedures and reference
materials at all levels, must be prepared. The protocol must be
meticulously followed to ensure the reproducibility of results.
13.2 Traceability takes into account the fact that the validity of labo-ratory
investigations is limited by uncertainties. It applies to measure-ment
procedures as well as to reference materials used for the
calibration of such procedures.
13.3 For the majority of quantities, a variety of measurement proce-dures
have been developed to meet the requirements of the intended
purpose of analysis.
13.4 Both quantitative and qualitative measurement procedures are
available (8).
13.5 Quantitative measurement procedures provide numerical re-sults
that vary in terms of their precision, accuracy, and the analytical
sensitivity and selectivity of measurement. A hierarchy of procedures
can be established on the basis of the accuracy of measurement, as
follows:
(a) Measurement procedures of the highest metrological order (pri-mary
reference measurement procedures). These are used to
quantitatively measure a quantity of known physicochemical
structure with a negligible measurement error (bias). The re-sult
obtained by the use of such a procedure, which some experts.50
refer to as a definitive method, is nearest to the “true value”.
(Examples include weighing, gas chromatography–mass spectro-metry
and isotope dilution techniques.)
(b) Reference measurement procedures (secondary reference
measurement procedures). The accuracy of such procedures is
assessed by:
(i) comparing the results of measurement by such a procedure
with those of a measurement procedure of highest metro-logical
order;
(ii) calibration with an international reference material with an
assigned value in arbitrary units;
(iii) calibration with a primary reference material (e.g. an
International Chemical Reference Substance). (Examples
include flame photometry, atomic absorption spectroscopy
and assay methods.)
(c) A routine measurement procedure (selected measurement pro-cedure).
This measures with sufficient reliability and practicality
for its intended purpose. The extent of any systematic deviation
of the results from their true value, as determined by a routine
measurement method, should be known.
13.6 “Semi-quantitative” measurement procedures provide results
that are less accurate and less precise than those obtained by quanti-tative
measurement. Such procedures measure a quantity in discrete
concentration intervals. In pharmacopoeias, these tests are referred
to as “limit tests”; they compare the response of the test substance
with that of the reference substance at the limiting level. The intervals
are expressed as rough estimates on an ordinal scale. In laboratory
observations made after geometrical dilution of the specimen, the
results are expressed in terms of titres. Typically, no linear relation
exists between the signal of observation and the concentration of the
quantity.
13.7 Qualitative measurement procedures are descriptive, and may
distinguish between the absence and presence of a quantity in
samples. The results are expressed in terms of a nominal scale. The
distinction between the presence and absence of the quantity in a
sample is related to the ability of the measurement procedure to
detect that quantity at a minimal concentration. The minimal concen-tration
of a quantity that will be positively indicated by the test system
(limit of detection), or the ability to quantify the analyte in the pres-ence
of other components of the specimen (limit of quantification),
may vary from one test system to another. A different approach is.51
used for pharmacopoeial standards and for substances that are estab-lished
and distributed by pharmacopoeial authorities, which give the
information provided by certificates of analysis together with expiry
dates.
13.8 Reference materials are used for the calibration of measurement
procedures, and have assigned values of a quantity. These values
should be established, whenever possible, by means of a method of
highest metrological order. The assigned values may also be estab-lished
by means of more than one measurement procedure, provided
that the results are not significantly different. A hierarchy of refer-ence
materials also exists, as follows:
(a) A designated primary chemical substance is one that is widely
acknowledged to possess the appropriate qualities within a speci-fied
context, and whose value is accepted without comparison
with another chemical substance being required (8).
(b) A secondary chemical reference substance is a substance whose
characteristics are assigned and/or calibrated by comparison with
a primary chemical reference substance. The extent of characteri-zation
and testing of a secondary chemical reference substance
may be less than that required for a primary chemical reference
substance. This definition may apply, inter alia, to working stan-dards
(see below).
(c) International biological standards are biological reference mate-rials
which have been exhaustively studied and which meet inter-national
requirements for accuracy, consistency and stability.
They are established by the WHO Expert Committee on Biologi-cal
Standardization. Such standards are generally assigned po-tency
values expressed in terms of International Units (IU) of
biological activity, on the basis of an extensive international col-laborative
study.
(d) A working standard (working calibrator) has an assigned value of
a quantity using one or more selected measurement procedures.
This calibrator is sometimes called a “manufacturer’s master cali-brator”
or an “in-house calibrator”. The working standard should
be compatible with the manufacturer’s selected measurement
procedure and with the procedure to be calibrated.
(e) A manufacturer’s product calibrator is used for the calibration of
a routine measurement procedure of an end user.
(f) A control material is used for testing the precision and accuracy
of the results. Such a material should have a matrix similar to that.52
of the samples to be measured. Assigned values, together with the
uncertainty of measurement appropriate to the intended use,
should be given.
Part Three. Working procedures
14. Incoming samples
14.1 Guidelines on sampling procedures for industrially manufac-tured
pharmaceuticals were adopted by the WHO Expert Committee
on Specifications for Pharmaceutical Preparations at its thirty-first
meeting (13). A compendium of guidelines is also available (14).
14.2 Samples received by the laboratory may be routine samples for
control, samples suspected of not complying with the specifications,
or samples submitted in connection with a marketing authorization
process. Close collaboration with those providing the samples is im-portant.
In particular, pharmaceutical inspectors who frequently sub-mit
samples should note that the sample must be large enough to
enable, if required, a number of replicate tests to be carried out (see
Part Three, section 16.3) and for part of the sample to be retained (see
Part Three, section 18).
14.3 It is common for three samples to be taken; these must be sealed
and documented. Where non-compliance is suspected, two samples
are retained in the laboratory and the third is retained by the manu-facturer.
The first sample is tested in accordance with the specifica-tion.
If it is non-compliant and the manufacturer objects to the results,
the third sample is analysed in the presence of the manufacturer’s
specialist. The second sample is analysed in case of dispute.
14.4 The laboratory must have a sampling plan and an internal proce-dure
for sampling, available to all analysts and technicians within the
laboratory.
Test request
14.5 A standard test request form must be filled out during sampling
and must accompany each sample submitted to the laboratory.
14.6 The test request form must provide or leave space for the follow-ing
information:
(a) the name of the institution or inspector that supplied the sample;
(b) the source of the material;
(c) a full description of the drug, including its composition, Interna-tional
Nonproprietary Name (INN) (if available), brand name(s),.53
dosage form and concentration or strength, the manufacturer, the
batch number (if available) and the marketing authorization
number;
(d) the size of the sample;
(e) the reason for requesting the analysis;
(f) the date on which the sample was collected;
(g) the size of the consignment from which it was taken, when
appropriate;
(h) the expiry date (for pharmaceutical products) or the retest date
(for starting materials or pharmaceutical excipients);
(i) the pharmacopoeial specifications or other official specifications
to be used for testing;
(j) a record of any further comments (e.g. discrepancies found);
(k) the required storage conditions.
Registration and labelling
14.7 All newly delivered samples and the accompanying documents
(e.g. the test request) must be assigned a registration number. Sepa-rate
registration numbers must be assigned to requests referring to
two or more drugs, different dosage forms, or different batches of the
same drug. If applicable (see Part Three, section 18), a registration
number must also be assigned to any incoming retained sample.
14.8 A label bearing the registration number must be affixed to each
container of the sample. Care must be taken to avoid obliterating any
other markings or inscriptions.
Central register
14.9 A central register must be kept, which may be a record book, a
card file, or data-processing equipment, where the following informa-tion
is recorded:
(a) the registration number of the sample;
(b) the date of receipt;
(c) the specific unit to which the sample was forwarded.
Inspection of the submitted sample
14.10 The sample received must immediately be inspected by labora-tory
staff to ensure that the labelling is in conformity with the infor-mation
contained in the test request. The findings must be recorded,.54
dated and initialled. If discrepancies are found, or if the sample is
obviously damaged, the fact must be recorded without delay on the
test request form. Any queries must be immediately referred back to
the provider of the sample.
Storage
14.11 The sample prior to testing (see Part Three, section 16.1), the
retained sample (see Part Three, section 18) and any portions of the
sample remaining after performance of all the required tests must be
stored safely taking into account, if necessary, the storage conditions
(15, 16) specified for the sample.
Forwarding to testing
14.12 The specific unit to which the sample is sent to for testing is
determined by the head of central registry.
14.13 The examination of a sample must not be started before the
relevant test request has been received.
14.14 The sample must be properly stored until all relevant documen-tation
has been received.
14.15 A request for analysis may be accepted verbally only in case of
emergencies. All details must immediately be placed on record, pend-ing
the receipt of written confirmation.
14.16 Data must be recorded on the analytical worksheet (see Part
Three, section 15).
14.17 Copies or duplicates of all documentation must accompany
each numbered sample when sent to the specific unit.
14.18 Testing must be performed as described under Part Three,
section 16.
15. Analytical worksheet
15.1 The analytical worksheet is an internal document in printed
form for recording information about the sample, the test procedure
and the results of testing. It may be complemented by the raw data
obtained in the analysis.
Purpose
15.2 The analytical worksheet contains:
(a) confirmation that the sample being examined is in accordance
with the requirements;
(b) documentary evidence to support regulatory action, if necessary..55
Use
15.3 A separate analytical worksheet must be used for each num-bered
sample.
15.4 If necessary, a further set of analytical worksheets in duplicate
can be used for a collaborating unit (after testing, all the results
should be assembled in a single analytical worksheet, using the data
from all collaborating units).
Content
15.5 The analytical worksheet must provide or leave space for the
following information:
(a) the registration number of the sample (see Part Three, section
14.7);
(b) page numbering, including the total number of pages (including
annexes);
(c) the date of the test request;
(d) the date on which the analysis was performed;
(e) the name and signature of the analyst;
(f) a description of the sample received;
(g) references to the specifications to which the sample was tested,
including the limits (adding any special methods employed) (see
Part Three, section 14.6), and the reference number of the speci-fications,
if available (e.g. pharmacopoeial monograph);
(h) the results obtained with the tested sample (see Part Three, sec-tion
16.4);
(i) the interpretation of the results and the final conclusions
(whether or not the sample was found to comply with the
specifications), signed by each of the analysts involved and ini-tialled
by the supervisor;
(j) the identity of the test equipment used (see Part Two, section 12);
(k) any further comments, for example, for internal information (see
Part Three, section 16.1). The above information may be comple-mented
by:
(i) detailed notes on the specifications selected and the methods
of assessment used (see Part Three, section 15.7);
(ii) whether and when portions of the sample were forwarded to
other units for special tests (for example, mass spectrometry,.56
X-ray diffraction), and the date when the results were
received;
(iii) the identification number of any reference material (see Part
Two, section 11.5);
(iv) if applicable, the results of an instrument verification;
(v) if applicable, the results of a reagent verification.
15.6 The completed analytical worksheet must be signed by the re-sponsible
analyst(s) and initialled by the supervisor.
Selection of the specifications to be used
15.7 The specifications necessary to assess the sample may be those
given in the test request; these are usually an existing particular
pharmacopoeial monograph, or the manufacturer’s specifications. If
no precise instruction is given, the specifications in the officially rec-ognized
national pharmacopoeia may be used or, failing this, the
manufacturer’s officially approved or other nationally recognized
specifications. If no suitable method is available:
(a) the specifications contained in the product licence may be re-quested
from the manufacturer and validated, if the general
policy of the laboratory permits this action (see Part Two, section
9.4); or
(b) the requirements are drafted in the laboratory itself on the basis
of published information and any other relevant documentation
and should be validated by the testing laboratory before they are
adopted as a SOP (1–3).
15.8 For official specifications, the current version must be available
(see Part Two, section 9.1).
Filing
15.9 The analytical worksheet must be placed on file for safe keeping,
together with any attachments, including calculations and tracings of
instrumental analyses.
15.10 If the analytical worksheet is stored in a central archive, a copy
should be retained in the specific unit concerned for easy reference.
15.11 The analytical test report (see Part Three, sections 17.3 and
17.4) must be prepared on the basis of the worksheet (see Appendix
1 and Annex 10).
15.12 When mistakes are made in analytical worksheets or when data
or text need to be amended, the old information should be deleted by.57
means of a single line (not erased nor made illegible) and the new
information added alongside. All such alterations should be initialled
or signed by the person making the correction and the date of the
change inserted. The reason for the change should also be given on
the worksheet.
16. Testing
16.1 The sample must be tested in accordance with the workplan of
the laboratory after completion of the preliminary procedures. If this
is not feasible, the reasons must be noted, for example in the analyti-cal
worksheet (see Part Three, section 15), and the sample must be
stored in a special place which is kept locked (see Part Three, section
14.11).
16.2 Specific tests required, such as mass spectrometry or X-ray dif-fraction,
may need to be carried out by another unit or by a special-ized
external laboratory. The responsible person should prepare the
request and arrange for the transfer of the required number of units
(bottles, vials, tablets) from the sample. Each of these units must bear
the correct registration number.
Guidance for performing test methods
16.3 Detailed guidance on official pharmacopoeial requirements is
usually given in the general notices and specific monographs of the
pharmacopoeia concerned. Where system suitability criteria are
defined in the method, they should be fulfilled.
16.4 All values obtained from each test, including blank results, must
immediately be entered on the analytical worksheet, and all graphical
data, whether obtained from recording instruments or plotted by
hand, must be attached (see Part Three, section 15).
17. Evaluation of test results
17.1 Test results must be reviewed and, where appropriate, evaluated
statistically after completion of all the tests to determine whether they
are mutually consistent and if they meet the specifications used. The
evaluation should take into consideration the results of all the tests.
Whenever doubtful results are obtained, they should be investigated.
The complete testing procedure needs to be checked according to the
internal quality system (see also Part One, section 2). Doubtful results
can be rejected only if they are clearly due to error, which has been
identified.
17.2 All conclusions must be entered on the analytical worksheet (see
Part Three, section 15) by the analyst and initialled by the supervisor..58
Analytical test report
17.3 The analytical test report (see Appendix 1) is a compilation of
the results and states the conclusions of the examination of a sample.
It must be:
(a) issued by the laboratory;
(b) based on the analytical worksheet (see Part Three, section 15).
Content of the analytical test report
17.4 The analytical test report must provide the following informa-tion
(see Appendix 1):
(a) the registration number of the sample;
(b) the name and address of the laboratory testing the sample;
(c) the name and address of the originator of the request for
analysis;
(d) the name and description and batch number of the sample,
where appropriate;
(e) a reference to the specifications used for testing the sample,
including the limits;
(f) the results of all the tests performed, or the numerical results of
all the tests performed (if applicable);
(g) a conclusion whether or not the sample was found to be within
the limits of the specifications used;
(h) the date on which the test was performed;
(i) the signature of the head of the laboratory or authorized person;
(j) the name and address of the repacker and/or trader, if
applicable;
(k) the name and address of the original manufacturer;
(l) whether or not the sample complies with the requirements;
(m) the date on which the sample was received;
(n) the expiry date.
18. Retained samples
18.1 Samples are retained for at least 6 months if they are found to
comply with the requirements and for at least 12 months or until their
expiry date (whichever is longer) in the case of non-compliance (for
storage, see Part Three, section 14.11)..59
Part Four. Safety
19. General rules
19.1 General and specific safety instructions must be made available
to each staff member and supplemented regularly as appropriate (e.g.
with written material, poster displays, audiovisual material and occa-sional
seminars).
19.2 General rules for safe working in accordance with national regu-lations
and SOPs normally include the following requirements:
(a) safety data sheets must be available to staff before testing is
carried out;
(b) smoking, eating and drinking in the laboratory must be
prohibited;
(c) staff must be familiar with the use of fire-fighting equipment,
including fire extinguishers, fire blankets and gas masks;
(d) staff must wear laboratory coats or other protective clothing,
including eye protection;
(e) special care must be taken, as appropriate, in handling, for ex-ample,
highly potent, infectious or volatile substances;
(f) all containers of chemicals must be fully labelled and include
prominent warnings (e.g. “Poison”, “Flammable”, “Radiation”,
etc.) whenever appropriate;
(g) adequate insulation and spark-proofing must be provided for
electrical wiring and equipment, including refrigerators;
(h) safety rules in handling cylinders of compressed gases must be
observed, and staff must be familiar with the relevant colour
identification codes;
(i) staff must be aware of the need to avoid working alone in the
laboratory;
(j) first-aid materials must be provided, and staff instructed in first-aid
techniques, emergency care and the use of antidotes.
19.3 Protective clothing must be available, including eye protection,
masks and gloves. Water showers should be installed. Rubber suction
bulbs must be used on manual pipettes and siphons. Staff must be
instructed in the safe handling of glassware, corrosive reagents and
solvents, and particularly in the use of safety containers or baskets
to avoid spillage from containers. Warnings, precautions and
instructions must be given for work with violent, uncontrollable or.60
dangerous reactions when handling specific reagents (e.g. mixing
water and acids, or acetone–chloroform and ammonia), flammable
products, oxidizing or radioactive agents, and especially biologicals
such as infectious agents. Peroxide-free solvents should be used. Staff
must be aware of methods for the safe disposal of unwanted corrosive
or dangerous products by neutralization or deactivation and of the
need for safe and complete disposal of mercury and its salts (see also
Part One, section 7.14).
19.4 Poisonous or hazardous products must be singled out and la-belled
appropriately, but it must not be taken for granted that all
other chemicals and biologicals are safe. Unnecessary contact with
reagents, especially solvents and their vapours, must be avoided. The
use of known carcinogens and mutagens must be limited or totally
excluded if required by local regulations. Replacement of toxic
solvents and reagents by less toxic materials or reduction of their
use must always be the aim, particularly when new techniques are
developed.
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Report Series, No. 863).
16. Product assessment and registration. In: Quality assurance of
pharmaceu-ticals. A compendium of guidelines and related materials. Vol. 1. Geneva,
World Health Organization, 1997:31–104..62
Appendix 1
Model analytical test report for active
pharmaceutical ingredients, excipients and
pharmaceutical products
Registration no.:
1
Name and address of laboratory testing the sample:
Name and address of originator requesting analysis (if applicable):
Sample information
Name of product (INN,
2
brand name(s), etc.):
Dosage form (if applicable):
Concentration or strength (if applicable):
Marketing authorization number (if applicable):
Description (appearance of container and contents):
Batch number(s):
Required storage conditions (if applicable):
Date received:
Date of manufacture (if known):
Expiry date (for pharmaceutical products) or retest date (for starting
materials or pharmaceutical excipients):.63
Name and address of original manufacturer:
Telephone: Fax:
Name and address of repacker/trader (if applicable):
Telephone: Fax:
Test procedure Result Acceptance criteria
(reference) (numerical) (limits)
(if applicable) (if applicable)
Conclusions
Compliance with acceptance criteria: yes _ no _
Date test performed/finalized:
Name and address of head of laboratory/authorized person:
Telephone: Fax:
Signature:
Explanatory notes
1
Of sample or analytical test report.
2
The International Nonproprietary Name should be used whenever possible..64
Appendix 2
Equipment for a first-stage and medium-size
pharmaceutical control laboratory
A list of equipment considered by the Committee to be adequate
either for a first-stage or medium-size pharmaceutical control labora-tory
is given below.
National drug regulatory authorities or laboratories wishing to per-form
pharmaceutical analyses should consider the following list in the
establishment or upgrading of their testing facilities. For budgetary
reasons, it is necessary, besides the cost of equipment, to take into
consideration the cost of reference materials, reagents, solvents,
glassware, other laboratory commodities and personnel charges. Ex-perience
has shown that for sustainability, a laboratory should allow
a margin of 10–15% per year of the purchasing expenditure on equip-ment
to cover the cost of maintenance.
Guidance and information on the cost of equipment can be obtained
from the Secretariat.
First-stage laboratory
Equipment and major instruments Quantity
Top-loading balance 1
Analytical balance, semi-micro (4 digits) 1
Melting-point apparatus 1
pH meter (with assorted electrodes) 1
Microscope (binocular) 1
Polarimeter (manual) 1
High-performance liquid chromatograph with ultraviolet
detector 1
Ultraviolet/visible spectrophotometer 1
Infrared spectrophotometer with pellet press 1
Agate mortar with pestle 1
Equipment for thin-layer chromatography (TLC),
including spreader 1
TLC spotter 1
Developing chambers 6
Atomizers 6
Ultraviolet viewing lamp 1.65
Disintegration test equipment (1 basket for 6 tablets) 1
Soxhlet extraction apparatus (60 ml) 1
Micrometer callipers 1
Pycnometers 2
Burettes 5
Desiccator 1
Centrifuge (table-top model, 4-place swing rotor) 1
Water-bath (20 litres) 1
Hot plates with magnetic stirrers 3
Vacuum pump (rotary, oil) 1
Drying oven (60 litres) 1
Vacuum oven (17 litres) 1
Muffle furnace 1
Refrigerator (explosion-proof) 1
Water distilling apparatus (8 litres/hour) 1
Water deionizer (10 litres/hour) 1
Dehumidifier (where needed) 1
Fume hood 1
Optional items
Analytical balance, micro (5 digits) 1
Flame photometer (including air compressor) 1
Refractometer 1
Viscometer 1
Vortex mixer 1
Shaker (wrist-action) 1
Pipette rinser 1
Constant temperature water-bath 1
Ultrasonic cleaner (5 litres) 1
Medium-size laboratory
General laboratory equipment Quantity
Top-loading balance 1 or 2
Analytical balance, semi-micro (4 digits) 2
Analytical balance, micro (5 digits) 1.66
Microscope (binocular) 1 or 2
Equipment for TLC, including spreader 1
TLC multispotter 1
Developing chambers 6
Atomizers 6
Ultraviolet viewing lamp 1
Potentiometric titrimeter 1
Micro-Kjeldahl equipment (including fume flasks) 1
Burettes 6
Micrometer callipers 1
Heating mantles for flasks (assorted sizes: 50, 200 and
2000ml) 6
Sieves (assorted sizes) 2 sets
Centrifuge (floor model) 1
Shaker (wrist-action) 1
Vortex mixers 2
Water-bath (electrical, 20 litres) 2 or 3
Hot plates with magnetic stirrers 3 or 4
Vacuum pump (rotary, oil) 2
Vacuum rotary evaporator 1 or 2
Drying oven (60 litres) 2 or 3
Muffle furnace (23 litres) 1
Vacuum oven (17 litres) 1
Desiccators 2
Refrigerator (explosion-proof) 1
Freezer 1
Ultrasonic cleaners (5 litres) 2
Ultrasonic pipette cleaner 1
Water distilling apparatus (8 litres/hour) 1
Water deionizing equipment (10 litres/hour) 1
Fume hoods 2
Major instruments
Melting-point apparatus 1
Polarimeter 1
pH meters (with assorted electrodes) 2
High-performance liquid chromatograph with variable
wavelength ultraviolet/visible detector 1.67
Ultraviolet/visible spectrophotometer, double-beam 1
Infrared spectrophotometer with pellet press 1
Agate mortar with pestle 1
Gas chromatograph (flame ionization, direct head space) 1
Refractometer 1
Karl Fischer titrator 1
Potentiograph 1
Oxygen flask combustion apparatus 1
Disintegration test equipment (1 basket for 6 tablets) 1
Dissolution test equipment (for 6 tablets/capsules) 1
Optional items
Atomic absorption spectrophotometer 1
Spectrofluorometer 1
High-performance liquid chromatograph: 1
— with fluorescence detector 1
— with diode-array detector 1
— with refractive index detector 1
— with conductivity detector 1
TLC scanner 1
Crushing strength tester 1
Friability tester 1
Viscometer 1
Ice machine 1
Solvent-recovery apparatus 1
Equipment for microbiology unit
pH meter 1
Ultraviolet/visible spectrophotometer, single-beam 1
Microscopes (for bacteriology) 2
Membrane filter assembly for sterility tests 1
Colony counter with magnifier 1
Laminar air flow unit 1
Hot-air sterilizer 1
Incubators, 60 litres 2 or 3
Anaerobic jar 1
Zone reader 1
Centrifuge 1.68
Water-bath (thermostatically controlled) 2
Autoclaves (100 litres, top-loading) 2
Refrigerators (340 litres) 2
Deep freezer 1
Cleaning device for glassware, including pipettes 2.69
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 4
Considerations for requesting analysis of drug
samples
1
Many WHO Member States do not have adequate drug quality con-trol
facilities of their own. For drugs imported into such countries,
manufacturers’ batch certificates issued in accordance with the WHO
Certification Scheme (1) will normally provide sufficient information
on the quality and origin of a product. This assumes that an official
inspection of the manufacturing site has been performed and that the
manufacturer complies with good manufacturing practices (2). For
domestically manufactured pharmaceuticals, manufacturers’ batch
certificates may be relied upon to indicate the quality of a product.
This implies that the results of an inspection by the competent
national authority have shown that the manufacturer is capable of
reliably producing a product of the required quality.
However, in certain situations a need may arise for national authori-ties
to test drug samples when testing facilities are not available. For
this purpose, laboratories in other countries or contract laboratories
in the same or in another country may be contacted (for a model
certificate of analysis, see Annex 10). General considerations before
approaching them are set out below.
Important note: Any laboratory contacted has the right to decline
a request for analysis without furnishing any explanation or
remark.
Reason for analysis
Full-scale pharmacopoeial testing is expensive. The national author-ity
may prefer to limit analysis to those products which:
— show physical signs of instability or deterioration (3);
— are of unidentifiable origin;
— emanate from a supplier suspected of dealing in substandard
products;
— have given rise to disputed analytical results;
— are suspected of causing adverse reactions;
1
These considerations are applicable to national drug regulatory authorities, but may also
apply to the independent analysis of pharmaceuticals in trade..70
— will be used as evidence in litigation;
— are provided through drug donations.
Where the information on the quality of a product is important and
needs to be communicated rapidly (such as the presence of products
of deterioration or a new impurity profile), selected purity tests may
be performed instead of full-scale pharmacopoeial testing. These tests
should include a potency test, and any tests additional to those in the
pharmacopoeial monograph that might be required. Since the se-lected
tests may not always be capable of detecting all the impurities
of unknown source, a combination of analytical methods, such as
several different chromatographic methods or differential scanning
calorimetry together with gas or liquid chromatography, could be
used. The suitability of the pharmacopoeial monograph from the
point of view of the detection of impurities should be evaluated,
especially if the drug is from a new source, which may cause it to have
a different impurity profile. If necessary, the advice of an experienced
laboratory should be sought.
Communication before samples are submitted
Before a sample of a product is sent to a laboratory in another country
or a contract laboratory and its analysis is requested, the laboratory
concerned must be asked whether it is willing to carry out the analysis.
The request should be accompanied, as a minimum, by the following
information, which should be given in writing:
— the reason(s) for the request;
— the name and address of the manufacturer and/or distributor;
— the marketing authorization and its number or reference;
— the pharmaceutical dosage form;
— the composition of the product (using International Non-proprietary
Names (INNs), where possible);
— the concentration or strength;
— the date of manufacture;
— details of the storage conditions and the expiry date;
— any background information about the route of synthesis of the
ingredients, if available;
— a reference to pharmacopoeial or other specifications, including
details of the analytical methods that should be used;
— the purpose of the analyses;
— the number of separate samples to be analysed and their batch
(lot) number(s);
— the proposed mode of payment for the analysis;
— the preferred language and format of the report containing the
results (see below)..71
It is recommended that a contract between the requesting party and
the laboratory that will perform the tests should be drawn up to settle
issues such as liability, and the mode of payment for the expenses
involved. The responsibilities of the two parties should be defined.
The laboratory that has been contacted should indicate, at the earliest
possible opportunity, its decision whether or not to undertake the
analyses.
If the laboratory agrees to undertake the analysis, the following
should be communicated to the requesting party:
— the nature and size of the sample required;
— any additional non-pharmacopoeial tests which may be required;
— the cost and the mode of payment;
— a tentative estimate of the time that the analysis will take;
— the method to be used to transmit the results.
Submission of samples
Upon agreement with a laboratory, the sample should be dispatched
by the national drug regulatory authority or the requesting party.
The sample must be suitably packaged and labelled (4). It should be
divided into two portions, each of which must be properly packed and
sealed. The laboratory should analyse one sealed portion only, and
retain the other for presenting during litigation or investigation. In
the case of products that are subject to legal controls on exportation,
appropriate arrangements must be made by the national drug regula-tory
authority to ensure due compliance with customs requirements.
Analytical results
All analyses undertaken by a laboratory should be in accordance with
the specified pharmacopoeial or other specifications mentioned in
the request for analysis, or as subsequently agreed (see Annex 3). If
requested, results of the analyses can be transmitted by facsimile or
other means (e.g. electronic mail), and confirmed with a detailed
signed report. The report should be in the working language of the
laboratory, or as agreed between the parties (see Annex 3).
References
1. Guidelines for implementation of the WHO Certification Scheme on the
Quality of Pharmaceutical Products Moving in International Commerce. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 10
(WHO Technical Report Series, No. 863).
2. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second.72
report. Geneva, World Health Organization, 1992, Annex 2 (WHO Technical
Report Series, No. 823).
3. The international pharmacopoeia, 3rd ed. Vol. 4. Tests, methods, and general
requirements. Quality specifications for pharmaceutical substances,
excipients, and dosage forms. Geneva, World Health Organization, 1994.
4. Sampling procedure for industrially manufactured pharmaceuticals. In: WHO
Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-first report. Geneva, World Health Organization, 1990, Annex 2 (WHO
Technical Report Series, No. 790)..73
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 5
Basic elements of good manufacturing practices in
pharmaceutical production
Poor-quality medicines are not only a health hazard, but a waste of
money for both governments and individual consumers, since they
may contain toxic substances that have been unintentionally added.
For example, in Haiti in 1996, more than 80 children died after receiv-ing
a syrup for cough and colds containing glycerol contaminated with
diethylene glycol (1). If the manufacturer had followed good manufac-turing
practices (GMP), these deaths could have been prevented.
In addition, a medicine that contains little or none of the claimed
active ingredient will not have the intended therapeutic effect. An
antibiotic with some — but not enough — of the active ingredient will
not cure infections. Even worse, bacteria exposed to low levels of the
antibiotic may not be killed and may become resistant to the drug,
even at the correct dosage, putting more lives at risk.
Good manufacturing practices help boost pharmaceutical export
opportunities
Most countries will accept the import and sale of medicines only if
they have been manufactured according to internationally recognized
GMP. For this reason, governments seeking to promote their coun-try’s
export of pharmaceuticals can do so by making GMP mandatory
for all pharmaceutical production and by training their inspectors in
GMP requirements.
What are good manufacturing practices?
GMP are that part of quality assurance which ensures that products
are consistently produced and controlled according to quality stan-dards.
They are designed to minimize the main risks involved in
pharmaceutical production that cannot be eliminated through testing
of the final product. These risks are:
— the unexpected contamination of products, causing damage to
health or even death;
— incorrect labels on containers, which could mean that patients
receive the wrong medicine;
— insufficient or too much active ingredient, resulting in ineffective
treatment or adverse effects..74
GMP cover all aspects of production, from the starting materials,
premises and equipment to the training and personal hygiene of staff.
Detailed, written procedures are essential for each process that could
affect the quality of the finished product. Systems must be established
to provide documented proof that correct procedures are consistently
followed at each step in the manufacturing process — every time a
product is made.
WHO has established detailed guidelines for GMP (2), and many
countries have formulated their own GMP requirements based on
those of WHO. Others have harmonized their requirements, e.g. in
the Association of South-East Asian Nations (ASEAN), in the Euro-pean
Union and through the Pharmaceutical Inspection Convention.
Are good manufacturing practices necessary if there is a quality
control laboratory?
Good quality must be built in during the manufacturing process;
testing products after they have been manufactured is not enough.
GMP prevent errors that cannot be eliminated through quality con-trol
of the finished product. Without GMP it is impossible to be sure
that every unit of medicine is of the same quality as those tested in the
laboratory.
In the early 1970s, a manufacturer in the United Kingdom produced an
infusion fluid which caused the death of five patients because it was
heavily contaminated with bacteria ( 3). Before distributing the fluid, the
manufacturer had tested several bottles and found them to be sterile.
Eventually a technical fault was found in the sterilizer: the bottles at the
bottom had not been properly sterilized. The bottles that the manufac-turer
had tested were from the upper part, giving the false impression that
all the bottles were sterile.
Can manufacturers afford to implement good manufacturing
practices?
Making poor-quality products does not save money. In the long run,
it is more expensive finding mistakes after they have been made than
preventing them in the first place. GMP are designed to ensure that
mistakes do not occur.
Implementation of GMP is an investment in good-quality medicines,
and will improve the health of both the individual patient and the
community, as well as benefiting the pharmaceutical industry and
health professionals..75
Making and distributing poor-quality medicines leads to loss of
credibility for everyone, including public and private health care ser-vices
and pharmaceutical manufacturers.
References
1. Fatalities associated with ingestion of diethylene glycol — contaminated
glycerol used to manufacture acetaminophen syrup — Haiti, November
1995–June 1996. Morbidity and Mortality Weekly Report, 1996, 45(30):649–
650.
2. Quality assurance of pharmaceuticals. A compendium of guidelines and
related materials. Vol. 2. Good manufacturing practices and inspection.
Geneva, World Health Organization, 1999.
3. Meers PD et al. Intravenous infusion of contaminated dextrose solution: the
Devonport incident. Lancet, 1973, ii(7839):1189–1192..76
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 6
Good manufacturing practices for sterile
pharmaceutical products
Introductory note 76
1. General considerations 76
2. Quality control 77
3. Sanitation 77
4. Manufacture of sterile preparations 78
5. Sterilization 83
6. Terminal sterilization 85
7. Aseptic processing and sterilization by filtration 88
8. Personnel 89
9. Premises 90
10. Equipment 92
11. Finishing of sterile products 93
References 93
Introductory note
This document is a revision of section 17 of Part Three of “Good
manufacturing practices [GMP] for pharmaceutical products” (1),
which emphasizes specific points for the manufacture of sterile prepa-rations
to minimize the risks of microbiological, particulate and pyro-gen
contamination. It is not exhaustive in character, and some
technical requirements may change in line with developments in the
field of GMP or advances in engineering design.
1. General considerations
1.1 The production of sterile preparations should be carried out in
clean areas, entry to which should be through airlocks for personnel
and/or for equipment and materials. Clean areas should be main-tained
to an appropriate standard of cleanliness and supplied with air
that has passed through filters of the required efficiency.
1.2 The various operations of component preparation (such as those
involving containers and closures), product preparation, filling and.77
sterilization should be carried out in separate areas within a clean
area. These areas are classified into four grades (see section 4.1).
1.3 Manufacturing operations are divided here into two categories:
first, those where the product is terminally sterilized, and second,
those which are conducted aseptically at some or all stages.
2. Quality control
2.1 Samples taken for sterility testing should be representative of the
whole of the batch, but should, in particular, include samples taken
from parts of the batch considered to be most at risk of contamina-tion,
for example:
(a) for products that have been filled aseptically, samples should
include containers filled at the beginning and end of the batch and
after any significant interruption of work;
(b) for products that have been heat sterilized in their final con-tainers,
consideration should be given to taking samples from
that part of the load that is potentially the coolest.
2.2 The sterility of the finished product is ensured by validation of the
sterilization cycle in the case of terminally sterilized products, and by
“media-fills” runs for aseptically processed products. Batch process-ing
records and, in the case of aseptic processing, environmental
quality records, should be examined in conjunction with the results of
the sterility tests. The sterility test procedure should be validated for
a given product. Pharmacopoeial methods must be used for the vali-dation
and performance of the sterility test.
2.3 For injectable products, the water for injection and the intermedi-ate
and finished products should be monitored for endotoxins, using
an established pharmacopoeial method that has been validated for
each type of product. For large-volume infusion solutions, such
monitoring of water or intermediates should always be done, in addi-tion
to any tests required by an approved monograph for the finished
product. When a sample fails a test, the cause of such failure should be
investigated and remedial action taken where necessary.
3. Sanitation
3.1 The sanitation of clean areas is particularly important. They
should be cleaned frequently and thoroughly in accordance with an
approved written programme. Monitoring should be regularly under-taken
in order to detect the emergence of resistant strains of micro-organisms.
In view of its limited effectiveness, ultraviolet light should
not be used as a substitute for chemical disinfection..78
3.2 Disinfectants and detergents should be monitored for microbio-logical
contamination; dilutions should be kept in previously cleaned
containers and should only be stored for defined periods unless steri-lized.
Disinfectants and detergents used in grade A and B areas (see
section 4.1) should be sterilized before use.
3.3 In order to control the microbiological cleanliness of the various
grades in operation, the clean areas should be monitored. Where
aseptic operations are performed, monitoring should be frequent and
methods such as settle plates, and volumetric air and surface sampling
(e.g. swabs and contact plates) should be used. The zones should not
be contaminated through the sampling methods used in the opera-tions.
The results of monitoring should be considered when batch
documentation for release of the finished product is reviewed. Both
surfaces and personnel should be monitored after critical operations.
3.4 Levels (limits) of detection of microbiological contamination
should be established for alert and action purposes, and for monitor-ing
the trends in air quality in the facility. Limits expressed in colony-forming
units (CFU) for the microbiological monitoring of clean
areas in operation are given in Table 1. The sampling methods and
numerical values included in the table are not intended to represent
specifications, but are for information only.
4. Manufacture of sterile preparations
4.1 Clean areas for the manufacture of sterile products are classified
according to the required characteristics of the environment. Each
manufacturing operation requires an appropriate environmental
cleanliness level in the operational state in order to minimize the risks
of particulate or microbiological contamination of the product or
materials being handled.
Table 1
Limits for microbiological contamination
a
Grade
b
Air sample Settle plates Contact plates Glove print
(CFU/m
3
) (diameter 90 mm) (diameter 55 mm) (5 fingers)
(CFU/4 hours)
c
(CFU/plate) (CFU/glove)
A <3 <3 <3 <3
B 105 55
C 100 50 25 —
D 200 100 50 —
a
These are average values. The grades are defined in section 4.1.
b
The airborne particulate classification for the four grades is given in Table 2.
c
Individual settle plates may be exposed for less than 4 hours..79
In order to meet “in operation” conditions, these areas should be
designed to reach certain specified air-cleanliness levels in the “at
rest” occupancy state. This latter state is the condition where the
installation is complete, and production equipment has been installed
and is operating, but no operating personnel are present. The “in
operation” state is the condition where the installation is functioning
in the defined operating mode and the specified number of personnel
are present.
For the manufacture of sterile pharmaceutical preparations, four
grades are distinguished here, as follows:
• Grade A: The local zone for high-risk operations, e.g. filling and
making aseptic connections. Normally such conditions are provided
by a laminar-airflow workstation. Laminar-airflow systems should
provide a homogeneous air speed of approximately 0.45m/s ± 20%
(guidance value) at the working position.
• Grade B: In aseptic preparation and filling, the background envi-ronment
for the grade A zone.
• Grades C and D: Clean areas for carrying out less critical stages in
the manufacture of sterile products.
The airborne particulate classification for the four grades is given in
Table 2.
To obtain air of the required characteristics, methods specified by
national authorities should be used. It should be noted that:
• In order to reach the B, C and D air grades, the number of air
changes should be appropriate for the size of the room and the
equipment and personnel present in it. At least 20 air changes per
hour are usually required for a room with a good airflow pattern
and appropriate high-efficiency particulate air (HEPA) filters.
Table 2
Airborne particulate classification for manufacture of sterile pharmaceutical
preparations
Grade At rest In operation
Maximum number Maximum number
of particles permitted/m
3
of particles permitted/m
3
0.5–5.0 m m >5.0 m m 0.5–5.0 m m >5.0 m m
A 3500 0 3500 0
B 3500 0 350000 2000
C 350000 2000 3500000 20000
D 3500000 20000 Not defined Not defined.80
• Detailed information on methods for determining the microbio-logical
and particulate cleanliness of air, surfaces, etc. is not given
here. Reference should be made to other guidelines published
in compendia such as the European, Japanese or United States
pharmacopoeias, or in documents issued by the European Commit-tee
for Standardization and the International Organization for
Standardization (ISO).
The different airborne particulate classification systems for clean
areas are shown in Table 3.
4.2 The particulate conditions given in Table 2 for the “at rest” state
should be achieved in the absence of the operating personnel after a
short “clean-up” period of about 15–20 minutes (guidance value),
after completion of the operations. The particulate conditions given
in Table 2 for grade A “in operation” should be maintained in the
zone immediately surrounding the product whenever the product or
open container is exposed to the environment. It is accepted that it
may not always be possible to demonstrate conformity with particu-late
standards at the point of fill when filling is in progress, owing to
the generation of particles or droplets from the product itself.
4.3 In order to control the particulate cleanliness of the various clean
areas during operation, they should be monitored.
4.4 Appropriate alert and action limits should be set for the results
of particulate and microbiological monitoring. If these limits are
exceeded, the appropriate corrective actions should be taken, as
prescribed in the operating procedures.
4.5 The area grades as specified in sections 4.6–4.14 must be selected
by the manufacturer on the basis of the nature of the process opera-tions
being performed and validation runs (e.g. sterile media fills).
The determination of an appropriate process area environment and
Table 3
Comparison of different airborne particulate classification systems for clean
areas
a
WHO United States United States ISO/TC EEC
(GMP) (209E) (customary) (209) (GMP)
Grade A M 3.5 Class 100 ISO 5 Grade A
Grade B M 3.5 Class 100 ISO 5 Grade B
Grade C M 5.5 Class 10000 ISO 7 Grade C
Grade D M 6.5 Class 100000 ISO 8 Grade D
EEC: European Commission; ISO/TC: International Organization for Standardization Technical
Committee.
a
Source: references 1–4..81
a time limit should be based on the microbiological contamination
(bioburden) found.
Terminally sterilized products
4.6 Components and most products should be prepared in at least a
grade D environment in order to give low microbial and particulate
counts, suitable for filtration and sterilization. Where the product is at
unusual risk of microbial contamination (e.g. because it actively sup-ports
microbial growth, must be held for a long period before steril-ization,
or is necessarily not processed mainly in closed vessels), the
preparation should generally be done in a grade C environment.
4.7 The filling of products for terminal sterilization should generally
be done in at least a grade C environment.
4.8 Where the product is at unusual risk of contamination from the
environment (e.g. because the filling operation is slow or the contain-ers
are wide-necked or are necessarily exposed for more than a few
seconds before sealing), the filling should be done in a grade A zone
with at least a grade C background.
4.9 The preparation and filling of ointments, creams, suspensions and
emulsions should generally be done in a grade C environment before
terminal sterilization.
Aseptic preparation
4.10 Components after washing should be handled in at least
a grade D environment. The handling of sterile starting materials and
components, unless subjected to sterilization or filtration through a
microorganism-retaining filter later in the process, should be done in
a grade A environment with a grade B background.
4.11 The preparation of solutions which are to be sterile filtered
during the process should be done in a grade C environment; if not
sterile filtered, the preparation of materials and products should be
done in a grade A environment with a grade B background.
4.12 The handling and filling of aseptically prepared products, as
well as the handling of exposed sterile equipment, should be done in
a grade A environment with a grade B background.
4.13 The transfer of partially closed containers, as used in freeze–
drying, should, before stoppering is completed, be done either in a
grade A environment with a grade B background or in sealed transfer
trays in a grade B environment.
4.14 The preparation and filling of sterile ointments, creams, suspen-sions
and emulsions should be done in a grade A environment with a.82
grade B background when the product is exposed and is subsequently
filtered.
Processing
4.15 Precautions to minimize contamination should be taken during
all processing stages, including the stages before sterilization.
4.16 Preparations containing live microorganisms should not be
made or containers filled in areas used for the processing of other
pharmaceutical products; however, vaccines consisting of dead organ-isms
or of bacterial extracts may be dispensed into containers, after
validated inactivation and validated cleaning procedures, in the same
premises as other sterile pharmaceutical products.
4.17 The validation of aseptic processing should include simulating
the process using a nutrient medium. The form of the nutrient me-dium
used should generally be equivalent to the dosage form of the
product. The process-simulation test should imitate as closely as pos-sible
the routine aseptic manufacturing process and include all
the critical subsequent manufacturing steps. Consideration should be
given to simulation of the worst expected condition. The process-simulation
test should be repeated at defined intervals and after any
significant modification to the equipment and process. The number of
containers used for a medium fill should be sufficient to ensure a valid
evaluation. For small batches, the number of containers for the me-dium
fill should be at least equal to the size of the product batch.
4.18 Care should be taken to ensure that any validation does not
compromise the processes.
4.19 Water sources, water-treatment equipment and treated water
should be monitored regularly for chemicals, biological contamina-tion
and contamination with endotoxins to ensure that the water
complies with the specifications appropriate to its use. Records should
be maintained of the results of the monitoring and of any action
taken.
4.20 Activities in clean areas, especially when aseptic operations
are in progress, should be kept to a minimum, and the movement of
personnel should be controlled and methodical, so as to avoid exces-sive
shedding of particles and organisms due to over-vigorous activity.
The ambient temperature and humidity should not be uncomfortably
high because of the nature of the garments worn.
4.21 The presence of containers and materials liable to generate
fibres should be minimized in clean areas and avoided completely
when aseptic work is in progress..83
4.22 Components, bulk-product containers and equipment should
be handled after the final cleaning process in such a way that they are
not recontaminated. The stage of processing of components, bulk-product
containers and equipment should be properly identified.
4.23 The interval between the washing and drying and the steriliza-tion
of components, bulk-product containers and equipment, as
well as between sterilization and use, should be as short as possible
and subject to a time-limit appropriate to the validated storage
conditions.
4.24 The time between the start of the preparation of a solution and
its sterilization or filtration through a bacteria-retaining filter should
be as short as possible. A maximum permissible time should be set
for each product that takes into account its composition and the
prescribed method of storage.
4.25 Any gas that is used to purge a solution or blanket a product
should be passed through a sterilizing filter.
4.26 The bioburden of products should be monitored before steriliza-tion.
There should be a working limit on the contamination of prod-ucts
immediately before sterilization that is related to the efficiency
of the method to be used and the risk of pyrogens. All solutions, in
particular large-volume parenterals, should be passed through a
microorganism-retaining filter, if possible immediately before the
filling process. Where aqueous solutions are held in sealed vessels,
any pressure-release outlets should be protected, e.g. by hydrophobic
microbiological air filters.
4.27 Components, bulk-product containers, equipment and any other
articles required in a clean area where aseptic work is in progress
should be sterilized and, wherever possible, passed into the area
through double-ended sterilizers sealed into the wall. Other proce-dures
that prevent the introduction of contamination (e.g. triple
wrapping) may be acceptable in some circumstances.
4.28 The efficacy of any new processing procedure should be vali-dated,
and the validation should be repeated at regular intervals
thereafter or when any significant change is made in the process or
equipment.
5. Sterilization
5.1 Whenever possible, products intended to be sterile should prefer-ably
be terminally sterilized by heat in their final container. Where
it is not possible to carry out terminal sterilization by heating due to
the instability of a formulation, a decision should be taken to use an.84
alternative method of terminal sterilization following filtration and/or
aseptic processing.
5.2 Sterilization can be achieved by the use of moist or dry heat, by
irradiation with ionizing radiation (but not with ultraviolet radiation
unless the process is thoroughly validated), by ethylene oxide (or
other suitable gaseous sterilizing agents) or by filtration with subse-quent
aseptic filling of sterile final containers. Each method has its
particular advantages and disadvantages. Where possible and practi-cable,
heat sterilization is the method of choice.
5.3 The microbiological contamination of starting materials should
be minimal, and their bioburden should be monitored before steriliza-tion.
Specifications should include requirements for microbiological
quality when the need for this has been indicated by monitoring.
5.4 All sterilization processes must be validated. Particular attention
should be given when the adopted sterilization method is not in
accordance with pharmacopoeial or other national standards or when
it is used for a preparation that is not a simple aqueous or oily
solution.
5.5 Before any sterilization process is adopted, its suitability for the
product and its efficacy in achieving the desired sterilizing conditions
in all parts of each type of load to be processed should be demon-strated
by physical measurements and by biological indicators, where
appropriate. The validity of the process should be verified at sched-uled
intervals, at least annually, and whenever significant modifica-tions
have been made to the equipment. Records should be kept of
the results.
5.6 For effective sterilization, the whole of the material should be
subjected to the required treatment and the process should be
designed to ensure that this is achieved.
5.7 Biological indicators should be considered only as an additional
method of monitoring the sterilization process. They should be stored
and used according to the manufacturer’s instructions, and their qual-ity
checked by positive controls. If they are used, strict precautions
should be taken to avoid any transfer of microbiological contamina-tion
from them.
5.8 There should be a clear means of differentiating products that
have not been sterilized from those that have. Each basket, tray, or
other carrier of products or components should be clearly labelled
with the name of the material, its batch number, and an indication of
whether or not it has been sterilized. Indicators such as autoclave tape
may be used, where appropriate, to indicate whether or not a batch.85
(or sub-batch) has passed through a sterilization process, but they do
not give a reliable indication that the batch is, in fact, sterile.
5.9 Sterilization records should be available for each sterilization run.
They should be approved as part of the batch-release procedure.
6. Terminal sterilization
Sterilization by heat
6.1 Each heat-sterilization cycle should be recorded by means of
appropriate equipment of suitable accuracy and precision, e.g. on a
time/temperature chart with a suitably large scale. The temperature
should be recorded by a probe at the coolest part of the load or loaded
chamber, this point having been determined during the validation; the
temperature should preferably be checked against a second indepen-dent
temperature probe located at the same position. The chart, or a
photocopy of it, should form part of the batch record. Chemical or
biological indicators may also be used but should not take the place of
physical controls.
6.2 Sufficient time must be allowed for the whole of the load to reach
the required temperature before measurement of the sterilizing time
is started. This time must be determined for each type of load to be
processed.
6.3 After the high-temperature phase of a heat sterilization cycle,
precautions should be taken against contamination of a sterilized load
during cooling. Any cooling fluid or gas in contact with the product
should be sterilized.
Sterilization by moist heat
6.4 Sterilization by moist heat (heating in an autoclave) is suitable
only for water-wettable materials and aqueous formulations. Both
temperature and pressure should be used to monitor the process. The
temperature recorder should normally be independent of the control-ler,
and there should be an independent temperature indicator, the
reading from which should be routinely checked against the chart
recorder during the sterilization period. For sterilizers fitted with a
drain at the bottom of the chamber, it may also be necessary to record
the temperature at this position throughout the sterilization period.
There should be regular leak tests on the chamber when a vacuum
phase is part of the cycle.
6.5 The items to be sterilized, other than products in sealed con-tainers,
should be wrapped in a material that allows the removal of
air and the penetration of steam but prevents recontamination after.86
sterilization. All parts of the load should be in contact with water or
saturated steam at the required temperature for the required time.
6.6 Care should be taken to ensure that the steam used for steriliza-tion
is of suitable quality and does not contain additives at a level that
could cause contamination of the product or equipment.
Sterilization by dry heat
6.7 Sterilization by dry heat may be suitable for non-aqueous liquids
or dry powder products. The process used should include air circula-tion
within the chamber and the maintenance of a positive pressure to
prevent the entry of non-sterile air. If air is supplied, it should be
passed through a microorganism-retaining filter (e.g. an HEPA filter).
Where sterilization by dry heat is also intended to remove pyrogens,
challenge tests using endotoxins will be required as part of the
validation.
Sterilization by radiation
6.8 Sterilization by radiation is used mainly for the sterilization of
heat-sensitive materials and products. Many pharmaceutical products
and some packaging materials are radiation-sensitive, so this method
is permissible only when the absence of deleterious effects on the
product has been confirmed experimentally. Ultraviolet irradiation is
not an acceptable method for terminal sterilization.
6.9 If sterilization by radiation is carried out by an outside contractor,
the manufacturer is responsible for ensuring that the requirements of
section 6.8 are met, and that the sterilization process is validated. The
responsibilities of the radiation plant operator (e.g. for using the
correct dose) should also be specified.
6.10 During the sterilization procedure, the radiation dose should be
measured. For this purpose, the dosimeters used must be independent
of the dose rate and must provide a quantitative measurement of the
dose received by the product itself. Dosimeters should be inserted in
the load in sufficient number, and close enough together to ensure
that there is always a dosimeter in the chamber. Where plastic dosim-eters
are employed, they should be used within the time-limit of their
calibration. Dosimeter absorbances should be read shortly after expo-sure
to radiation. Biological indicators may be used only as an addi-tional
control. Radiation-sensitive colour discs may be used to
differentiate between packages that have been subjected to irradia-tion
and those that have not; they are not indicators of successful
sterilization. The information obtained should constitute part of the
batch record..87
6.11 Validation procedures should ensure that consideration is given
to the effects of variations in the density of the packages.
6.12 Handling procedures should prevent any misidentification of
irradiated and non-irradiated materials. Each package should carry a
radiation-sensitive indicator to show whether or not it has been sub-jected
to radiation treatment.
6.13 The total radiation dose should be administered within a prede-termined
period of time.
Sterilization by gases and fumigants
6.14 This method of sterilization should only be used for products
where there is no suitable alternative.
6.15 Various gases and fumigants may be used for sterilization (e.g.
ethylene oxide, hydrogen peroxide vapour). Ethylene oxide should be
used only when no other method is practicable. During process vali-dation
it should be shown that the gas has no damaging effect on the
product and that the conditions and time allowed for degassing are
such as to reduce any residual gas and reaction products to defined
acceptable limits for the type of product or material concerned. These
limits should be incorporated in the specifications.
6.16 Direct contact between gas and microorganisms is essential; pre-cautions
should therefore be taken to avoid the presence of organisms
likely to be enclosed in materials such as crystals or dried protein. The
nature and quantity of packaging materials can significantly affect the
process.
6.17 Before exposure to the gas, materials should be brought into
equilibrium with the humidity and temperature required by the pro-cess.
This requirement should be balanced against the need to mini-mize
the waiting time before sterilization.
6.18 Each sterilization cycle should be monitored with suitable bio-logical
indicators, using the appropriate number of test pieces distrib-uted
throughout the load. The information so obtained should form
part of the batch record.
6.19 Biological indicators should be stored and used according to the
manufacturer’s instructions, and their performance checked by
positive controls.
6.20 For each sterilization cycle, records should be made of the time
taken to complete the cycle, of the pressure, temperature and humidity
within the chamber during the process, and of the gas concentration.
The pressure and temperature should be recorded on a chart through-out
the cycle. The records should form part of the batch record..88
6.21 After sterilization, the load should be stored in a controlled
manner under ventilated conditions to allow concentrations of re-sidual
gas and reaction products to fall to their prescribed levels. This
process should be validated.
7. Aseptic processing and sterilization by filtration
7.1 The objective of aseptic processing is to maintain the sterility
of a product that is assembled from components, each of which
has been sterilized by one of the above methods (see sections 5
and 6).
7.2 The operating conditions should be such as to prevent microbial
contamination.
7.3 In order to maintain the sterility of the components and the
product during aseptic processing, careful attention needs to be given
to: (a) the environment; (b) the personnel; (c) the critical surfaces;
(d) the container/closure sterilization and transfer procedures; (e) the
maximum holding period of the product before filling into the final
container; and (f) the sterilizing filter.
7.4 Certain solutions and liquids that cannot be sterilized in the final
container can be filtered through a sterile filter of nominal pore size
0.22 m m (or less), or with at least equivalent microorganism-retaining
properties, into a previously sterilized container. Such filters can
remove bacteria and moulds, but not all viruses or mycoplasmas.
Consideration should be given to complementing the filtration
process with some degree of heat treatment.
7.5 Owing to the potential additional risks of the filtration method as
compared with other sterilization processes, a double filter layer or
second filtration via a further sterilized microorganism-retaining
filter immediately prior to filling may be advisable. The final sterile
filtration should be carried out as close as possible to the filling point.
7.6 The fibre-shedding characteristics of filters should be minimal
(virtually zero). Asbestos-containing filters must not be used under
any circumstances.
7.7 The integrity of the filter should be checked by an appropriate
method such as a bubble-point, diffusive-flow or pressure-hold test,
immediately after use (it may also be useful to test the filter in this
way before use). The time taken to filter a known volume of bulk
solution and the pressure difference to be used across the filter should
be determined during validation, and any significant differences from
these values should be noted and investigated. The results of these
checks should be recorded in the batch record. The integrity of critical.89
gas and air vent filters should be confirmed after use. The integrity of
other filters should be confirmed at appropriate intervals. Consider-ation
should be given to increased monitoring of filter integrity in
processes that involve harsh conditions, e.g. the circulation of high-temperature
air.
7.8 The same filter should not be used for more than 1 working day
unless such use has been validated.
7.9 The filter should not affect the product either by removing ingre-dients
from it or by releasing substances into it.
8. Personnel
8.1 Only the minimum number of personnel required should be
present in clean areas; this is particularly important during aseptic
processes. Inspections and controls should be conducted from outside
such areas as far as possible.
8.2 All personnel (including those concerned with cleaning and main-tenance)
employed in such areas should receive initial and regular
training in disciplines relevant to the correct manufacture of sterile
products, including hygiene and the basic elements of microbiology.
When outside staff who have not received such training (e.g. building
or maintenance contractors) need to be brought in, particular care
should be taken over their instruction and supervision.
8.3 Staff who have been engaged in the processing of animal-tissue
materials or of cultures of microorganisms other than those used in
the current manufacturing process should not enter sterile-product
areas unless rigorous and clearly defined decontamination procedures
have been followed.
8.4 High standards of personal hygiene and cleanliness are essential,
and personnel involved in the manufacture of sterile preparations
should be instructed to report any conditions that may cause the
shedding of abnormal numbers or types of contaminants; periodic
health checks for such conditions are desirable. The action to be taken
in respect of personnel who might be introducing undue microbiologi-cal
hazards should be decided by a designated competent person.
8.5 Outdoor clothing should not be brought into clean areas, and
personnel entering changing rooms should already be clad in standard
factory protective garments. Changing and washing should follow a
written procedure designed to minimize the contamination of clean
area clothing or the carry-through of contaminants to clean areas.
8.6 Wrist-watches and jewellery should not be worn in clean areas,
and cosmetics that can shed particles should not be used..90
8.7 The clothing worn and its quality should be appropriate for the
process and the grade of the working area (workplace). It should be
worn in such a way as to protect the product from contamination. The
clothing required for each grade is as follows:
• Grade D. The hair and, where relevant, beard and moustache
should be covered. Protective clothing and appropriate shoes or
overshoes should be worn. Appropriate measures should be taken
to avoid any contamination from outside the clean area.
• Grade C. The hair and, where relevant, beard and moustache
should be covered. A single or two-piece trouser suit, gathered at
the wrists and with a high neck, and appropriate shoes or overshoes
should be worn. The clothing should shed virtually no fibres or
particulate matter.
• Grades A/B. Headgear should totally enclose the hair and, where
relevant, beard and moustache. A single or two-piece trouser suit,
gathered at the wrists and with a high neck, should be worn. The
headgear should be tucked into the neck of the suit. A face mask
should be worn to prevent the shedding of droplets. Appropriate,
sterilized, non-powdered rubber or plastic gloves and sterilized or
disinfected footwear should be worn. Trouser-bottoms should be
tucked inside the footwear and garment sleeves into the gloves. The
protective clothing should shed virtually no fibres or particulate
matter and should retain particles shed by the body.
8.8 Outdoor clothing should not be brought into changing rooms
leading to grade B and C rooms. For every worker in a grade A/B room,
clean sterilized or adequately sanitized protective garments should be
provided at each work session, or at least once a day if monitoring
results justify this. Gloves should be regularly disinfected during op-erations.
Masks and gloves should be changed at least at every working
session. The use of disposable clothing may be necessary.
8.9 Clothing used in clean areas should be laundered or cleaned in
such a way that it does not gather additional particulate contaminants
that can later be shed. Separate laundry facilities for such clothing are
desirable. If fibres are damaged by inappropriate cleaning or steriliza-tion,
there may be an increased risk of shedding particles. Washing
and sterilization operations should follow standard operating
procedures.
9. Premises
9.1 All premises should, as far as possible, be designed to avoid the
unnecessary entry of supervisory or control personnel. Grade B areas.91
should be designed so that all operations can be observed from
outside.
9.2 In clean areas, all exposed surfaces should be smooth, impervious
and unbroken in order to minimize the shedding or accumulation of
particles or microorganisms and to permit the repeated application of
cleaning agents and disinfectants, where used.
9.3 To reduce the accumulation of dust and to facilitate cleaning,
there should be no uncleanable recesses and a minimum of projecting
ledges, shelves, cupboards and equipment. Doors should be carefully
designed to avoid uncleanable recesses; sliding doors are undesirable
for this reason.
9.4 False ceilings should be sealed to prevent contamination from the
space above them.
9.5 Pipes and ducts and other utilities should be installed so that they
do not create recesses, unsealed openings and surfaces that are
difficult to clean.
9.6 Sinks and drains should be avoided wherever possible and should
be excluded from grade A/B areas where aseptic operations are car-ried
out. Where installed, they should be designed, located and main-tained
so as to minimize the risks of microbiological contamination;
they should be fitted with effective, easily cleanable traps and with air
breaks to prevent back-flow. Any floor channels should be open
and easily cleanable and be connected to drains outside the area in a
manner that prevents the ingress of microbiological contaminants.
9.7 Changing rooms should be designed as airlocks and used to sepa-rate
the different stages of changing, thus minimizing particulate and
microbiological contamination of protective clothing. They should be
effectively flushed with filtered air. The use of separate changing
rooms for entering and leaving clean areas is sometimes necessary.
Hand-washing facilities should be provided only in the changing
rooms, not in areas where aseptic work is done.
9.8 Airlock doors should not be opened simultaneously. An inter-locking
system and a visual and/or audible warning system can be
installed to prevent the opening of more than one door at a time.
9.9 A filtered air supply should be used to maintain a positive pres-sure
and an airflow relative to surrounding areas of a lower grade
under all operational conditions; it should flush the area effectively.
Adjacent rooms of different grades should have a pressure differen-tial
of approximately 10–15 pascals (guidance value). Particular atten-tion
should be paid to the protection of the zone of greatest risk,.92
i.e. the immediate environment to which the product and the cleaned
components in contact with it are exposed. The various recom-mendations
regarding air supplies and pressure differentials may
need to be modified where it becomes necessary to contain certain
materials, e.g. pathogenic, highly toxic, radioactive or live viral or
bacterial materials or products. The decontamination of the facilities
and the treatment of air leaving a clean area may be necessary for
some operations.
9.10 It should be demonstrated that airflow patterns do not present a
contamination risk; for example, care should be taken to ensure that
particles from a particle-generating person, operation or machine are
not conveyed to a zone of higher product risk.
9.11 A warning system should be included to indicate failure in the
air supply. An indicator of pressure difference should be fitted be-tween
areas where this difference is important, and the pressure
difference should be regularly recorded.
9.12 Consideration should be given to restricting unnecessary access
to critical filling areas, e.g. grade A filling zones, by means of a
physical barrier.
10. Equipment
10.1 A conveyor belt should not pass through a partition between a
grade A or B clean area and a processing area of lower air cleanliness,
unless the belt itself is continuously sterilized (e.g. in a sterilizing
tunnel).
10.2 Whenever possible, equipment used for processing sterile prod-ucts
should be chosen so that it can be effectively sterilized by steam
or dry heat or other methods.
10.3 As far as possible, equipment fittings and services should be
designed and installed so that operations, maintenance and repairs
can be carried out outside the clean area. Equipment that has to be
taken apart for maintenance should be resterilized after complete
reassembly, wherever possible.
10.4 When equipment maintenance is carried out within a clean area,
clean instruments and tools should be used, and the area should be
cleaned and disinfected again, where appropriate, before processing
recommences if the required standards of cleanliness and/or asepsis
have not been maintained during the maintenance work.
10.5 All equipment, including sterilizers, air-filtration systems, and
water-treatment systems, including stills, should be subject to planned.93
maintenance, validation and monitoring; its approved use following
maintenance work should be documented.
10.6 Water-treatment plants and distribution systems should be de-signed,
constructed and maintained so as to ensure a reliable source of
water of an appropriate quality. They should not be operated beyond
their designed capacity. Consideration should be given to including a
testing programme in the maintenance of a water system. Water for
injection should be produced, stored and distributed in a manner
which prevents the growth of microorganisms, e.g. by constant circu-lation
at a temperature above 70°C or not more than 4°C.
11. Finishing of sterile products
11.1 Containers should be closed by appropriately validated meth-ods.
Samples should be checked for integrity according to appropriate
procedures.
11.2 Containers sealed under vacuum should be sampled and the
samples tested, after an appropriate predetermined period, to ensure
that the vacuum has been maintained.
11.3 Filled containers of parenteral products should be inspected
individually. When inspection is done visually, it should be done
under suitable and controlled conditions of illumination and back-ground.
Operators doing the inspection should pass regular eyesight
checks, with spectacles if worn, and be allowed frequent breaks from
inspection. Where other methods of inspection are used, the process
should be validated and the performance of the equipment checked at
intervals. The results should be recorded.
References
1. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823).
2. Airborne particulate cleanliness classes in cleanrooms and clean zones.
Federal Standard 209E. Mount Prospect, IL, Institute of Environmental
Sciences, 1992.
3. Cleanrooms and associated controlled environments. Part 1: classification of
airborne particulates. Geneva, International Organization for Standardization,
1999.
4. The rules governing medicinal products in the European Union. Vol. 4. Good
manufacturing practices: medicinal products for human and veterinary use.
Brussels, European Commission, 1998..94
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 7
Guidelines on pre-approval inspections
1. General 94
2. Glossary 94
3. Objectives 95
4. Priorities 96
5. Preparation for the inspection 96
6. Carrying out the inspection 97
7. Sample collection and testing 99
8. Follow-up regulatory/administrative decisions 100
References 100
1. General
The advice provided here extends that given in the “Provisional
guidelines on the inspection of pharmaceutical manufacturers” (1).
The objectives of an inspection, as given in the introduction to the
guidelines, are:
— to control and enforce compliance with general good manufactur-ing
practices (GMP) (2); and
— to authorize the manufacture of specific pharmaceutical products,
normally in response to a licensing application.
These guidelines are applicable mainly to inspections of the first type,
whether performed as a condition for the issue of a manufacturing
licence/authorization, or on a periodic, routine basis. They are essen-tially
concerned with inspections of manufacturing and quality-control
facilities conducted before a marketing authorization (product
licence or registration) for a pharmaceutical product is granted.
2. Glossary
The definitions given below apply to the terms used in this guide.
They may have different meanings in other contexts.
application
A marketing authorization for a new drug application..95
manufacturer
A company that carries out at least one step of manufacture (2).
manufacture
All operations concerned with the purchase of materials and prod-ucts,
production (including packaging), quality control, release,
storage, the distribution of pharmaceutical products, and the related
controls (2).
method validation/verification
Method validation is conducted where non-compendial analytical
methods are included in the application to confirm that the applicants’
proposed analytical methods are suitable for regulatory purposes. A
side-by-side comparison with a compendial method, if available,
should be included. Method verification is conducted where the meth-ods
are compendial, to confirm whether the product as compounded
can be analysed satisfactorily by the official method.
pre-approval batches
Pilot or laboratory-scale batches, upon which the application is based,
e.g. batches used for pivotal clinical trials and/or those used for
bioavailability, bioequivalence and stability studies, and scale-up
batches.
3. Objectives
Before any application is approved, it is necessary to determine
whether all establishments participating in the manufacture of the
finished dosage form are in compliance with GMP and the application
commitments. Pre-approval inspections have the following specific
objectives:
• Evaluation of the establishment’s compliance with GMP require-ments,
particularly regarding proper environment, quality manage-ment,
personnel, facilities and equipment.
• Evaluation of the procedures and controls implemented in the
manufacture of the product (pre-approval batches), to determine
whether they are in conformity with the application commitments.
• Audit of the completeness and accuracy of the manufacturing and
testing information submitted with the application, and of the con-formity
of pre-approval batches with planned commercial batches
(process validation protocol).
• The collection of samples for the validation or verification of the
analytical methods included in the application..96
4. Priorities
Pre-approval inspections are considered to be an important part of
the application review and approval process. However, since this
represents a considerable workload, inspections are not normally
carried out routinely, but rather only in specific cases where non-compliance
is possible. Thus inspections may be required for:
— new chemical entities;
— drugs of narrow therapeutic range, and drugs for serious condi-tions
requiring an assured therapeutic response;
— products previously associated with serious adverse effects, com-plaints,
recalls, etc.;
— products that are difficult to manufacture or test, or that are of
doubtful stability (and therefore associated with the risk of
defects);
— new applicants or manufacturers; and
— applications from manufacturers who have previously failed to
comply with GMP or official quality specifications.
For other applications, the drug regulatory authority will rely on the
results of recent inspections of the applicant’s or manufacturer’s
facilities for the production of dosage forms similar to that of the
proposed product.
5. Preparation for the inspection
An inspection team should, where possible, include analysts and
other specialists, e.g. in pharmaceutical technology, or if available,
persons with expertise in these fields, when needed. Team members
may be assigned to inspect new operations or manufacturing sites
associated with product failures. When possible, the analyst involved
in the laboratory evaluation of the product under review should par-ticipate
in the inspection. Pre-approval inspection is often carried out
by a single inspector.
It is necessary to verify that the applicant holds an appropriate manu-facturing
authorization and that manufacturing is carried out in con-formity
with that authorization (licence).
An essential step in the review of applications is determining whether
the commitments made by the manufacturer are reflected in actual
practice. A review of the application information is also important
in preparing for inspections of firms or processes with which the
inspector is unfamiliar. The drug regulatory authority should provide
inspectors with relevant information on the application. (Some
countries request an additional copy of this information from appli-cants
which is forwarded to the inspection team.) The information.97
provided should include a copy of the manufacturing and controls
section of the application, together with information relating to pre-approval
batches.
Reasonable efforts should be made to conduct pre-approval inspec-tions
at the earliest possible opportunity, since unnecessary delays
will prevent the timely review of applications. However, in some
facilities the development or the manufacturing processes may not
have been completed. In addition, changes may have occurred in the
status of the application, e.g. major deficiencies in the application or
the closure of an ancillary facility may affect the need for an inspec-tion.
In any case, the timing of the inspection should be coordinated
between the inspectorate and the applicant.
For the inspection of major new facilities involving many applications,
special coordination efforts are often beneficial.
When desirable, pre-approval inspections should be coordinated with
the laboratory scheduled for method validation so as to enable it to
participate in the inspection and in the collection of samples.
6. Carrying out the inspection
Emphasis should be placed on the evaluation of the manufacturing
process, including data verification and the assessment of compliance
with GMP. The production and control procedures described in the
application must be compared with those used for the manufacture of
pre-approval batches. If warranted by records of past label mix-ups,
packaging and labelling control procedures should be evaluated. A
programme of ongoing stability testing needs to be addressed.
The inspection team will determine whether the application provides
the scientific data justifying full-scale production procedures and
controls. The validation of pertinent manufacturing procedures,
including equipment qualification, will also be evaluated.
1
However,
inspectors should not recommend withholding approval of applica-tions
based on a lack of complete full-scale, multiple-batch validation
of sterile and non-sterile processes, unless the data submitted in the
application are found to be of questionable validity or completeness.
It should be understood that full-scale validation may be completed
after approval of the application, but before shipment of the first
commercial batches. Nevertheless, certain data must be included in
the application to demonstrate that the sterilization or aseptic fill
process has been qualified. The inspection team is expected to audit
the data to determine their authenticity, accuracy and completeness.
1
For details of recommended validation programmes, see reference 3..98
Investigational products are often produced in facilities other than
those used for full-scale production (4). These facilities and the asso-ciated
manufacturing and control procedures are not routinely in-spected
unless validation of the transfer of the methods from the
“investigational” facilities to the full-scale facilities is lacking or ques-tionable.
The facilities may be periodically inspected when this is
required by national legislation/regulation.
All suppliers and manufacturers of starting materials used in
the formulation of pre-approval batches should be identified. The
physical characteristics and specifications of the drug substance
should be reviewed. This is particularly important for solid oral dos-age
forms where the physical characteristics of the drug substance
often affect uniformity, dissolution and absorption of the dose.
When a pharmaceutical manufacturer replaces the supplier or
manufacturer of the drug substance used for the manufacture of the
pre-approval batches by another supplier or manufacturer, the
application should include data demonstrating that the dosage forms
formulated with the drug substance from the two different sources are
equivalent in terms of conformity with established specifications, in-cluding
those given in the application. Specifications should also cover
the physical characteristics of the drug substances.
The addition of any new drug substance and/or dosage form to a
production environment must be carefully evaluated in terms of its
impact on other products already under production. Any changes that
may be necessary in the building and facility must be assessed for
their effect on overall compliance with GMP requirements. For ex-ample,
a new toxic, potent or highly sensitizing product may require
additional measures against cross-contamination, and facilities al-ready
operating at full capacity may not have adequate space for
additional products. The evaluation should also include an assess-ment
of whether any change in the manufacturing authorization is
necessary.
Laboratory equipment and procedures must be qualified and vali-dated.
Every pre-approval inspection should include an evaluation of
laboratory controls and procedures, and a review of some of the raw
data used to generate results. The authenticity and accuracy of the
data used in the development of a test method should be reviewed.
The inspection team should pay special attention to any newly estab-lished
facilities, newly installed equipment and/or new raw material
suppliers. If unapproved facilities are in use, this should be reported
immediately. Inspections of these facilities are not normally required..99
7. Sample collection and testing
The pre-approval inspection may include the collection of samples for
validation of the analytical methods. Normally the sample size should
be sufficient for three full analyses. Unless otherwise indicated by the
laboratory, samples of the following sizes may be taken, depending on
the dosage form of the product:
— tablets and capsules: 300 units of production;
— injections (single component): 100 units of production;
— injections (combination): 100 units of production plus 10 samples
of each component;
— oral powders for reconstitution: 10 units of production;
— oral liquids: 1 litre.
It is important to collect, with the samples, the relevant manu-facturer’s
analytical documentation, namely a copy of the analytical
methods used by the inspected laboratory and the report of the analy-ses
performed by the applicant on the batch sampled. A method
validation report may be of some use in better understanding and
reproducing the analytical methods. Problems encountered in the
performance of the analyses may be resolved by an exchange of
information between the applicant and the government laboratory.
Samples are tested in accordance with methods described in the appli-cation.
If there are problems with the methods that require additional
information from the applicant, the laboratory director must review
the situation and decide whether the applicant should be contacted.
The written request should be included in the documentation submit-ted
to the review analyst.
Each method validation/verification report should contain the
following:
• The identification of the test samples received, a description of the
product tested, and confirmation of conformity with the product
described in the application.
• The original analytical worksheets with calculations, the results of
all tests performed, comments by the analyst(s), associated spectra,
chromatograms, etc., and a comparison of the results obtained with
the applicant’s data and with the applicable specifications.
• An evaluation of each test performed by the applicant and the
laboratory.
• A recommendation as to whether the methods are acceptable,
acceptable only after specified changes have been made, or
unacceptable.
If samples have not been collected in the course of a pre-approval
inspection, the results of the analytical examination of the samples.100
submitted by the applicant may nevertheless be used as supporting
information.
The reserve samples, associated documentation and copies of labora-tory
reports should be stored in an orderly and retrievable way for
a time period specified by national regulations. It is usually recom-mended
that all material should be kept for a minimum of 3 years or
for 1 year after the expiry date of the finished product.
8. Follow-up regulatory/administrative decisions
The inspectorate (inspection group of the drug regulatory authority)
should recommend withholding approval when significant deviations
from GMP requirements and other application commitments have
occurred having an adverse effect on the product covered by the
application. Examples of significant problems are:
• Misrepresentation of data or conditions relating to pre-approval
batches.
• Pre-approval batches not manufactured in accordance with GMP.
• Inconsistencies and/or discrepancies raising significant questions
concerning the validity of the records.
If applications are refused because of significant non-compliance with
GMP, action must be taken to ensure that the necessary corrective
measures are taken.
The drug regulatory authority is expected to advise the applicant that
the inspectorate has recommended withholding approval of the appli-cation
and give the reasons for this recommendation.
References
1. Provisional guidelines on the inspection of pharmaceutical manufacturers. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-second report. Geneva, World Health Organization, 1992, Annex 2
(WHO Technical Report Series, No. 823).
2. Quality assurance of pharmaceuticals. A compendium of guidelines and
related materials. Vol. 2. Good manufacturing practices and inspection.
Geneva, World Health Organization, 1999.
3. Good manufacturing practices: guidelines on the validation of manufacturing
processes. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996,
Annex 6 (WHO Technical Report Series, No. 863).
4. Good manufacturing practices: supplementary guidelines for the manufacture
of investigational pharmaceutical products for clinical trials in humans. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-fourth report. Geneva, World Health Organization, 1996, Annex 7 (WHO
Technical Report Series, No. 863)..101
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 8
Quality systems requirements for national good
manufacturing practice inspectorates
Background 101
1. Introduction 102
2. Glossary 102
3. Administrative structure 103
4. Terms of reference 104
5. Organizational structure 104
6. Inspection personnel 106
7. Documentation 107
8. Records 109
9. Inspection procedures 109
10. Inspection facilities required 112
11. Quality manual 113
12. Confidentiality 114
13. Publications 115
14. Appeals 115
15. Internal audit and periodic review 116
16. Complaints 117
17. Recalls 117
References 118
Background
Following the provisional guidelines on the inspection of pharmaceu-tical
manufacturers (1), the WHO Expert Committee on Specifica-tions
for Pharmaceutical Preparations acknowledged that additional
guidelines concerning national inspectorates would be of value in
strengthening the implementation of good manufacturing practices
(GMP) (2) and enhancing mutual recognition among inspectorates.
A trend has recently become apparent in WHO Member States
for non-commercial institutions, such as certification bodies, testing.102
laboratories, etc., to introduce quality systems principles in their inter-nal
operations. The same principles are also being applied by govern-mental
pharmaceutical inspectorates and drug control laboratories.
The Pharmaceutical Inspection Convention (PIC) has published a
document (3), with the objective of adapting the standards of the
International Organization for Standardization (ISO) of the 9000
series and related norms (4–8) to the activities of the GMP
inspectorates of Member States. It is based on European Standard
EN 45012, General criteria for certification bodies operating quality
systems certification (9), but has been modified for this particular
purpose.
1. Introduction
These requirements are applicable to quality systems for the opera-tion
of inspection services within competent authorities concerned
with GMP inspections. It is intended that each inspection service
should use these requirements as the basis for developing its own
quality system.
The establishment and operation of a quality system is an essential
element in the mutual recognition of national GMP inspections. The
willingness to accept national inspections is significantly enhanced
when it is known that the GMP inspectorate of the competent author-ity
follows uniform procedures incorporating quality system prin-ciples.
The quality system should include all the activities involved in
the inspection.
2. Glossary
authorized person
A person (among key personnel of a manufacturing establishment)
responsible for the release of batches of finished products for sale
(10).
quality audit
An examination and assessment of all or part of a quality system with
the specific purpose of improving it. A quality audit is usually con-ducted
by outside or independent specialists or a team designated by
the management for this purpose. Such audits may also be extended
to suppliers and contractors (2).
quality manual
A handbook that describes the various elements of the system for
assuring the quality of the test results generated by a laboratory (see
section 11)..103
quality system
An appropriate infrastructure, encompassing the organizational
structure, procedures, processes and resources necessary to ensure
adequate confidence that a product (or service) will satisfy given
requirements for quality (2).
standard operating procedure (SOP)
An authorized written procedure giving instructions for performing
operations not necessarily specific to a given product or material but
of a more general nature (e.g. equipment operation, maintenance and
cleaning; validation; cleaning of premises and environmental control;
sampling and inspection). Certain SOPs may be used to supplement
product-specific master and batch production documentation (2).
3. Administrative structure
3.1 The structure, membership and operation of the GMP inspec-torate
should be such that impartiality is safeguarded.
3.2 The national inspection services are responsible for ensuring that
the requirements of the relevant national legislation are satisfied.
3.3 All personnel employed or used by the GMP inspectorate, includ-ing
outside inspectors or subcontracted personnel, should not be
subject to any commercial, financial or other pressures which might
affect their judgement. They should not be under the control of
pharmaceutical manufacturers, and must be assessed and licensed.
3.4 The system for obtaining fees should not improperly influence the
inspection procedure.
Recommended procedure
The administrative structure, membership, operation and legal status
of the GMP inspectorate should be described in the quality manual
(see section 11).
The quality manual should show how all personnel working for the
GMP inspectorate, including subcontracted staff or advisers, and
persons serving on committees providing advice, can maintain their
impartiality. The GMP inspectorate should ensure that such persons:
(a) are not subject to any commercial, financial or other pressures
which might influence their judgement;
(b) are not improperly influenced in their inspection of pharmaceuti-cal
manufacturers or persons assessed;
(c) have not been involved in the design or maintenance of inspected
facilities by way of any consultancy service or commercial
arrangement..104
The remuneration of GMP inspectorate personnel engaged in inspec-tion
activities should not depend on the result of such activities or on
the granting of a marketing authorization.
Only in exceptional cases may GMP inspectorates provide advisory
or consultancy services. Where the GMP inspectorate does provide
such services, it should develop a code of conduct or defined policy
which clearly distinguishes between the process of inspection and that
of providing an advisory or consultancy service to clients. This service
should be of benefit to all of industry, and not solely to individual
manufacturers.
4. Terms of reference
4.1 The functions of the GMP inspectorate should be clearly defined
and should cover:
(a) legal responsibilities;
(b) the formulation of policies;
(c) an overview of the implementation of its policies;
(d) an overview of its finances;
(e) as required, the setting-up of committees to which defined activ-ities
are delegated.
Recommended procedure
The terms of reference, legal responsibilities and functions of the
GMP inspectorate and the way in which policy guidelines are estab-lished
should be documented in the quality manual.
For any committee established to advise the GMP inspectorate or the
chief inspector, the following details should be included:
(a) its role and function;
(b) the procedure for selecting and appointing the members (the
names of the chairperson, secretary and members, their current
appointments and the interests, if any, which they represent on
the committee, should be available);
(c) the rules of procedure.
5. Organizational structure
5.1 The GMP inspectorate should have an organization that enables
it to maintain the capability to perform its technical functions
satisfactorily..105
5.2 The GMP inspectorate should have:
(a) documentation clearly identifying its legal status;
(b) an organizational chart showing clearly the responsibility and
reporting structure of the inspectorate and, in particular, the
relationship between its inspection and authorization (licensing)
functions;
(c) a description of the means by which the inspectorate obtains
financial support;
(d) a description of the relationship between the GMP inspectorate and
other departments within the drug regulatory authority and other
government agencies, where they operate as separate bodies.
5.3 The GMP inspectorate should have and make available a formal
statement explaining how the results of inspections are taken into
account in granting and maintaining authorizations (licences).
5.4 The senior management of the GMP inspectorate should make a
formal commitment to the recommended principles by ensuring that
the quality policy of the inspectorate is documented, relevant to the
objectives, and implemented.
5.5 The responsibility, authority and reporting structure of the GMP
inspectorate should be clearly defined and documented (see above)
and should be supported by written job descriptions for each member
of staff.
5.6 An appropriately experienced, responsible and qualified person
(2) should be nominated to carry out the quality assurance function,
including implementing and maintaining the quality system. This per-son
should have direct access to senior management. If necessary, this
task may be assigned to more than one person.
5.7 The GMP inspectorate should have sufficient resources at all
levels to enable it to attain its objectives effectively and efficiently.
Senior management should ensure that all personnel are competent
to carry out their assigned duties. They should receive appropriate
training that should be documented and its effectiveness assessed.
5.8 Periodic management reviews of the quality system should be
conducted and documented; records of these reviews should be
retained for a specified period of time.
Recommended procedure
The above-mentioned recommendations are intended to ensure a
reasonable level of transparency, both nationally and internationally..106
The organizational chart, source(s) of finance, legal status of the GMP
inspectorate and its relationship with the drug regulatory authority
and other government agencies should be documented in the quality
manual, together with a description of the quality system.
6. Inspection personnel
6.1 The personnel of the GMP inspectorate should be competent to
perform the functions that they undertake.
6.2 The GMP inspectorate should maintain information on the
relevant qualifications, training and experience of each inspector.
Records of training and experience should be kept up to date.
6.3 Personnel should have clear, documented instructions specifying
their duties and responsibilities. These instructions should be kept up
to date.
6.4 When work is subcontracted to an external body or use is made of
experts, the inspectorate should ensure that the personnel employed
meet the relevant requirements of the quality system. The liability of
third party inspectors should be clearly defined in the contract or
agreement.
6.5 The GMP inspectorate should possess the required personnel,
expertise and other resources to perform inspections of manufactur-ers
and wholesale distributors to determine whether they comply with
the principles and guidelines of current good practices and with the
relevant legislation.
6.6 The staff responsible for inspections should have appropriate
qualifications, training, experience and knowledge of the inspection
process. They should have the ability to make professional judge-ments
as to the conformity of the inspected party with the require-ments
of good practices and the relevant legislation and be able to
make an appropriate risk assessment. Knowledge of current technol-ogy
is essential, including computerized systems and information
technology.
6.7 The GMP inspectorate should establish a documented system for
recruiting and training its personnel. The training received and the
training needs of each member of staff should be regularly reviewed,
and individual training records should be maintained.
Recommended procedure
The credibility of the GMP inspection process will depend to a large
degree on the technical competence and integrity of the inspectors.
The quality manual should provide up-to-date details of the names,.107
qualifications, experience and terms of reference (job description and
duties to be performed) of each member of staff engaged in the GMP
inspection process (see also section 10).
Formal arrangements should exist for personnel training, and details
of these arrangements should be documented. Training undertaken
by each member of staff engaged in GMP inspections should be
documented (see also “Recommended procedure” in section 10).
A documented procedure for selecting the members of an inspection
team and deciding on its size should be available. The inspection team
may include a person or persons with specialist knowledge and/or
experience of a particular area of technology.
If an inspection is carried out on behalf of the GMP inspectorate by
an external body or person, the GMP inspectorate should ensure that
the external personnel satisfy the relevant requirements contained in
these recommendations.
GMP inspectors working with or advising the GMP inspectorate
should:
(a) be academically qualified in a recognized scientific/technological
discipline related to pharmaceuticals (normally pharmacy, chemi-stry
or microbiology); direct personal experience of pharmaceuti-cal
manufacture or control is not a requirement but would be
considered as a valuable asset for an inspector;
(b) have satisfactorily completed a recognized training course on
auditing quality management systems;
(c) undergo at least 10 days of training per year (e.g. courses, sympo-sia,
conferences, etc.);
(d) have a competent working knowledge of the WHO guidelines on
GMP for pharmaceutical products (2) and/or the GMP inspection
procedures of the relevant national regulatory authority;
(e) have undergone appropriate training in the current procedures
and techniques of GMP inspections before conducting an inspec-tion
alone;
(f) have the necessary personal qualities of integrity, tact and charac-ter
to perform the duties of a GMP inspector.
7. Documentation
7.1 The GMP inspectorate should maintain a system for the control
of all documentation relating to GMP inspections of manufacturers
and recommendations relating to authorization holders, and should
ensure that:.108
(a) the current versions of the appropriate documentation are avail-able
at all relevant locations;
(b) all revised documents or amendments to documents are correctly
authorized and processed in a manner which ensures that they are
introduced without delay;
(c) superseded documents are removed from use throughout the
GMP inspectorate and elsewhere in the organization and its
agencies, but are retained for a defined period of time.
7.2 The GMP inspectorate should ensure that all of its activities
are described in SOPs that clearly describe the responsibilities, policy
and actions. These should include, but not be limited to, training
(introduction, GMP and task-related), inspections, reporting after
inspections, handling of complaints, licensing (issue, suspension, re-vocation),
certification, documentation control, planning and han-dling
of appeals.
7.3 Proper and accessible records should be maintained of the activ-ities
carried out, including training, as well as the assessment of
inspectors after training, the preparation of inspection reports, the
handling of complaints, and the drawing-up of authorized checklists
(where in use) and other related documents.
7.4 Reports should be prepared on all inspections performed. They
should be prepared in the approved format, and signed and dated by
the relevant inspector.
7.5 The documentation system should ensure that any changes to
documents are made in a controlled manner and are properly author-ized.
There should be a means of identifying changes in individual
documents.
Recommended procedure
The following information should be included or referred to in the
quality manual:
(a) a list of all the documents used;
(b) for each document, the name(s) or position(s) of the person(s)
responsible for authorizing its issue and any subsequent amend-ments
or changes;
(c) a description of the system whereby relevant documents and
subsequent amendments are made available at the appropriate
location from the point of view of the functioning of the inspec-tion
process;.109
(d) the method by which amendments and changes are made, so that
documents are speedily updated, changes recorded and super-seded
documents promptly withdrawn and archived.
8. Records
8.1 The GMP inspectorate should maintain a system of records to
suit its particular method of operation and circumstances. It must
comply with the relevant obligations under national legislation and
demonstrate that the quality system is operating satisfactorily.
8.2 Records should be available which demonstrate that all the
relevant procedures have been followed in the performance of each
GMP inspection, including the initial inspection, the recommendation
for issue of a marketing authorization, routine inspections and correc-tive
action.
8.3 All records should be safely stored for an adequate period, and
held under conditions that guarantee their security and confidential-ity,
unless otherwise required by the national legislation.
Recommended procedure
The quality manual should describe or refer to separate SOPs which
describe the system adopted by the GMP inspectorate for maintain-ing
its records. The manual should include blank specimen copies of
the various checklists, certificates and reports used during the inspec-tion
process and describe the way in which these are processed, stored
and archived, and/or disposed of.
The procedures for recommending to the authorization holder the
issue, suspension or revocation of marketing authorizations should be
described.
Documented staff instructions on security and on the use and
handling of inspection reports should be identified and described in
accordance with the confidentiality requirements specified in national
legislation. Information as to who should have access to confidential
information should be given and such access should be controlled.
Records associated with inspection activities should be retained for a
minimum period of three full inspection cycles or for 6 years, which-ever
is the longer.
9. Inspection procedures
9.1 The GMP inspectorate should have the required resources
(financial, human, facilities and others) and documented procedures
to enable the inspection of manufacturing operations to be carried out.110
in accordance with the requirements of the WHO guidelines on GMP
(2) and/or the national GMP guidelines.
9.2 The GMP inspectorate should require the manufacturer to have
documented procedures in accordance with a quality management
system, and complying with the WHO guidelines on GMP (2) and/or
the national GMP guidelines.
9.3 The GMP inspectorate should perform regular inspections of the
manufacturing premises, procedures and quality systems of authori-zation
holders at least once every 2 years in accordance with a written
inspection programme. Written inspection reports should be pre-pared
and sent to the national regulatory authority to keep it in-formed
of the outcome of such inspections.
9.4 The planning of inspections of manufacturers and the assessment
of compliance with the planning regarding the performance of the
different types of inspections should be documented. The types of
inspections should include as a minimum routine inspections, specific
inspections, follow-up inspections and concise inspections.
9.5 The activity of the GMP inspectorate should be described, indi-cating
how it relates to the system(s) for granting manufacturers’ and
product authorizations.
9.6 The activities relating to post-marketing surveillance and product
testing should be described. The description should also cover the
process of handling non-conforming products (e.g. substandard or
counterfeit products).
9.7 The procedure for operations in support of a surveillance sam-pling
programme should be documented.
9.8 The GMP inspectorate should have the documented procedures
and resources to enable the inspection of manufacturing and wholesale
distribution operations to be carried out in accordance with the official
guidelines and national legislation. A formal inspection plan should be
followed. All instructions, standards or written procedures, work-sheets,
checklists and reference data relevant to the work of the GMP
inspectorate should be kept up to date and be readily available to staff.
9.9 A chief inspector should be appointed to coordinate inspection
activities if more than one inspector is involved in an inspection. The
lead inspector, who should be selected by all the participating inspec-tors,
should normally prepare the inspection report.
9.10 Observations and/or data obtained in the course of inspections
should be recorded in a timely manner to prevent loss of relevant
information..111
9.11 Completed inspections should be reviewed to ensure that the
requirements have been met.
Recommended procedure
The procedures covering initial inspections of new applicants for
marketing authorizations and ongoing inspections of authorization
holders should be documented.
Manufacturers should be inspected at least every 1 or 2 years, al-though
new authorization holders should be inspected more fre-quently
until inspectors are confident that the manufacturers are
complying with the WHO guidelines on GMP and/or the national
GMP guidelines. The frequency of inspection should not normally fall
below once every 2 years as lack of continuity may give rise to a
reduced awareness of current GMP or allow significant deficiencies to
develop.
The time available for undertaking inspections should be adequate to
enable sufficient investigations and enquiries to be made to give
confidence in the findings of the inspection.
The report to the authorization holders following GMP inspections
should include as a minimum:
(a) the name and location of the manufacturing site(s);
(b) the date(s) of the inspection(s);
(c) the reason for the inspection and the product categories and
manufacturing areas inspected;
(d) the suitability of key personnel, including the authorized person;
(e) observations, failures to comply with the WHO guidelines on
GMP and/or the national GMP guidelines, and the recommended
frequency of reinspection;
(f) a recommendation on the issue/continuation, suspension or revo-cation
of the marketing authorization.
The GMP inspectorate should have the power, under the national or
regional legislation or other arrangements, to require reinspection of
a manufacturer’s premises if there are changes in personnel, facilities,
internal organization or scope of activity, or if analysis of a complaint
or any other information indicates that the manufacturer is failing to
comply with the requirements of the WHO guidelines on GMP and/
or the national GMP guidelines, or with the conditions imposed by
the marketing authorization..112
10. Inspection facilities required
10.1 The inspection service should have the required facilities in
terms of staff, expertise, equipment and other resources to perform
inspections of manufacturers to determine compliance with the re-quirements
of the WHO guidelines on GMP and/or the national GMP
guidelines. This does not preclude the use of external resources, when
necessary, provided that the requirements as described for “subcon-tracting”
are met (see section 3.3).
10.2 If inspections are carried out on behalf of the GMP inspectorate
by an external body or person, the GMP inspectorate should ensure
that this body or person satisfies the requirements specified in section
3.3. A properly documented agreement covering these arrangements,
including confidentiality aspects and the declaration of any conflict of
interests, should be drawn up.
Recommended procedure
A sufficient number of competent personnel should support the GMP
inspectorate, whether employed or contracted for the functions that
they undertake.
The quality manual should describe the procedures for the manage-ment
of the GMP inspectors and of the necessary records. A record
should be kept for each individual employed to carry out GMP in-spections
(whether an employee or under contract), which should
include the following information:
(a) the name;
(b) the designated area of responsibility within the declared scope of
the GMP inspectorate;
(c) the educational qualifications;
(d) the professional qualifications, where relevant to the activities of
the GMP inspectorate;
(e) the work experience;
(f) details of the GMP inspector training received, supported by
documentary evidence of course attendance and assessment
results.
Where an external body or person carries out a GMP inspection, the
quality manual should describe the process adopted by the GMP
inspectorate to comply with the above-mentioned requirements.
Whenever an external body or person is used to carry out any func-tion
on behalf of a GMP inspectorate, the GMP inspectorate should.113
have documented evidence to demonstrate that the external body or
person concerned is competent to do so.
Staff members authorized to carry out audits of external bodies or
persons should be identified.
Documented agreements with all external bodies or persons should
be available for scrutiny.
A register of all external bodies or persons employed by the GMP
inspectorate should be maintained. The register should include:
(a) the name of the external body or person;
(b) the legal status of the external body and details of any relation-ship
with a parent company, group of companies or any other
organization of which the external body or person is part, with
specific reference to possible conflicts of interest;
(c) the names and qualifications of all personnel engaged in GMP
inspection work for the GMP inspectorate.
11. Quality manual
11.1 The GMP inspectorate should define and document its policy
and objectives for, and commitment to, quality in a quality manual. It
should ensure that this policy is understood, implemented and main-tained
at all levels in the organization.
11.2 The information contained in the quality manual and proce-dures
should include at least:
(a) a quality policy statement;
(b) a brief description of the legal status of the GMP inspectorate
(see section 4.1(a));
(c) a code of ethics and conduct relating to GMP inspection
activities;
(d) a description of the organization of the GMP inspectorate,
including details of any governing board, its constitution, terms
of reference and rules of procedure (see section 5.2(b));
(e) the names, qualifications, experience and terms of reference
of the senior staff and other GMP inspection personnel, both
internal and external (see sections 6 and 10);
(f) details of training arrangements for inspection personnel (see
sections 6 and 10);
(g) an organizational chart showing the responsibility and reporting
structure of the inspectorate and the allocation of functions.114
stemming from the person in charge of the GMP inspectorate
(see section 5.2(b));
(h) details of the documented procedures for inspecting manufac-turers
under the WHO guidelines on GMP and/or the national
GMP guidelines (see section 8);
(i) details of the documented procedures for recommendations to
the authorization holder for the issue, suspension or revocation
of marketing authorizations (see sections 7.2 and 8.1);
(j) a list of any subcontractors used for GMP inspections and details
of the documented procedures for assessing and monitoring their
competence (see section 6);
(k) details of appeals procedures (see section 14);
(l) a procedure for ensuring that complaints made to the GMP
inspectorate are investigated so that any shortcomings of the
authorization holders are revealed (see section 16);
(m) a list of those staff members responsible for investigating com-plaints
and those with the authority to take remedial action (see
section 16);
(n) details of internal quality audits (see section 15);
(o) details of testing of samples (see sections 9.6–9.8);
(p) the control of non-conforming products (see section 9.6).
Recommended procedure
In order to keep the quality manual brief, reference may be made to
other documents and/or procedures contained in other manuals.
12. Confidentiality
12.1 The GMP inspectorate should have adequate arrangements
to ensure confidentiality of the information obtained in the course
of its inspection activities at all levels of its organization, including
committees.
12.2 The exchange of inspection reports between countries should be
described. The format and content of reports should be specified.
Recommended procedure
The quality manual should describe how the GMP inspectorate
discharges its responsibility for ensuring that all communications
between itself and the companies inspected are kept confidential. The
following are necessary:.115
(a) instructions to personnel on confidentiality;
(b) a written undertaking by all personnel not to divulge to third
parties any information gained about any business affairs of
clients;
(c) the inclusion of provisions in all subcontracts to maintain
confidentiality;
(d) provisions to ensure the physical security of all documents and
records relating to inspection activities.
13. Publications
13.1 The GMP inspectorate should produce and update, as neces-sary,
a list of authorization holders, together with an outline of the
scope of the marketing authorization issued to each manufacturer.
The extent to which this list will be distributed should be specified.
13.2 An outline of the inspection and marketing authorization system
should be available in published form.
13.3 Other publications, such as GMP guidelines and other guide-lines
and information brochures, should be available to industry and
other interested parties, as appropriate.
Recommended procedure
The quality manual should list the publications issued by the authori-zation
holder and GMP inspectorate. The following information
should also be provided:
(a) the name of the person responsible for compiling and updating
each publication;
(b) the frequency with which each publication is updated;
(c) how the publications are distributed and to whom;
(d) the procedure for issuing amendments.
14. Appeals
14.1 The GMP inspectorate should have procedures for the con-sideration
of appeals against its decisions.
Recommended procedure
Appeals procedures should be established by the GMP inspectorate
and should include:
(a) the method by which an appeal may be lodged;
(b) the method by which an impartial appeals panel, independent of
the activity under review, is selected;.116
(c) the names and positions of the members of the GMP inspectorate
to whom appeals are referred, and the procedure for handling
them;
(d) a register of all appeals and their outcome.
15. Internal audit and periodic review
15.1 The GMP inspectorate should implement a system of planned
and documented internal audits and periodic reviews of its compli-ance
with the criteria of these guidelines.
15.2 There should be procedures for corrective and preventive action
whenever faults are detected in the quality system, or in the perfor-mance
of inspections and the general performance of the inspection
service.
15.3 The management of the inspectorate should periodically review
the quality system for its continuing suitability and effectiveness.
15.4 Inspectors should be evaluated before being allowed to perform
inspections. Periodic reviews should also be undertaken to examine
the performance of individual inspectors in order to ensure consist-ency
among them, and in the operations and procedures of the GMP
inspectorate.
15.5 A record of all audits and reviews should be kept and should
include the findings, conclusions, recommendations and follow-up
action. These records should be retained for a specified period of
time.
Recommended procedure
Internal periodic review procedures should be documented. The
review procedure should include internal audits by staff competent
to ensure that all formulated procedures are adhered to. Based on
the results of these audits, management must ensure that the GMP
inspection system remains effective and that inspections conducted
by different inspectors arrive at similar conclusions when the same
operation is inspected under the same conditions.
Internal audit procedures should state:
(a) the names or positions of staff members authorized to conduct
internal audits;
(b) what is to be examined and how often (a schedule for the exami-nation
of the whole organization over a given period should be
drawn up);.117
(c) how the audit will be conducted;
(d) to whom the results will be reported;
(e) who will initiate any corrective action.
Management reviews should take account of the results of internal
audits and should include:
(a) consideration of the overall operation of the GMP inspectorate;
(b) uncovering defects or irregularities in the operation of the GMP
inspection system;
(c) ensuring that action has been taken to effectively correct defects
revealed in previous reviews and audits.
Periodic audit by an experienced person or persons from another
national regulatory authority is a useful means of providing an
independent review of the GMP inspectorate’s operations and
procedures.
16. Complaints
16.1 The GMP inspectorate should have documented procedures for
dealing with complaints arising from its activities.
16.2 A record should be maintained of all complaints received and
the actions taken by the GMP inspectorate. These records should be
retained for a specified period of time.
Recommended procedure
The GMP inspectorate should require each authorization holder to
keep a record of all complaints received, as well as remedial actions
relating to the manufacturing activities and products covered by the
marketing authorization.
The GMP inspectorate should have a procedure for recording and
investigating complaints received about its inspection activities. The
procedure should include a list of those staff members responsible for
investigating complaints and those with the authority to take remedial
action.
17. Recalls
17.1 The GMP inspectorate should have a documented procedure for
dealing with recalls and withdrawals of products from the market.
17.2 Records should be maintained of all recalls and withdrawals
registered and dealt with by the inspectorate..118
References
1. Provisional guidelines on the inspection of pharmaceutical manufacturers.
In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-second report. Geneva, World Health Organization,
1992, Annex 2 (WHO Technical Report Series, No. 823).
2. Quality assurance of pharmaceuticals. A compendium of guidelines and
related materials. Vol. 2. Good manufacturing practices and inspection.
Geneva, World Health Organization, 1999.
3. Recommendations on quality system requirements for GMP inspectorates of
PIC Contracting States. Geneva, Pharmaceutical Inspection Convention,
1994 (unpublished document PH/7/94; available from EFTA Secretariat,
9–11 rue de Varembé, 1211 Geneva 20, Switzerland).
4. Quality management and quality assurance standards — guidelines for
selection and use. International Standard ISO 9000. Geneva, International
Organization for Standardization, 1990.
5. Quality systems — model for quality assurance in design/development,
production, installation and servicing. International Standard ISO 9001.
Geneva, International Organization for Standardization, 1994.
6. Quality systems — model for quality assurance in production, installation
and servicing. International Standard ISO 9002. Geneva, International
Organization for Standardization, 1994.
7. Quality systems — model for quality assurance in final inspection and test.
International Standard ISO 9003. Geneva, International Organization for
Standardization, 1994.
8. Quality management and quality system elements — guidelines.
International Standard ISO 9004. Geneva, International Organization for
Standardization, 1990.
9. General criteria for certification bodies operating quality systems
certification. European Standard EN 45012. Brussels, European Committee
for Standardization, 1989 (available from CEN Central Secretariat, 36 rue de
Stassart, B-1050 Brussels, Belgium).
10. Good manufacturing practices: authorized person — role, functions and
training. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-fifth report. Geneva, World Health Organization, 1999,
Annex 4 (WHO Technical Report Series, No. 885)..119
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 9
Guidelines on packaging for pharmaceutical
products
Introductory note 120
Glossary 121
1. Aspects of packaging 125
1.1 General considerations 125
1.2 Functions of packaging 127
1.2.1 Containment 127
1.2.2 Protection 127
1.3 Presentation and information 129
1.3.1 Labels 129
1.3.2 Repacking, relabelling and dispensing 130
1.3.3 Package inserts for patients (patient information leaflets) 131
1.4 Compliance 131
1.5 Protection of patients 131
1.6 Detection of counterfeiting 131
2. Packaging materials and closures 132
2.1 Types of material 132
2.1.1 Glass 132
2.1.2 Plastics 133
2.1.3 Metal 133
2.2 Closures 134
2.2.1 Rubber closures 134
2.2.2 Caps or overseals 135
2.2.3 Special types of closure 135
3. Quality assurance aspects of packaging 137
3.1 General considerations 137
3.2 Quality control 137
3.2.1 Sampling 138
3.2.2 Testing programme 139
3.3 Inspection and audit 139
3.3.1 Rules 139
3.3.2 Audits of suppliers 140
4. Protection of the environment 140
4.1 Packaging waste 140
4.2 Waste policies 141
5. Quality specifications 142
5.1 Requirements in The international pharmacopoeia 142
5.1.1 Packaging materials 142
5.1.2 Requirements for dosage form containers 142.120
5.2 Pharmacopoeial requirements for containers in Europe, Japan
and the USA 144
5.2.1 Glass containers 144
5.2.2 Plastic containers 144
5.2.3 Rubber closures 144
5.3 International Standards 145
References 145
Bibliography 147
Appendix 1
Storage areas 150
Appendix 2
Labels 151
Appendix 3
Self-inspection and quality audits 152
Appendix 4
International Standards on packaging 154
Introductory note
This review of the various elements of the packaging of a pharmaceu-tical
product is aimed at ensuring that medicines arrive safely in the
hands of the patients for whom they are prescribed.
In the manufacture of pharmaceutical products, quality assurance is
defined as “the totality of the arrangements made with the object of
ensuring that pharmaceutical products are of the quality required for
their intended use” (1).
In addition, the system of quality assurance for the manufacture of
pharmaceutical products should ensure that “arrangements are made
for the manufacture, supply and use of the correct starting and pack-aging
materials” (1).
Public opinion sometimes considers packaging to be superfluous.
However, it must be emphasized that packaging preserves the stabil-ity
and quality of medicinal products and protects them against all
forms of spoilage and tampering.
All medicinal products need to be protected and “consequently need
to be packaged in containers that conform to prescribed standards,
particularly with respect to the exclusion of moisture and light and the
prevention of leaching of extractable substances into the contents and
of chemical interaction with the contents. . . . However, the limits of
acceptability in these various respects depend, at least in part, on
climatic variables. Recommendations in The international pharmaco-poeia
can only be advisory; precise quantitative standards will have to
be locally determined” (2)..121
The complexity of packaging materials and the highly technological
nature of medicinal products is such that manufacturers are con-fronted
with significant problems. Interaction between packaging and
such products is possible due to the combination of a multiplicity of
container components and active pharmaceutical ingredients, excipi-ents
and solvents used in a variety of dosage forms.
The quality of the packaging of pharmaceutical products plays a very
important role in the quality of such products. It must:
— protect against all adverse external influences that can alter the
properties of the product, e.g. moisture, light, oxygen and tem-perature
variations;
— protect against biological contamination;
— protect against physical damage;
— carry the correct information and identification of the product.
The kind of packaging and the materials used must be chosen in such
a way that:
— the packaging itself does not have an adverse effect on the product
(e.g. through chemical reactions, leaching of packaging materials
or absorption);
— the product does not have an adverse effect on the packaging,
changing its properties or affecting its protective function.
The resulting requirements must be met throughout the whole of the
intended shelf-life of the product. Given the link between the quality
of a pharmaceutical product and the quality of its packaging, phar-maceutical
packaging materials and systems must be subject, in
principle, to the same quality assurance requirements as pharmaceu-tical
products.
The appropriate system of quality assurance for the manufacture of
pharmaceutical products should therefore follow the WHO guide-lines
for good manufacturing practices (GMP) (1).
The requirements to be met by pharmaceutical packaging and pack-aging
materials as described in compendia (pharmacopoeias) and
standards (e.g. those of the International Organization for Standard-ization
(ISO)) must be considered only as general in character. The
suitability of packaging or packaging material for any particular
requirements and conditions can only be ascertained through detailed
packaging and stability studies on the product concerned.
Glossary
The definitions given below apply specifically to the terms used in
these guidelines. They may have different meanings in other contexts..122
General
bulk product
Any product that has completed all the processing stages up to, but
not including, final packaging (1).
containers
A container for pharmaceutical use is an article which holds or is
intended to contain and protect a drug and is or may be in direct
contact with it. The closure is a part of the container. The container
and its closure must not interact physically or chemically with the
substance within in any way that would alter its quality. The following
terms include general requirements for the permeability of containers
(3):
• Well-closed containers must protect the contents from extraneous
matter or from loss of the substance under normal conditions of
handling, shipment or storage.
• Tightly closed containers must protect the contents from extraneous
matter, from loss of the substance, and from efflorescence, deli-quescence
or evaporation under normal conditions of handling,
shipment or storage. If the container is intended to be opened on
several occasions, it must be designed to be airtight after reclosure.
• Hermetically closed containers must protect the contents from ex-traneous
matter and from loss of the substance, and be impervious
to air or any other gas under normal conditions of handling, ship-ment
or storage.
Substances and dosage forms requiring protection from light should
be maintained in a light-resistant container that — either by reason of
the inherent properties of the material of which it is composed, or
because a special coating has been applied to it — shields the contents
from the effects of light. Alternatively, the container may be placed
inside a suitable light-resistant (opaque) covering and/or stored in a
dark place (3).
labels
All finished drug products should be identified by labelling, as
required by the national legislation, bearing at least the following
information:
(a) the name of the drug product;
(b) a list of the active ingredients (if applicable, with the Interna-tional
Nonproprietary Names (INNs)), showing the amount of.123
each present, and a statement of the net contents, e.g. number of
dosage units, mass or volume;
(c) the batch number assigned by the manufacturer;
(d) the expiry date in an uncoded form;
(e) any special storage conditions or handling precautions that may
be necessary;
(f) the directions for use, and any warnings and precautions that may
be necessary;
(g) the name and address of the manufacturer or the company or
person responsible for placing the product on the market.
marketing authorization (product licence, registration certificate)
A legal document issued by the competent drug regulatory authority
that establishes the detailed composition and formulation of the prod-uct
and the pharmacopoeial or other recognized specifications of
its ingredients and of the final product itself, and includes details of
packaging, information given on the label, product information and
shelf-life (1).
materials
A term used to denote starting materials, process aids, intermediates,
active pharmaceutical ingredients, packaging and labelling materials.
packaging material
Any material, including printed material, employed in the packaging
of a pharmaceutical product, excluding any outer packaging used for
transportation or shipment. Primary packaging materials are those
that are in direct contact with the product (1).
packaging process
All operations, including filling and labelling, that a bulk product has
to undergo in order to become a finished product (1).
production
All operations involved in the preparation of a pharmaceutical prod-uct,
from receipt of the starting materials, through processing and
packaging, to completion of the finished product (1).
quarantine
The status of starting or packaging materials, intermediates, or bulk
or finished products isolated physically or by other effective means
while a decision is awaited on their release, rejection or reprocessing
(1)..124
Containers for pharmaceuticals
1
ampoule
A container sealed by fusion and to be opened exclusively by break-ing.
The contents are intended for use on one occasion only.
bag
A container consisting of surfaces, whether or not with a flat bottom,
made of flexible material, closed at the bottom and at the sides by
sealing; the top may be closed by fusion of the material, depending on
the intended use.
blister
A multi-dose container consisting of two layers, of which one is
shaped to contain the individual doses. Strips are excluded.
bottle
A container with a more or less pronounced neck and usually a flat
bottom.
cartridge
A container, usually cylindrical, suitable for liquid or solid pharma-ceutical
dosage forms; generally for use in a specially designed appa-ratus
(e.g. a prefilled syringe).
gas cylinder
A container, usually cylindrical, suitable for compressed, liquefied or
dissolved gas, fitted with a device to regulate the spontaneous outflow
of gas at atmospheric pressure and room temperature.
injection needle
A hollow needle with a locking device intended for the administration
of liquid pharmaceutical dosage forms.
injection syringe
A cylindrical device with a cannula-like nozzle, with or without a fixed
needle and a movable piston, used for the administration, usually
parenteral, of an accurately measured quantity of a liquid pharmaceu-tical
form. The syringe may be prefilled, and can be for single-dose or
multi-dose use.
1
Based on a list of terms drawn up in response to a request from the European
Commission to revise and replace the guidelines of the Committee for Proprietary
Medicinal Preparations (III/3593/91)..125
pressurized container
A container suitable for compressed, liquefied or dissolved gas fitted
with a device that, after its actuation, produces a controlled spon-taneous
release of the contents at atmospheric pressure and room
temperature.
single-dose container
A container for single doses of solid, semi-solid or liquid preparations.
strip
A multi-dose container consisting of two layers, usually provided with
perforations, suitable for containing single doses of solid or semi-solid
preparations. Blisters are excluded.
tube
A container for multi-dose semi-solid pharmaceutical forms consist-ing
of collapsible material; the contents are released via a nozzle by
squeezing the package.
vial
A small container for parenteral medicinal products, with a stopper
and overseal; the contents are removed after piercing the stopper.
Both single-dose and multi-dose types exist.
1. Aspects of packaging
1.1 General considerations
Packaging may be defined as the collection of different components
(e.g. bottle, vial, closure, cap, ampoule, blister) which surround the
pharmaceutical product from the time of production until its use.
The aspects of packaging to be considered (4) include:
— the functions of packaging;
— the selection of a packaging material;
— the testing of the material selected;
—filling and assembling;
— sterilization;
— storage and stability.
Packaging materials (see section 2) include printed material em-ployed
in the packaging of a pharmaceutical product, but not any
outer packaging used for transportation or shipment. Examples of the
types of materials used are shown in Table 1.
A distinction must be made between primary and secondary packag-ing
components. The primary packaging components (e.g. bottles,.126
vials, closures, blisters) are in direct physical contact with the product,
whereas the secondary components are not (e.g. aluminium caps,
cardboard boxes). The choice of primary and/or secondary packaging
materials will depend on the degree of protection required, compat-ibility
with the contents, the filling method and cost, but also the
presentation for over-the-counter (OTC) drugs and the convenience
of the packaging for the user (e.g. size, weight, method of opening/
reclosing (if appropriate), legibility of printing).
Containers may be referred to as primary or secondary, depending on
whether they are for immediate use after production of the finished
product or not. Both single-dose and multi-dose containers exist.
Containers may be well-closed, tightly closed, hermetically closed or
light-resistant, as defined in the glossary (3).
The packaging process, as defined in the glossary, is the process
that a bulk material must undergo to become a finished product. The
properties and attributes of the product should be as specified by the
manufacturer and required by the user. The packaging process con-sists
of the following stages:
Table 1
Types of raw materials used in packaging
Types of materials Uses
Cardboard Boxes
Display units
Paper Labels
Leaflets
Glass Ampoules
Bottles
Vials
Syringes
Cartridges
Plastic Closures
Bottles
Bags
Tubes
Laminates with paper or foil
Metal, e.g. aluminium Collapsible tubes
Rigid cans
Foils
Needles
Gas cylinders
Pressurized containers
Rubber Closures, including plungers.127
—filling and assembling;
— sterilization in the final container, if applicable;
— placing labels on the container;
— storage at the manufacturing and shipping sites.
Packaging documentation (1) includes aspects related to:
— specifications and quality control, including batch records;
— labels, inks and adhesive materials (e.g. glue);
— package inserts for patients.
Apart from primary and secondary packaging, two types of special
packaging are currently in use, as follows:
• Unit-dose packaging. This packaging guarantees safer medication
by reducing medication errors; it is also more practical for the
patient. It may be very useful in improving compliance with treat-ment
and may also be useful for less stable products.
• “Device” packaging. Packaging with the aid of an administration
device is user-friendly and also improves compliance. This type
of packaging permits easier administration by means of devices
such as prefilled syringes, droppers, transdermal delivery systems,
pumps and aerosol sprays. Such devices ensure that the medicinal
product is administered correctly and in the right amount.
1.2 Functions of packaging
1.2.1 Containment
The containment of the product is the most fundamental function of
packaging for medicinal products. The design of high-quality packag-ing
must take into account both the needs of the product and of the
manufacturing and distribution system. This requires the packaging:
— not to leak, nor allow diffusion and permeation of the product;
— to be strong enough to hold the contents when subjected to nor-mal
handling;
— not to be altered by the ingredients of the formulation in its final
dosage form.
1.2.2 Protection
The packaging must protect the product against all adverse external
influences that may affect its quality or potency, such as:
— light
— moisture
— oxygen
— biological contamination
— mechanical damage..128
The compatibility of the packaging with the active pharmaceutical
ingredients is very important in maintaining the integrity of the
product.
Stability. Information on stability is given in the guidelines for stabil-ity
testing of pharmaceutical products containing well-established
drug substances in conventional dosage forms (4).
For primary packaging, it is necessary to know the possible interac-tions
between the container and the contents. Normally, product/
component stability and compatibility are confirmed during the pri-mary
research and development stage.
While excluding the effect of external factors on the product, the
packaging itself should not interact with it so as to introduce unac-ceptable
changes. There are numerous possibilities of interactions
between (primary) packaging materials and pharmaceutical products,
such as:
— the release of chemicals from components of the packaging
materials;
— the release of visible and/or subvisible particles;
— the absorption or adsorption of pharmaceutical components by
the packaging materials;
— chemical reactions between the pharmaceutical product and the
packaging materials;
— the degradation of packaging components in contact with the
pharmaceutical products;
— the influence of the manufacturing process (e.g. sterilization) on
the container.
The active pharmaceutical ingredients should remain within their
specification limits over the shelf-life of the pharmaceutical product.
The question of whether a packaging will provide the required protec-tion
for the pharmaceutical product and the required stability over
a certain time period can only be answered by means of real-time
stability studies. Such studies must evaluate the changes in the quality
of the product, in contact with its packaging, during a period equiva-lent
to its intended shelf-life.
In addition, packaging must meet the following requirements:
— it must preserve the physical properties of all dosage forms and
protect them against damage or breakage;
— it must not alter the identity of the product;
— it must preserve the characteristic properties of the product, so
that the latter complies with its specifications;.129
— it must protect the product against undesirable or adulterating
chemical, biological or physical entities.
Storage. Packaging materials should be stored in accordance with
GMP for storage areas (1; see Appendix 1). The characteristics of the
active pharmaceutical ingredients will determine whether different
packaging will be needed. For example, the packaging requirements
of medicinal products kept at temperatures between 2 and 8°C may
differ from those of products intended for tropical countries or light-sensitive
products. If the contents are sterile, sterility must be main-tained,
including that of any unused remaining product.
The shelf-life and utilization period are always determined in relation
to storage conditions and the stability of the active pharmaceutical
ingredient.
Normal storage conditions are defined as “storage in dry, well-ventilated
premises at temperatures of 15–25°C or, depending on
climatic conditions, up to 30 °C. Extraneous odours, other indications
of contamination, and intense light have to be excluded” (5).
1.3 Presentation and information
Packaging is also an essential source of information on medicinal
products. Such information is provided by labels and package inserts
for patients.
The information provided to the patient may include the following:
— the name of the patient;
— the identification number for dispensing records;
— the name, strength, quantity and physical description or identifica-tion
of the medicinal product;
— directions for use and cautionary statements, if applicable;
— the storage instructions;
— the date of dispensing and period of use (related to the expiry
date);
— the name and address of the dispenser.
1.3.1 Labels
Throughout manufacturing, a succession of specific outer labels are
applied to the container of the medicinal product. The level of pro-cessing
is indicated by the following words:
— quarantine
— storage
— distribution..130
Specifications for labels for finished drug products are defined in
the WHO guidelines on GMP for pharmaceutical products (1; see
Appendix 2).
Written labels on the packaging:
• Permit the identification of each active ingredient by means of its
INN, and also give the dosage form and the trade name/trademark.
All information concerning the medicinal product, as required by
national legislation, must be stated on the packaging.
• Preserve the stability of the medicinal product by giving advice on
its storage (4):
After the stability of the product has been evaluated, one of the following
recommendations as to storage conditions can be prominently indicated on
the label:
— store under normal storage conditions;
— store between 2 and 8 °C (under refrigeration, no freezing);
— store below 8 °C (under refrigeration);
— store between -5 and -20 °C (in a freezer);
— store below -18 °C (in a deep freezer).
• Permit the follow-up of a specific medicinal product by means of
the batch number on the labels. It must be possible to follow the
route of distribution of a product from the manufacturing process
to its administration to the patient with the aim of locating and
identifying products that are of potential risk (e.g. blood products,
blood-derived products).
• Mask the real identity of the medicinal product in clinical studies.
This is extremely important in clinical trials in determining the real
efficacy of a medicinal product in blinded studies. If the identity is
masked by a code, it must be possible to disclose it at any time in a
medical emergency.
National legislation must be followed with regard to the information
provided to the patient, as well as the record-keeping and packaging
instructions.
1.3.2 Repacking, relabelling and dispensing
In some countries, it is common practice not to dispense drugs in the
original packaging, but rather in a personalized manner to each pa-tient.
This applies especially to solid oral dosage forms, and involves
the “repacking” and “relabelling” of drugs in small quantities. Differ-ent
drugs may even be included in “customized” medication pack-ages,
also referred to as “patient med packs”. The quantities of drugs
supplied in this way are usually enough only for a short period of time,.131
i.e. to provide drugs for immediate use. It should be remembered,
however, that data obtained in stability studies undertaken by the
manufacturer are no longer valid for drugs removed from the original
package.
Where repacking and relabelling are necessary, the WHO guidelines
on GMP for pharmaceutical products (1) should be followed to avoid
any mix-up or contamination of the product, which could place the
patients’ safety at risk.
1.3.3 Package inserts for patients (patient information leaflets)
Product information must help patients and other users to understand
the medication. The patient package insert, together with the label,
provides the patient with key information concerning the proper use
of the product, potential adverse drug reactions and interactions,
storage conditions and the expiry date.
In OTC medicinal products, the package insert, together with the
label, may constitute the only pharmaceutical advice that the patient
receives.
1.4 Compliance
Packaging and labelling may help to reinforce the instructions given
by the physician or the pharmacist, and improve compliance with
drug therapy. In this respect, packaging becomes a compliance aid.
The design of pharmaceutical packaging should be such that the
product can easily be administered in a safe manner to the patient. If
the patient feels at ease with the packaging and route of administra-tion,
the design of the packaging may become a key factor in increas-ing
compliance. This is also an important factor in clinical trials.
1.5 Protection of patients
Packaging must not only increase compliance through its design, but
must also protect the patient and indicate the integrity of the product.
Packaging equipped with a tamper-evident device protects against
incidental and accidental poisoning. To protect children, several
child-resistant closures have been developed (see section 2.2.3).
1.6 Detection of counterfeiting
The Forty-first World Health Assembly, after reviewing the report of
the Executive Board on the implementation of WHO’s revised drug
strategy, requested: “. . . governments and pharmaceutical manufac-turers
to cooperate in the detection and prevention of the increasing.132
incidence of the export or smuggling of falsely labelled, spurious,
counterfeited or substandard pharmaceutical preparations” (6).
Several documents (2, 6–9) show that counterfeit pharmaceutical
products are in wide circulation. In November 1985, during the WHO
Conference of Experts on the Rational Use of Drugs in Nairobi,
Kenya, concern was expressed regarding the extent to which counter-feit
pharmaceutical products were in circulation in developing coun-tries
(10). In view of the importance of this issue, a text has been drafted
to provide model provisions to deal with counterfeit drugs (11).
The design of the packaging must therefore contribute to preventing
tampering with, or the counterfeiting of, certain medicinal products.
Such tamper-evident containers can allow the visual inspection of the
medicinal product before use, and this may serve as a first stage in
detecting counterfeit drugs.
2. Packaging materials and closures
In accordance with the methods of use and administration of medici-nal
products, packaging materials, closures and containers vary a
great deal and have to meet a wide variety of different requirements.
All the routes used for systemic access have demanding requirements,
which often can only be met by complex structured and formulated
medicinal products. This is particularly true of the new medicinal
products that are now appearing, such as those administered via
transdermal delivery systems.
To ensure the efficacy of a product during its total shelf-life, pharma-ceuticals
must be regarded as a combination of the medicinal product
itself and the packaging.
2.1 Types of material
Only the most commonly used packaging materials and containers
are described here.
2.1.1 Glass
For a large number of pharmaceuticals, including medicinal products
for oral and local administration, glass containers are usually the first
choice (e.g. bottles for tablets, injection syringes for unit- or multi-dose
administration). Different types of glass may be necessary,
depending on the characteristics and the intended use of the medici-nal
products concerned.
Manufacturers should arrange with their suppliers to obtain the
appropriate type of glass container for the intended use. Suppliers.133
should provide the raw and packaging materials in conformity with
industrial norms. Classifications of types of glass are given in the
European and United States pharmacopoeias, whereas no such
classification exists in the Japanese pharmacopoeia.
Glass can be tested for light transmission and hydrolytic resistance. In
the Japanese pharmacopoeia, such tests are described only for glass
containers for injection, whereas in the European and United States
pharmacopoeias they are given for all types of glass containers.
2.1.2 Plastics
Some containers are now being made of plastics; the main use is for
bags for parenteral solutions. Plastic containers have several advan-tages
compared with glass containers:
— they are unbreakable
— they are collapsible
— they are light.
The European, Japanese and United States pharmacopoeias all de-scribe
materials of the same type, but there are considerable differ-ences
in the classification and presentation.
As far as tests are concerned, the three pharmacopoeias are
extremely difficult to compare. The European pharmacopoeia is the
most detailed and requires tests in relation to the use and routes of
administration of the medicinal product. Moreover, the same concept
is extended to bulk containers for active ingredients.
2.1.3 Metal
Metal containers are used solely for medicinal products for non-parenteral
administration. They include tubes, packs made from foil
or blisters, cans, and aerosol and gas cylinders. Aluminium and stain-less
steel are the metals of choice for both primary and secondary
packaging for medicinal products. They have certain advantages and
provide excellent tamper-evident containers.
Since metal is strong, impermeable to gases and shatterproof, it is the
ideal packaging material for pressurized containers.
Descriptions and tests can be found in the norms and standards of the
ISO; these have been established in collaboration with manufactur-ers.
Requirements are not given in pharmacopoeias; the suitability of
a particular material for a container is normally established by con-ducting
stability studies in which the material is in contact with the
drug in question..134
2.2 Closures
Closures used for the purpose of covering drug containers after the
filling process should be as inert as possible. They should not give rise
to undesired interactions between the contents and the outside envi-ronment,
and should provide a complete seal. Besides their protective
function, closures must also allow the easy and safe administration of
the drug.
Depending on the application, closures may have to be pierced with a
needle for intravenous sets. Such closures are made from elastomeric
materials (rubbers), while those that cannot be pierced are generally
made from plastics such as polyethylene or polypropylene.
Depending on the type of container, closures may have different
shapes and sizes, e.g. stoppers for infusion or injection bottles or
plungers for prefilled syringes. A special design of stopper may also
be required for some pharmaceutical production processes such as
lyophilization.
Closures, as primary packaging components, are of critical impor-tance
and must be carefully selected. They are an essential compo-nent
of the container and, as such, an integral part of the drug
preparation.
A container type which does not require a removable closure at the
time of administration is usually preferred since such a container/
closure system avoids, or at least minimizes, the risk of biological and
other contamination as well as tampering.
For parenteral preparations, the combination of glass containers and
elastomeric closures, usually secured by an aluminium cap, is widely
used. Typical examples are infusion bottles, injection vials and
prefilled syringes. The rubber closures used within such a system must
be carefully selected in accordance with the intended purpose. Most
often, improper rubber closures are the cause of incompatibility
between the packaging and the drug.
2.2.1 Rubber closures
Rubber consists of several ingredients, one of which is elastomer.
Modern rubber compounds used in packaging pharmaceuticals con-tain
only a limited number of ingredients, which are very difficult to
extract. Closures made from such materials generally do not pose any
problems, and can be used in contact with a large number of drug
preparations.
Rubber closures for pharmaceutical use must meet the relevant re-quirements
of the most important pharmacopoeias (the European,.135
Japanese and United States pharmacopoeias). International stan-dards
have also been established (ISO 8871). It should be emphasized
that the requirements of pharmacopoeias and standards must be
seen as minimal requirements. The suitability of a rubber closure for
a given application can only be established by means of stability
studies.
2.2.2 Caps or overseals
Caps or overseals are used to secure the rubber closure to the
container in order to maintain the integrity of the seal under
normal conditions of transport, handling and storage during the in-tended
shelf-life of the product. Such caps are usually made of alu-minium
and can be equipped with a plastic top to facilitate opening.
Caps also provide evidence of tampering: once opened or removed
they cannot be repositioned. This is especially true for caps with a
plastic top.
2.2.3 Special types of closure
Demographic trends are causing new problems for packaging design-ers.
Thus while child-resistant closures safeguard children against
drug intoxication, opening such packaging may prove difficult for the
increasing number of elderly persons in the population.
Tamper-evident closures. Tampering includes three aspects, namely
altering, pilfering and falsifying the pharmaceutical product.
To prevent tragic accidents and especially malicious tampering,
manufacturers try to create safe packaging and governments con-tinue
to update regulations to include new tamper-evident technol-ogy.
In 1975, the United States Food and Drug Administration issued
a regulatory requirement for tamper-evident packaging to be used
for ophthalmic preparations, thus ensuring that such preparations
remained sterile until their use (12). This regulation specifies that
the closures must be sealed in such a manner that the contents
cannot be used without destroying the seal. In 1982, a further regula-tion
(13) on tamper-evident packaging for OTC human drug products
described such packaging as “having an indicator or barrier to entry
which, if breached or missing, can reasonably be expected to provide
visible evidence to consumers that tampering has occurred”.
The concept of tamper-evident packaging is also found in the “Gen-eral
Notice” and “Requirements” of the United States pharmaco-poeia,
which stipulate that all OTC drugs must comply with the
tamper-evident packaging and labelling requirements of the Food
and Drug Administration, unless specifically exempted. Products cov-ered
by the regulation include all OTC drugs, toothpaste and topical.136
dermatological products, oral cosmetic liquids, contact lens solutions
and tablets.
In May 1992, the Food and Drug Administration (14) listed 11 tech-nologies
capable of satisfying the definition of tamper-evident pack-aging,
while a twelfth was added for sealed cartons. The list includes
film wrappers, blister packs, bubble packs, heat-shrunk bands or
wrappers, paper foil or plastic packs, bottles with inner mouth seals,
tape seals, breakable cap-ring systems, sealed tubes or plastic blind-end
heat-sealed tubes, sealed cartons, aerosol containers and all metal
and composite cans.
Child-resistant closures. Tragic accidents involving the drug intoxica-tion
of children has led to new legislation making it difficult for drug
packaging to be opened by young children, while allowing adults easy
access. Such packaging is designated as child-resistant.
Certain protocols for child-resistant packaging were established in
the USA in 1966. In 1970, the Poison-Prevention Packaging Act was
passed and placed under the jurisdiction of the Food and Drug
Administration. This Act was transferred in 1973 to the Consumer
Product Safety Commission, which is responsible for drugs and
household substances (15). The use of child-resistant packaging has
proved effective in reducing child mortality from intoxication by oral
prescription drugs, and it is now recognized worldwide that children
must be protected against such intoxication.
The ISO has published an internationally agreed standard test proce-dure
for reclosable child-resistant packaging (16). In Europe several
norms have been introduced, which complement the ISO standard
(17, 18).
The European Committee for Standardization (CEN) has defined a
child-resistant package as one “which makes it difficult for young
children to gain access to the contents, but which is not too difficult
for adults to use properly in accordance with the requirement of this
European standard” (19).
The three most common reclosable child-resistant types of closure are
the “press–turn”, the “squeeze–turn” and a combination lock.
To determine whether a packaging is child-resistant, it must be
subjected to the ISO test procedure for reclosable child-resistant
packaging (14).
Most designs that are child-resistant require two hands to open the
closure. Such packaging can cause problems for elderly people, and
can even lead to the deliberate purchase of drugs with packaging that.137
is not child-resistant; alternatively, the child-resistant closure may not
be replaced on the container. An optional “elderly adult test” has
been inserted in the ISO standard to deal with this problem.
3. Quality assurance aspects of packaging
3.1 General considerations
To ensure that patients and consumers receive high-quality drugs, the
quality management system must take the following considerations
into account if the required quality of packaging is to be obtained:
— the requirements of the national authorities and the relevant
legislation
— the product
— the production process
— the manufacturers’ internal policies (safety, marketing, etc.).
Bad packaging which is the result of deficiencies in the quality as-surance
system for packaging can have serious consequences, and
packaging defects can create problems that may result in drug recalls.
Such defects may include breakage, and problems relating to printing
or inks, or errors on labels and package inserts (patient information
leaflets). The use of GMP and quality control will prevent the release
of a defective medicinal product.
Packaging processes and equipment need validation/qualification in
the same way as any other part of processing within a pharmaceutical
facility.
3.2 Quality control
Pharmacopoeial specifications and standards for quality control
established by national drug quality control laboratories, as already
mentioned, can only be regarded as general in character and must
be interpreted as minimum standards. The essential part of quality
control is performed by the manufacturer during the development,
production, release and post-marketing surveillance of the entire
medicinal product, i.e. the finished dosage form in its primary and
secondary packaging. As pointed out by the WHO Expert Committee
on Specifications for Pharmaceutical Preparations at its thirty-second
meeting (1):
Quality control is the part of GMP concerned with sampling, specifications
and testing, and with the organization, documentation and release
procedures which ensure that the necessary and relevant tests are actually
carried out and that materials are not released for use, nor products
released for sale or supply, until their quality has been judged to be
satisfactory. Quality control is not confined to laboratory operations but
must be involved in all decisions concerning the quality of the product..138
In the production chain, quality control for packaging contains sev-eral
critical points. The basic requirements for quality control are as
follows (1):
(a) Adequate facilities, trained personnel and approved procedures
must be available for sampling, inspecting and testing starting
materials, packaging materials, and intermediate, bulk and finished
products, and where appropriate for monitoring environmental
conditions for GMP purposes.
(b) Samples of starting materials, packaging materials, intermediate
products, bulk products and finished products must be taken
by methods and personnel approved of by the quality control
department.
(c) Test methods must be validated.
(d) Records must be made (manually and/or by recording instruments)
demonstrating that all the required sampling, inspecting and testing
procedures have actually been carried out and that any deviations
have been fully recorded and investigated.
(e) The finished products must contain ingredients complying with the
qualitative and quantitative composition of the product described in
the marketing authorization; the ingredients must be of the required
purity, in their proper container, and correctly labelled.
(f) Records must be made of the results of inspecting and testing
materials and intermediate, bulk and finished products against
specifications; product assessment must include a review and
evaluation of the relevant production documentation and an
assessment of deviations from specified procedures.
. . . The quality control department as a whole will also have other duties,
such as to establish, validate and implement all quality control procedures,
to evaluate, maintain and store the reference standards for substances, to
ensure the correct labelling of containers of materials and products, to
ensure that the stability of the active pharmaceutical ingredients and
products is monitored, to participate in the investigation of complaints
related to the quality of the product, and to participate in the environmental
monitoring. All these operations should be carried out in accordance with
written procedures and, where necessary, recorded.
Tests and assays are normally carried out at room temperature (be-tween
15 and 25°C, or up to 30°C in some climatic zones), unless
otherwise indicated. The international pharmacopoeia gives alterna-tive
methods to be used if certain instruments are not available.
3.2.1 Sampling
Sampling is used to check the correctness of the label, packaging
material or container reference, as well as in the acceptance of con-signments,
detecting adulteration of the medicinal product, obtaining
a sample for retention, etc.
The sampling procedure must take into account the homogeneity and
uniformity of the material so as to ensure that the sample is represen-tative
of the entire batch..139
The sampling procedure should be described in a written protocol.
Further details are given in “Sampling procedure for industrially
manufactured pharmaceuticals” (20).
3.2.2 Testing programme
The testing programme for quality control purposes may vary from
one manufacturer to another. Quality control tests are intended to
check the identity of the material concerned. Complete pharmaco-poeial
or analogous testing may also be carried out, as may special
tests, where necessary.
All written specifications for packaging materials and containers
should include the nature, extent and frequency of routine tests.
Routine tests vary according to the type of material and its immediate
packaging, the use of the product, and the route of administration.
Nevertheless, such tests usually include the following (21):
— visual inspection (cleanliness, defects)
— tests to identify the material
— dimensional tests
— physical tests
— chemical tests
— microbiological tests.
3.3 Inspection and audit
Self-inspection is covered in Appendix 3, which is taken from Annex
1 of the thirty-second report of the Committee (1).
3.3.1 Rules
It is extremely important to control the security and quality of pack-aging.
The requirements to be met by packaging for pharmaceutical
products are more stringent than those for the packaging of food
products, although many similarities exist. The goal of inspection is to
ascertain the quality of the products, and especially the quality of the
packaging. Items for self-inspection include documentation, storage
of starting materials and finished products, validation of programmes,
production and in-process controls, calibration of instruments or
measurement systems, control of labels, sanitation and hygiene, recall
procedures, premises (including personnel facilities), and mainte-nance
of buildings and equipment.
Labels play an important part in the quality of packaging. Packaging
and labelling errors in the manufacture of pharmaceutical products
are often reported..140
3.3.2 Audits of suppliers
Pharmaceutical manufacturers are usually audited or inspected by
national or international licensing authorities; the same applies to
suppliers of starting materials, active pharmaceutical ingredients,
excipients and packaging materials. All suppliers of pharmaceuticals
and packaging materials play an important role in the chain of quality
assurance of the final medicinal product.
Further details can be found in the twenty-fifth and thirtieth reports
of the Committee (2, 22), and “General requirements for dosage
forms” in The international pharmacopoeia (3).
4. Protection of the environment
The protection of the environment has become increasingly impor-tant
in many countries in recent years. Greater attention has been
paid to the disposal and recycling of waste, and legislation has been
introduced in many countries.
4.1 Packaging waste
Pharmaceutical packaging represents a very small percentage of
waste, but its disposal can cause problems for the environment. For
this reason, the Committee, at its thirty-second meeting (1), decided
that:
. . . Provisions should be made for the proper and safe storage of waste
materials awaiting disposal. Toxic substances and flammable materials
should be stored in suitably designed, separated, enclosed cupboards, as
required by national legislation.
. . . Waste material should not be allowed to accumulate. It should be
collected in suitable receptacles for removal to collection points outside the
buildings and disposed of safely and in a sanitary manner at regular and
frequent intervals.
Environmental problems result from the methods used for waste
disposal, and will depend on the type of packaging waste concerned.
Such waste may include:
— uncontaminated waste (assimilated to domestic waste: paper,
cardboard, glass, plastic);
— contaminated waste (paper, cardboard, glass, plastic), e.g. waste
that has been in contact with blood, blood-derived products,
radioactive products or cytotoxic products.
The method of disposal will therefore vary but should always be in
accordance with national legislation. Contaminated packaging is
often incinerated. The methods of disposal of uncontaminated
packaging are shown in Table 2..141
4.2 Waste policies
Waste is created at all stages in the production, supply and use of
a pharmaceutical product. At each step, care therefore needs to be
taken, either by the manufacturer or the end-user, to protect the
environment.
Environmental concerns in the international community have led to
certain changes in the conditions for the licensing of medicines (23).
Thus an environmental risk assessment may have to be carried out in
some cases in order to identify potential risks to the environment
arising from the storage, use and disposal of medicinal products. The
medicinal product as a whole may become the subject of the environ-mental
risk assessment so that consideration has to be given not only
to the active ingredient but also to the adjuvants/excipients in the
formulation, and the primary and secondary packaging.
Another major environmental issue affecting certain types of phar-maceutical
products concerns the chlorofluorocarbon (CFC) propel-lants,
and the threat that they represent to the ozone layer (24). A
European directive has been published on this subject (25).
In several European countries, manufacturers must dispose of their
drug waste, or must pay a specialized company to do so for them, and
are encouraged to salvage packaging waste. Faced with this problem,
manufacturers and pharmacists have, respectively, introduced new
directives and new process policies aimed at:
• Reducing packaging. Efforts should be made to reduce the volume
and weight of packaging materials, and to eliminate packaging
which is not essential for the protection of the contents of medicinal
products.
• Salvaging and recycling packaging. The use of environmental-friendly
packaging needs to be considered, i.e. recyclable or
degradable packaging. (Valuable packaging materials, such as
Table 2
Methods of disposal of uncontaminated packaging
Material Recycling Landfill Incineration
Paper, cardboard +++++++
Plastics ++++++
Glass +++++NA
Rubber ++++++
Metal ++++NA
+++: Highly recommended; ++: recommended; +: acceptable; NA: not applicable..142
aluminium, have been extensively recycled for many years. Recently,
paper, glass and plastic materials have joined the list of recyclable
packaging materials.) However, materials that have been in contact
with toxic or highly potent drugs require special consideration.
• Eliminating and incinerating packaging. Some plastic materials
cannot be recycled and are therefore incinerated. The burning
of polyvinyl chloride (PVC) is controversial since, if combustion is
not complete, it causes a potential increase in the levels of dioxin in
the environment. Incineration can be recommended if the combus-tion
heat produced by it can also be used for other purposes.
Developing countries are often short of incinerators. This method
is nevertheless regarded as the best available for the elimination of
contaminated packaging.
5. Quality specifications
5.1 Requirements in The international pharmacopoeia
5.1.1 Packaging materials
Monographs for inclusion in Volume 6 of The international pharma-copoeia
(3) have been proposed for glass containers and rubber
closures.
5.1.2 Requirements for dosage form containers
Every pharmaceutical preparation must comply with the labelling
requirements laid down in the WHO guidelines on GMP for pharma-ceutical
products (1).
Tablets. These should be kept in well-closed containers and protected
from light, moisture, crushing and mechanical shock. Any special
storage conditions should be stated on the label. Tablets should be
able to withstand handling, including packaging and transportation,
without losing their integrity. Moisture-sensitive forms, such as effer-vescent
tablets, should be stored in tightly closed containers or
moisture-proof packs, and may require the use of separate packages
containing water-adsorbent agents, such as silica gel.
Additional special recommendations for packaging, storage and
transportation are specified in the relevant individual monographs.
For effervescent tablets, the label should state “Not to be swallowed
directly”.
Capsules. These should be packaged and stored in a manner that
protects them from microbial contamination. Capsules should be kept
in well-closed containers. They should be protected from light, exces-sive
moisture, or dryness, and should not be subjected to tempera-tures
above 30°C..143
Additional special recommendations for packaging, storage and
transportation are specified in the relevant individual monographs.
Parenteral preparations. These are usually supplied in glass ampoules,
bottles or vials, plastic bottles or bags, and prefilled syringes, which
are coloured in the case of light-sensitive substances.
Except where otherwise indicated in the relevant individual mono-graphs,
the containers for parenteral preparations should be made
from a material that is sufficiently transparent to permit the visual
inspection of the contents. They should not adversely affect the qual-ity
of the preparation, allow diffusion of any kind into or across the
container, or release foreign substances into the preparation.
Closures for containers for parenteral preparations should be
equipped with a firm seal to prevent the entry of microorganisms and
other contaminants while permitting the withdrawal of a part or the
whole of the contents without removal of the closure. They should not
be made of materials that react with the contents, nor should they
allow foreign substances to diffuse into the preparation. The elas-tomers
of which the closure is made should be sufficiently firm to
allow the passage of a needle with the least possible shedding of
particles. Closures for multi-dose containers should be sufficiently
elastic to allow the puncture to reseal when the needle is withdrawn
and thus protect the contents from airborne contamination. A
tamper-evident container is fitted with a device that reveals clearly
whether it has ever been opened.
On visual inspection, solutions, reconstituted solutions and intrave-nous
infusions (except dispersions) should be clear and free from
visible particulate matter.
Topical semi-solid dosage forms. Containers for these dosage forms
should be made from a material that does not adversely affect the
quality of the preparation or allow diffusion of any kind into or across
the container into the preparation. Closures for these containers
should be of a design that minimizes microbial contamination and be
equipped with a device that reveals whether the container has ever
been opened.
Containers for topical semi-solid dosage forms should protect the
preparation from light, moisture, and damage during handling and
transportation. The use of suitable metal or plastic flexible tubes is
preferred. Preparations for nasal, aural, vaginal or rectal use should
be supplied in containers adapted for the appropriate delivery of the
product to the site of application, or should be supplied with a suitable
applicator..144
Topical semi-solid dosage forms should be kept in well-closed con-tainers.
The preparation should maintain its pharmaceutical integrity
throughout the shelf-life when stored at the temperature indicated on
the label; this should normally not exceed 25 °C. Special storage rec-ommendations
or limitations are indicated in the relevant individual
monographs.
5.2 Pharmacopoeial requirements for containers in Europe, Japan and
the USA
5.2.1 Glass containers
As previously mentioned in section 2.1.1, a classification of types of
glass for containers for pharmaceutical products does not exist in the
Japanese pharmacopoeia, while those given in the European and
United States pharmacopoeias are very similar.
Both the European and United States pharmacopoeias provide
specifications for glass containers for injections. The latter publication
also gives specific guidance for the packaging, repackaging and dis-pensing
of medicinal products. Both the European and United States
pharmacopoeias also provide specifications for light-resistant con-tainers
and tightly or well-closed closures for capsules and tablets.
The European pharmacopoeia gives a general account of the require-ments
for glass containers for pharmaceutical use, together with those
specifically applicable to glass containers for human blood and blood
products.
5.2.2 Plastic containers
Many different plastics are used for containers for medicinal products
and the requirements applicable to them differ greatly in the various
pharmacopoeias. It is very difficult to compare the tests described.
Other and possibly different requirements may be found in interna-tional
standards.
5.2.3 Rubber closures
A comparison of the requirements for rubber closures is as diffi-cult
as that for plastic containers. The European and Japanese
pharmacopoeias contain special requirements for rubber closures
intended for containers of aqueous parenteral preparations. The
United States pharmacopoeia describes more generally the use of
closures made from elastomers for injection bottles, but does not
specify the preparations for which they can be used.
Similarities exist between the tests given in the European, Japanese
and United States pharmacopoeias, but international standards also
exist which differ considerably from one another..145
5.3 International Standards
A list of recent International Standards on packaging is given in
Appendix 4.
References
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24. Matters relating to the replacement of CFCs in medicinal products (3BR2a).
In: The rules governing medicinal products in the European Union. Vol. 3B.
Safety, environment and information. Brussels, European Commission, 1998.
25. Assessment of potential risk to the environment posed by medicinal
products. European Directive No. 5504/94. London, Medicines Control
Agency, 1994..147
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Appendix 1
Storage areas
1
1. Storage areas should be of sufficient capacity to allow orderly
storage of the various categories of materials and products: starting
and packaging materials, intermediates, bulk and finished products,
products in quarantine, and released, rejected, returned or recalled
products.
2. Storage areas should be designed or adapted to ensure good
storage conditions. In particular, they should be clean and dry and
maintained within acceptable temperature limits. Where special
storage conditions are required (e.g. temperature, humidity) these
should be provided, checked and monitored.
3. Receiving and dispatch bays should protect materials and products
from the weather. Reception areas should be designed and equipped
to allow containers of incoming materials to be cleaned if necessary
before storage.
4. Where quarantine status is ensured by storage in separate
areas, these areas must be clearly marked and their access restricted
to authorized personnel. Any system replacing the physical quaran-tine
should give equivalent security.
5. There should normally be a separate sampling area for starting
materials. If sampling is performed in the storage area, it should
be conducted in such a way as to prevent contamination or cross-contamination.
6. Segregation should be provided for the storage of rejected, re-called
or returned materials or products.
7. Highly active materials, narcotics, other dangerous drugs, and sub-stances
presenting special risks of abuse, fire or explosion should be
stored in safe and secure areas.
8. Printed packaging materials are considered critical to the confor-mity
of the pharmaceutical product to its labelling, and special atten-tion
should be paid to the safe and secure storage of these materials.
1
Previously published in “Good manufacturing practices for pharmaceutical products”. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-
second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823)..151
Appendix 2
Labels
1
1. All finished drug products should be identified by labelling, as
required by the national legislation, bearing at least the following
information:
(a) the name of the drug product;
(b) a list of the active ingredients (if applicable, with the Interna-tional
Nonproprietary Names), showing the amount of each
present, and a statement of the net contents, e.g. number of
dosage units, weight or volume;
(c) the batch number assigned by the manufacturer;
(d) the expiry date in an uncoded form;
(e) any special storage conditions or handling precautions that may
be necessary;
(f) directions for use, and warnings and precautions that may be
necessary; and
(g) the name and address of the manufacturer or the company or the
person responsible for placing the product on the market.
1
Previously published in “Good manufacturing practices for pharmaceutical products”. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-
second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823)..152
Appendix 3
Self-inspection and quality audits
1
1. Principle. The purpose of self-inspection is to evaluate the
manufacturer’s compliance with GMP in all aspects of production and
quality control. The self-inspection programme should be designed to
detect any shortcomings in the implementation of GMP and to rec-ommend
the necessary corrective actions. Self-inspections should be
performed routinely, and may be, in addition, performed on special
occasions, e.g. in the case of product recalls or repeated rejections, or
when an inspection by the health authorities is announced. The team
responsible for self-inspection should consist of personnel who can
evaluate the implementation of GMP objectively; all recommenda-tions
for corrective action should be implemented. The procedure for
self-inspection should be documented, and there should be an effec-tive
follow-up programme.
Items for self-inspection
2. Written instructions for self-inspection should be established to
provide a minimum and uniform standard of requirements. These
may include questionnaires on GMP requirements covering at least
the following items:
(a) personnel
(b) premises including personnel facilities
(c) maintenance of buildings and equipment
(d) storage of starting materials and finished products
(e) equipment
(f) production and in-process controls
(g) quality control
(h) documentation
(i) sanitation and hygiene
(j) validation and revalidation programmes
(k) calibration of instruments or measurements systems
(l) recall procedures
(m) complaints management
(n) labels control
(o) results of previous self-inspections and any corrective steps
taken.
1
Previously published in “Good manufacturing practices for pharmaceutical products”. In:
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-
second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823)..153
Self-inspection team
3. Management should appoint a self-inspection team from local
staff who are expert in their own fields and familiar with GMP. The
members of the team may be appointed from inside or outside the
company.
Frequency of self-inspection
4. The frequency at which self-inspections are conducted may de-pend
on company requirements.
Self-inspection report
5. A report should be made at the completion of a self-inspection.
The report should include:
(a) self-inspection results
(b) evaluation and conclusions
(c) recommended corrective actions.
Follow-up action
6. The company management should evaluate both the self-inspection
report and the corrective actions as necessary.
Quality audit
7. It may be useful to supplement self-inspections with a quality
audit. A quality audit consists of an examination and assessment of all
or part of a quality system with the specific purpose of improving it. A
quality audit is usually conducted by outside or independent special-ists
or a team designated by the management for this purpose. Such
audits may also be extended to suppliers and contractors.
Suppliers’ audits
8. The quality control department should have responsibility to-gether
with other relevant departments for approving suppliers who
can reliably supply starting and packaging materials that meet estab-lished
specifications.
9. Before suppliers are approved and included in the specifications
they should be evaluated. The evaluation should take into account a
supplier’s history and the nature of the materials to be supplied. If the
audit is required, it should determine the supplier’s ability to conform
with GMP standards for active pharmaceutical ingredients..154
Appendix 4
International standards on packaging
A list is given below of the standards on packaging issued by the
International Organization for Standardization (ISO), as of 10 Octo-ber
1998, starting with the four main standards, after which they are
listed in numerical order.
Quality systems — model for quality assurance in design, development,
production, installation and servicing. International Standard ISO
9001. 1994.
Quality systems — model for quality assurance in production, installa-tion
and servicing. International Standard ISO 9002. 1994.
Quality systems — model for quality assurance in final inspection and
test. International Standard ISO 9003. 1994.
Quality management and quality systems elements. Part 1: Guidelines.
International Standard ISO 9004-1. 1994.
Quality management and quality systems elements. Part 2: Guidelines
for service. International Standard ISO 9004-2. 1994.
Quality management and quality systems elements. Part 3: Guidelines
for processed materials. International Standard ISO 9004-3. 1994.
Quality management and quality systems elements. Part 4: Guidelines
for quality improvement. International Standard ISO 9004-4. 1994.
Reusable all-glass or metal-and-glass syringes for medical use. Part 1:
Dimensions. International Standard ISO 595-1. 1986.
Reusable all-glass or metal-and-glass syringes for medical use. Part 2:
Design, performance requirements and tests. International Standard
ISO 595-2. 1987.
Transfusion equipment for medical use. Part 1: Glass transfusion
bottles, closures and caps. International Standard ISO 1135-1. 1987.
Plastics collapsible containers for human blood and blood com-ponents.
International Standard ISO 3826. 1993.
Injection containers for injectables and accessories. Part 1: Injection vials
made of glass tubing. International Standard ISO 8362-1. 1989.
Injection containers for injectables and accessories. Part 2: Closures for
injection vials. International Standard ISO 8362-2. 1988.
Injection containers for injectables and accessories. Part 3: Aluminium
caps for injection vials. International Standard ISO 8362-3. 1989..155
Injection containers for injectables and accessories. Part 4: Injection
vials made of moulded glass. International Standard ISO 8362-4. 1989.
Injection containers for injectables and accessories. Part 5: Freeze–
drying closures for injection vials. International Standard ISO 8362-5.
1995.
Injection containers for injectables and accessories. Part 6: Caps made
of aluminium–plastics combinations for injection vials. International
Standard ISO 8362-6. 1992.
Injection containers for injectables and accessories. Part 7: Injection
caps made of aluminium–plastics combinations without overlapping
plastics part. International Standard ISO 8362-7. 1995.
Infusion equipment for medical use. Part 4: Infusion sets for single use,
gravity feed. International Standard ISO 8536-4. 1998.
Infusion equipment for medical use. Part 5: Burette-type infusion sets.
International Standard ISO 8536-5. 1992.
Infusion equipment for medical use. Part 6: Freeze–drying closures for
infusion bottles. International Standard ISO 8536-6. 1995.
Infusion equipment for medical use. Part 7: Caps made of aluminium–
plastics combinations for infusion bottles. International Standard ISO
8536-7. 1992.
Sterile single-use syringes, with or without needle, for insulin. Interna-tional
Standard ISO 8537. 1991.
Elastomeric parts for aqueous parenteral preparations. International
Standard ISO 8871. 1990.
Aluminium caps for transfusion, infusion and injection bottles —
general requirements and test methods. International Standard ISO
8872. 1988.
Injection equipment for medical use. Part 1: Ampoules for injectables.
International Standard ISO 9187-1. 2000.
Injection equipment for medical use. Part 2: One-point-cut (OPC)
ampoules. International Standard ISO 9187-2. 1993.
Dental cartridge syringes. International Standard ISO 9997. 1999.
Caps made of aluminium–plastics combinations for infusion bottles
and injection vials — requirements and test methods. International
Standard ISO 10985. 1999.
Prefilled syringes. Part 1: Glass cylinders for dental local anaesthetic
cartridges. International Standard ISO 11040-1. 1992..156
Prefilled syringes. Part 2: Plungers and discs for dental local anaes-thetic
cartridges. International Standard ISO 11040-2. 1994.
Prefilled syringes. Part 3: Aluminium caps for dental local anaesthetic
cartridges. International Standard ISO 11040-3. 1993.
Prefilled syringes. Part 4: Glass barrels for injectables. International
Standard ISO 11040-4. 1996.
Prefilled syringes. Part 5: Plungers for injectables. International Stan-dard
ISO 11040-5. 1996.
Containers and accessories for pharmaceutical preparations. Part 1:
Drop-dispensing bottles. International Standard ISO 11418-1. 1996.
Containers and accessories for pharmaceutical preparations. Part 2:
Screw-neck bottles for syrups. International Standard ISO 11418-2.
1996.
Containers and accessories for pharmaceutical preparations. Part 3:
Screw-neck bottles (vials) for solid and liquid dosage forms. Interna-tional
Standard ISO 11418-3. 1996.
Containers and accessories for pharmaceutical preparations. Part 4:
Tablet bottles. International Standard ISO 11418-4. 1996.
Containers and accessories for pharmaceutical preparations. Part 5:
Dropper assemblies. International Standard ISO 11418-5. 1997.
Containers and accessories for pharmaceutical preparations. Part 7:
Screw-neck vials made of glass tubing for liquid dosage forms. Interna-tional
Standard ISO 11418-7. 1998.
Pen-injectors for medical use. Part 1: Requirements and test methods.
International Standard ISO 11608-1. 2000.
Pen-injectors for medical use. Part 2: Needles — requirements and test
methods. International Standard ISO 11608-2. 2000.
Pen-injectors for medical use. Part 3: Finished cartridges — require-ments
and test methods. International Standard ISO 11608-3. 2000.
Pen systems. Part 1: Glass cylinders for pen-injectors for medical use.
International Standard ISO 13926-1. 1998.
Pen systems. Part 2: Plungers and discs for pen-injectors for medical
use. International Standard ISO 13926-2. 1999.
Disposable hanging devices for transfusion and infusion bottles —
requirements and test methods. International Standard ISO 15010.
1998..157
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 10
Model certificate of analysis
It has been recommended in various fora that WHO should establish
a model certificate of analysis for use in trade in starting materials
and by manufacturers of pharmaceutical substances, excipients
and medicinal products. A model of such a certificate is shown in
Appendix 1. The items included are based on good practices
for national pharmaceutical control laboratories and good manu-facturing
practices (GMP) for pharmaceutical products (1). The
certificate lists the results and includes a final evaluation and the
conclusions of the examination of one or more samples.
In accordance with GMP, the certificate can be used in lieu of testing
by the manufacturer (except for the identification tests as a minimum
requirement), provided that the reliability of the supplier’s analysis
is established by the periodic validation of the test results by appro-priate
means and, if feasible, by on-site audits of the supplier’s
capabilities. Certificates must be originals (not copies or duplicates)
or their authenticity must otherwise be assured, i.e. they must be
issued by the supplier of the material concerned (manufacturer, bro-ker,
etc.), or based on the analytical worksheet of the laboratory
testing the sample(s). For further details, see Annex 3.
The certificate should include:
• The name and address of the laboratory performing the tests.
• The registration number of the certificate of analysis.
• The name, description (i.e. grade, quantity received, type of
container) and number (used by the original manufacturer and
repacker/trader) of the batch for which the certificate is issued, the
date of manufacture, and the expiry date (or retest date).
• The date on which the batch for which the certificate is issued was
received.
• A reference to the test procedure used, including the acceptance
criteria (limits).
• The results of all tests performed on the batch for which the
certificate is issued (in numerical form, where applicable) and a
comparison with the established acceptance criteria (limits)..158
• Any additional test results obtained on samples from the batch as
part of a periodic statistically based testing programme.
• A statement indicating whether the results were found to comply
with the requirements.
• The date(s) on which the test(s) was (were) performed.
• The signature of the head of the laboratory or an authorized
person.
• The name, address, and telephone and fax numbers of the original
manufacturer. If supplied by repackers or traders, the certificate
should show the name, address, and telephone and fax numbers of
the repacker/trader and a reference to the original manufacturer.
• A statement of the expected conditions of shipping, packaging,
storage and distribution, deviation from which would invalidate the
certificate.
• A copy of the certificate generated by the original manufacturer, if
the sample is supplied by a repacker or trader.
Reference
1. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical
Report Series, No. 823)..159
Appendix 1
Model certificate of analysis for active
pharmaceutical ingredients, excipients and
medicinal products
Registration number of sample or certificate:
Name and address of laboratory testing the sample:
Sample information
Name of product (INN, brand name(s), etc.):
Dosage form (if applicable):
Marketing authorization number (if applicable):
Description (appearance of container and contents):
Batch number(s):
Required storage conditions:
1
Date received: Date of manufacture:
Expiry date (for medicinal products) or retest date (for starting mate-rials
or excipients):
Name and address of original manufacturer:
Telephone: Fax:.160
Name and address of repacker and/or trader (if applicable):
Telephone: Fax:
Test procedure (reference Result (numerical Acceptance criteria
to test procedure) result)
2
(limits)
(if applicable) (if applicable)
A. Tests performed on
samples from batch for
which certificate is issued
B. Tests performed as
part of periodic
statistically based testing
programme
Conclusions:
Compliance with acceptance criteria: yes_ no_
Date test performed/finalized:
Name and address of head of laboratory/authorized person:
Telephone: Fax:
Signature:
Explanatory notes
1
Statement of expected conditions of shipping, packaging, storage and distribution,
deviation from which could render the certificate invalid.
2
Indicate if the results were obtained from periodic statistically based testing..161
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 11
Guidance on the selection of comparator
pharmaceutical products for equivalence
assessment of interchangeable multisource
(generic) products
Introduction
This annex provides a list of comparator products for equivalence
assessment of interchangeable multisource (generic) products. The
information on comparator pharmaceutical products was collected by
the Secretariat from drug regulatory authorities and pharmaceutical
companies. The list has been drawn up to assist regulatory authorities
and pharmaceutical companies in deciding on appropriate compara-tor
products in the context of multisource (generic) marketing autho-rization.
The information could also be used for drug procurement
purposes. Where the comparator pharmaceutical product is not
clearly defined, criteria are suggested that are provided in a decision-tree
format (see Figure 1). This permits the selection of a comparator
pharmaceutical product.
The guidelines on registration requirements to establish interchange-ability
of multisource (generic) pharmaceutical products published by
WHO (1) state that multisource products must satisfy the same stand-ards
of quality, safety and efficacy as those applicable to the corre-sponding
innovator product. They recommend that quality attributes
of a multisource product should be tested against the innovator prod-uct
for which interchange is intended.
The innovator product is usually the most logical comparator product
because its quality, safety and efficacy should have been well assessed
in pre- and post-marketing studies and, in addition, the data on its
safety and efficacy are usually linked to a pharmaceutical product
with defined specifications for quality and performance. Despite ac-ceptance
of the general objective, there is no agreement on the crite-ria
for selecting a list of international comparator products, nor does
a list of such products exist. The comparator product chosen is either
the most widely used “leading” product on the market or the product
that was first introduced in that market. For this reason, among
others, significant differences may exist between the comparator
products used in different countries..162
In the light of the various approaches currently under scientific and
regulatory discussion, the feasibility of developing a system of inter-national
comparator products was considered. This initiative led to
the recommendations given here, which replace those of Part Seven
of the previously published WHO guidelines on multisource pharma-ceutical
products (1).
A list of international comparator pharmaceutical products for
equivalence assessment of interchangeable multisource (generic)
products
1
is given in Table 1.
Figure 1
Decision-tree for use in identifying a comparator pharmaceutical product
1
The list is based on information collected by WHO from drug regulatory authorities and
supplemented with that from pharmaceutical companies. It will be periodically updated.
Comparator pharmaceutical product (CPP)
of known quality, safety and efficacy
Innovator product known?
Yes No
Available on local market? Present on List B?
Yes No Yes No
Consider innovator
product as CPP
Consider obtaining
innovator product: List A
Follow compendial
standards approach
Consider market
leader product
Innovator product
available?
Quality of market leader product
known and well documented?
Yes No Yes No
Consider innovator
product as CPP
Consider market
leader product
Consider market leader
product as CPP
Conduct comparative
compendial tests on
multisource and
market leader products
Acceptable test results?
Yes No
Consider market leader
product as CPP
Consider second market
leader product.163
Instructions on the use of the list
1. National regulatory authorities may issue this guidance together
with Lists A and B, which should be available to applicants/phar-maceutical
companies that plan to develop multisource pharma-ceutical
products intended to be interchangeable with innovator or
other pharmaceutical products of established quality, safety and
efficacy.
2. List A provides information about pharmaceutical products
from the WHO Model List of Essential Drugs (2), and includes
the innovator products (column headed “Trademark”) and the
national markets where the manufacturers in question consider
that their products’ quality, safety and efficacy are best docu-mented
(column headed “Primary market”).
3. Pharmaceutical companies planning to develop an interchangeable
multisource pharmaceutical product should determine whether the
innovator pharmaceutical product appearing in List A is available
on the local market.
4. If the innovator pharmaceutical product is available on the local
market, pharmaceutical companies should use this product in
equivalence assessment with their multisource product.
5. If the innovator product is not available on the local market, phar-maceutical
companies should obtain from the market a product
that is the best representative innovator product from the point
of view of its quality, safety and efficacy (see column headed
“Primary market” of List A).
6. The type of equivalence assessment of the comparator pharmaceu-tical
product and the multisource product under investigation may
vary, depending on local requirements and the availability of
resources. Recommendations on the type of equivalence studies to
be carried out when such studies are necessary are given in the
WHO guidelines on multisource pharmaceutical products (1).
7. For some pharmaceutical products, an innovator product cannot
be identified. Examples of these products from the WHO Model
List of Essential Drugs (2) appear in List B. For these products,
a local, national or regional pharmacopoeia or The international
pharmacopoeia (3) for both the drug substance and, when avail-able,
the product, supplemented by official reference texts, may
provide sufficient information and requirements to allow a phar-maceutical
company to develop a product of the requisite quality,
safety and efficacy. No international comparator product for these.164
pharmaceutical products will be available, and no equivalence as-sessment
can be performed.
Also included in List B are pharmaceutical products for which an
innovator product can be identified or a marker leader product
may be available, but for which there is insufficient information
available for them to appear in List A, e.g. products for which the
originator no larger exists or which cannot be traced. The List A
approach can also be applied to these products.
8. When a market leader product is available on the local market but
no innovator product can be identified or obtained from the pri-mary
market, the market leader product may be used as a com-parator
product if its quality, safety and efficacy have been estab-lished.
If this is not the case, the second market leader or
compendial standards approach (List B) can be followed.
Most of the pharmaceuticals listed are included in the WHO Model
List of Essential Drugs (2). In the case of products for which equiva-lence
testing is required, it should be performed in accordance with
the WHO guidelines on registration requirements to establish inter-changeability
of multisource (generic) products (1).
Layout of the list
Pharmaceutical Section Dosage Comparator pharmaceutical
name (1) no. (2) forms and products (4)
strengths (3)
Trademark Primary Manufacturer
market
albendazole 6.1.1 chtab, Zentel France SmithKline
200 mg Beecham
The list is divided into two parts, as follows:
• List A provides information on comparator pharmaceutical prod-ucts
— trademark and primary market — as given by manufac-turers
of innovator products.
• List B contains products for which information has not been given
by manufacturers of innovator or market leader products or diffi-culties
in providing the information were encountered because the
pharmaceutical products have been marketed for a long time.
(1) Pharmaceutical name: International Nonproprietary Names
(INNs) are used to identify the active drug substance as in the
WHO Model List of Essential Drugs..165
(2) Section no.: this corresponds to the WHO Model List of Essential
Drugs, and indicates the therapeutic uses/pharmacological effects
of the pharmaceutical.
(3) Dosage forms and strengths: these correspond to the WHO
Model List of Essential Drugs. A strike-through means that no
products of the dosage form or strength are available on the
market. An entry in bold signifies that a product of the dosage
form or strength is available on the market instead of, or in
addition to, those in the WHO Model List of Essential Drugs.
The following abbreviations are used:
cap capsule
chcap chewable capsule
chtab chewable tablet
cre cream
elix elixir
encotab enteric-coated tablet
eyd eye drop
eyo eye ointment
inh inhalation
inj injection/injectable solution
lot lotion
loz lozenge
multi multiple
nsp nasal spray
oilinj injection in oil
oilsl oily solution
oilsp oil suspension
oilspinj oil suspension injection
oin ointment
oosl oral oily solution
osl oral solution
osp oral suspension
pes pessary
pwinj powder for injection
pwosp powder for oral suspension
pwsl powder for solution
respsl respirator solution
sbltab tablet, sublingual
sctab scored tablet
sgtab sugar-coated tablet
sl solution
sr sustained-release preparation.166
sup suppository
syr syrup
tab tablet
topsl solution, topical
vagtab vaginal tablet
wminj water-miscible injection
(4) Comparator pharmaceutical products: “Trademark” and “Pri-mary
market” for List A indicate the innovator products and
the national markets where the manufacturers in question con-sider
that their products’ quality, safety and efficacy are best
documented.
List B, which does not give this information, follows the pharma-copoeial
standards approach.
The entry ***** means that additional information on the prod-uct
must be provided before it can be included in List A..167
Table
1
International
comparator
products
for
equivalence
assessment
of
interchangeable
multisource
(generic)
productsa
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
List Aalbendazole
6.1.1
chtab,
200
mg
Zentel
France
SmithKline
Beecham
amiloride,
hydrochloride
16
tab,
5
mg
Midamor
United
Kingdom
Merck,
Sharp
&
Dohme
aminophylline
25.1
tab,
100
mg,
200
mg
(sr),
Aminophylin
Germany
BYK
Gulden
Lomberg
125
mg
amitriptyline,
24.2.1
tab,
25
mg
Elavil
USA
Zeneca
hydrochlorideamoxicillin
6.2.1
cap,
250
mg,
500
mg
Amoxil
United
Kingdom
SmithKline
Beecham
pwosp,
125
mg/
5
ml
tab,
250
mg,
500
mg
atenolol
12.1
tab,
50
mg,
100
mg
Tenormin
United
Kingdom
Zeneca
12.2
tab,
50
mg,
100
mg
12.3
tab,
50
mg,
100
mg
atropine,
sulfate
21.5
eyd,
0.1%,
0.5%,
1%
Atropin
Dispersa
Switzerland
Ciba
Vision
(Novartis)
benznidazole
6.5.5
tab,
100
mg
Radanil
Argentina,
Brazil,
Roche
Switzerland
biperiden,
hydrochloride
9
tab,
2
mg
Akineton
Germany
Knoll
captopril
12.3
sctab,
25
mg
Capoten
USA
Bristol-
Myers
Squibb
carbamazepine
5
sctab,
100
mg,
200
mg
(sr)
Tegretol
Switzerland
Novartis
chloramphenicol
6.2.2
cap,
250
mg
Chloromycetin
USA
Parke-
Davis
chloramphenicol,
sodium
6.2.2
oilspinj,
0.5
g/
2
ml
Chloromycetin
USA
Parke-
Davis/
Parkedale
succinate
sodium
succinate
chloroquine,
phosphate
6.5.3
tab,
25
mg,
100
mg,
b
Alaren
phosphate
USA
Sanofi
Winthrop
150
mg,
b,
c
500
mg
chlorphenamine,
3
tab,
4
mg
Chlortrimeton
USA
Schering-
Plough
hydrogen maleateciclosporin
8.1
cap,
25
mg
Sandimmun
Switzerland
Novartis.168
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
cimetidine
17.1
tab,
200
mg
Tagamet
France
SmithKline
Beecham
ciprofloxacin,
6.2.2
tab,
250
mg
Ciprobay
Germany
Bayer
hydrochloride clofazimine
6.2.3
cap,
50
mg,
100
mg
Lamprene
Switzerland
Novartis
clomifene,
citrate
18.6
tab,
50
mg
Clomid
USA
Hoechst
Marion
Roussel
clomipramine,
24.4
cap,
10
mg,
25
mg
Anafranil
Switzerland
Novartis
hydrochloride clonazepam
5
sctab,
500
m
g
Rivotril
Switzerland
Roche
cloxacillin,
sodium
6.2.1
cap,
500
mg
Penstaphon
Belgium
Bristol-
Myers
Squibb
pwsl,
125
mg/
5
ml
Tegopen
USA
cyclophosphamide
8.2
tab,
25
mg,
50
mg
Endoxana
United
Kingdom
ASTA
Medica
dapsone
6.2.3
tab,
25
mg,
50
mg,
100
mg
Dapsone
USA
Jacobus
desmopressin,
acetate
10.2
nsp,
10
m
g/
metered
dose
DDAVP
USA
Ferring
dexamethasone
3
tab,
500
m
g,
4
mg
Decadron
USA
Merck,
Sharp
&
Dohme
18.1
tab,
500
m
g,
4
mg
diazepam
24.3
sctab,
2
mg,
5
mg
Valium
USA
Roche
doxazosin
mesilate
12.3
tab,
1
mg,
2
mg,
4
mg
Caldura
Germany
Pfizer
doxycycline,
hyclate
6.2.2
cap,
100
mg
Vibramycin
Germany
Pfizer
tab,
100
mg
epinephrine,
21.5
eyd,
2%
Suprarenin
Germany
Hoechst
Marion
Roussel
hydrochloride ergocalciferol
27
cap,
1.25
mg
(50
000
IU)
Drisdol
USA
Sanofi
osl,
250
m
g/
ml
(10
000
IU/
ml)
tab,
1.25
mg
(50
000
IU)
ethinylestradiol
18.4
tab,
10
m
g,
20
m
g,
50
m
g
Pregynon
C
Germany
Schering
ethinylestradiol
+
18.3.1
tab,
30
m
g
+
150
m
g,
50
m
g
Nordette-
21
USA
Wyeth-
Ayerst
levonorgestrel
+
250
m
g.169
ethosuximide
5
cap,
250
mg
Zarontin
USA
Parke-
Davis
syr,
250
mg/
5
ml
etoposide
8.2
cap,
100
mg
Vepesid
Netherlands
Bristol-
Myers
Squibb
inj,
20
mg/
ml,
50
mg/
ml
USA
flucytosine
6.3
cap,
250
mg
Ancobon
USA
ICN
Pharmaceuticals
fludrocortisone,
acetate
18.1
tab,
100
m
g
Florinef
USA
Bristol-
Myers
Squibb
fluorouracil
13.5
oin,
5%
Efudix
USA
Roche
fluphenazine,
decanoate
24.1
depot
inj,
25
mg/
ml
Prolixin
decanoate
USA
Bristol-
Myers
Squibb
fluphenazine,
enantate
24.1
depot
inj,
25
mg/
ml
Prolixin
enanthate
USA
Bristol-
Myers
Squibb
furosemide
16
tab,
40
mg
Lasix
Germany
Hoechst
Marion
Roussel
glyceryl
trinitrate
12.1
sbltab,
500
m
g
Nitroglycerin
Wander
Switzerland
Novartis
chcap,
800
m
g
griseofulvin
6.3
cap,
125
mg,
250
mg
Grisactin
USA
Zeneca
tab,
125
mg,
250
mg
Fulcin
USA
haloperidol
24.1
tab,
2
mg,
5
mg
Haldol
Belgium
Janssen
hydralazine,
12.3
tab,
25
mg,
50
mg
Apresoline
Netherlands
Novartis
hydrochloride
pwinj,
20
mg
United
Kingdom
hydrochlorothiazide
12.3
tab,
25
mg
Hydrosaluric
United
Kingdom
Merck,
Sharp
&
Dohme
16
tab,
25
mg,
50
mg
ibuprofen
2.1
tab,
200
mg
Nurofen
UK
Boots
idoxuridine
21.1
eyd,
0.1%
Herplex
USA
Allergan
eyo,
0.2%
imipenem
(monohydrate)
6.2.1
pwinj,
250
mg
+
250
mg,
Tienam
Italy
Merck,
Sharp
&
Dohme
+
cilastin
(sodium)
500
mg
+
500
mg
pwinj,
500
mg
+
500
mg
insulin
injection
(soluble)
18.5
inj,
40
IU/
ml,
80
IU/
ml,
Actrapid
Germany
Novo
Nordisk
100
IU/
ml
inj,
40
IU/
ml,
80
IU/
ml,
Actrapid
Zimbabwe
100
IU/
ml
inj,
40
IU/
ml,
80
IU/
ml,
Novolin
R
Japan,
USA
100
IU/
ml.170
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
intermediate-
acting
18.5
inj,
40
IU/
ml,
80
IU/
ml,
Humulin
L
USA
Eli
Lilly
insulin
(as
compound
100
IU/
ml
insulin zincsuspension) intermediate-
acting
18.5
inj,
40
IU/
ml,
80
IU/
ml,
Humulin
N
USA
Eli
Lilly
insulin
(as
isophane
100
IU/
ml
insulin) ipratropium
bromide
25.1
inh,
20
m
g/
metered
dose
Atrovent
USA
Boehringer
Ingelheim
iron
dextran
10.1
inj,
equiv.
to
50
mg
iron/
ml
Infed
USA
Shein
Pharmaceuticals
isosorbide
dinitrate
12.1
sbltab,
5
mg
Isordil
USA
Wyeth-
Ayerst
ivermectin
6.1.2
sctab,
6
mg
Mectizan/
Stromectol
Netherlands
Merck,
Sharp
&
Dohme
ketoconazole
6.3
osp,
100
mg/
5
ml
Nizoral
Belgium
Janssen
tab,
200
mg
levamisole,
hydrochloride
6.1.1
tab,
50
mg,
150
mg
Ergamisol
Belgium
Janssen
8.2
tab,
50
mg
levodopa
+
carbidopa
9
tab,
100
mg
+
10
mg,
Sinemet
Italy
Merck,
Sharp
&
Dohme
250
mg
+
50
mg
levonorgestrel
18.3.1
tab,
30
m
g
Microval
Germany
Wyeth-
Ayerst
lithium
carbonate
24.2.2
cap,
300
mg
Quilonum
Germany
SmithKline
Beecham
tab,
300
mg
mebendazole
6.1.1
chtab,
100
mg,
500
mg
Vermox
Belgium
Janssen
medroxyprogesterone
18.3.1
depot
inj,
150
mg/
ml
Depo-
Provera
USA
Pharmacia-
Upjohn
acetate
18.7
tab,
5
mg
Provera
mefloquine,
6.5.3
tab,
250
mg
Lariam
Switzerland
Roche
hydrochloridemethyldopa
12.3
tab,
250
mg
Aldomet
Spain
Merck,
Sharp
&
Dohme
metoclopramide,
17.2
tab,
10
mg
Primperan
France
Synthlabo
hydrochloride.171
miconazole,
nitrate
13.1
cre,
2%
Daktarin
Belgium
Janssen
oin,
2%
nalidixic
acid
6.2.2
tab,
500
mg
Neggran
USA
Sanofi
Winthrop
cap,
500
mg
neostigmine,
bromide
20
tab,
15
mg
Prostigmin
Germany
Roche
niclosamide
6.1.1
chtab,
500
mg
Yomesan
Germany
Bayer
nifedipine
12.3
cap,
10
mg
(sr)
Adalat
10
Germany
Bayer
tab,
10
mg
(sr)
Adalat
T
10
nifurtimox
6.5.5
tab,
30
mg,
120
mg,
250
mg
Lampit
Argentina
Bayer
nitrofurantoin
6.2.2
tab,
100
mg
Furadantin
Ireland,
United
Proctor
&
Gamble
Kingdom
norethisterone
enantate
18.3.1
oilsl,
200
mg/
ml
Noristerat
Mexico,
South
Schering
Africa
nystatin
6.3
loz,
100
000
IU
Nystan
United
Kingdom
Bristol-
Myers
Squibb
pes,
100
000
IU
Mycostatine
France
tab,
100
000
IU
France
tab,
500
000
IU
USA
vagtab,
100
000
IU
France
oxamniquine
6.1.3
cap,
250
mg
Mansil/
Vansil
Brazil
Pfizer
syr,
250
mg/
5
ml
paracetamol
2.1
sup,
100
mg,
125
mg,
250
mg,
Ben-
U-
Ron
Germany
Bene
500
mg,
1000
mg
penicillamine
4.2
cap,
250
mg
Cuprimine
USA
Merck,
Sharp
&
Dohme
tab,
250
mg
Depen
Cater-
Wallace
phenobarbital
5
tab,
15–
100
mg
Luminal
(100
mg)
Germany
Desitin
Luminaletten
(15
mg)
phenoxymethylpenicillin,
6.2.1
pwosp,
250
mg/
5
ml
V-
Cillin
K
USA
Eli
Lilly
potassium
tab,
250
mg
phenytoin,
sodium
5
cap,
25
mg,
30
mg,
50
mg,
Dilantin
Kapseals
USA
Parke-
Davis
100
mg
tab,
25
mg,
50
mg,
100
mg
Dilantin
Infatabs
phytomenadione
10.2
tab,
10
mg
Konakion
Switzerland
Roche.172
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
praziquantel
6.1.1
tab,
150
mg,
600
mg
Biltricide
Germany
Bayer
6.1.3
tab,
600
mg
prednisolone
3
tab,
5
mg
Scherisolon
Colombia,
Uruguay
Schering
8.3
tab,
5
mg
18.1
tab,
1
mg,
5
mg
21.2
eyd,
0.5%
Ultracortenol
Germany
Ciba
Vision
(Novartis)
procainamide,
12.2
tab,
250
mg,
500
mg
Pronestyl
USA
Bristol-
Myers
Squibb
hydrochlorideprocarbazine,
8.2
cap,
50
mg
Natulan
Switzerland
Roche
hydrochlorideproguanil,
hydrochloride
6.5.3
tab,
100
mg
Paludrine
United
Kingdom
Zeneca
propranolol,
7.2
tab,
20
mg,
40
mg
Inderal
Japan
Zeneca
hydrochloride

tab,
10
mg,
40
mg
United
Kingdom
pyrantel,
embonate
6.1.1
chtab,
250
mg
Combantrin
Germany
Pfizer
osp,
50
mg/
ml
pyrazinamide
6.2.4
tab,
400
mg,
500
mg
Zinamide
United
Kingdom
Merck,
Sharp
&
Dohme
pyridostigmine,
bromide
20
tab,
60
mg
Mestinon
Switzerland
Roche
rifampicin
6.2.3
cap,
150
mg,
300
mg
Rifadin
Italy
Gruppo
Lepetit
tab,
150
mg,
300
mg
6.2.4
cap,
150
mg,
300
mg
tab,
150
mg,
300
mg
rifampicin
+
isoniazid
6.2.4
tab,
150
mg
+
100
mg,
300
mg
Rifinah
Italy
Gruppo
Lepetit
+
150
mg
rifampicin
+
isoniazid
6.2.4
tab,
150
mg
+
75
mg
Rifater
Italy
Hoechst
Marion
Roussel
+
pyrazinamide
+
400
mg,
150
mg
+
150
mg
+
500
mg
silver
sulfadiazine
13.2
cre,
1%/
500
g
Silvadene
USA
Hoechst
Marion
Roussel.173
sulfadoxine
+
6.5.3
tab,
500
mg
+
25
mg
Fansidar
Switzerland
Roche
pyrimethaminesulfamethoxazole
+
6.2.2
osp,
200
mg
+
40
mg/
5
ml
Bactrim
Switzerland
Roche
trimethoprim
tab,
100
mg
+
20
mg,
400
mg
+
80
mg
sulfasalazine
17.4
tab,
500
mg
Azulfidine
USA
Pharmacia-
Upjohn
tamoxifen,
citrate
8.3
tab,
10
mg,
20
mg
Nolvadex
United
Kingdom
Zeneca
testosterone,
enantate
18.2
inj,
200
mg/
ml,
250
mg/
ml
Testorion
depot
Argentina,
Schering
Germany,
Mexico
theophylline
25.1
tab,
100
mg,
125
mg,
20
0
mg,
Euphylong
Germany
BYK-
Gulden
250
mg,
375
mg,
500
mg
timolol,
maleate
21.4
sl
(eyd),
0.25%,
0.5%
Timoptol
ophthalmic
France
Merck,
Sharp
&
Dohme
solution
eyd,
0.25%,
0.5%
(unit
dose)
Timoptol
Ocudose
gel
(eyd),
0.25%,
0.5%
Timoptol
LP
tolbutamide

tab,
500
mg
Rastinon
Germany
Hoechst
Marion
Roussel
triclabendazole
6.1.3
tab,
250
mg
Egaten
Egypt
Novartis
tropicamide
14.1
eyd,
0.5%
Mydriacyl
United
Kingdom
Alcon
verapamil,
hydrochloride
12.1
tab,
40
mg,
80
mg
(sr)
Isoptin
Germany
Knoll
12.2
tab,
40
mg,
80
mg
(sr)
List Bacetazolamide
21.4
tab,
250
mg
*****
acetylsalicylic
acid
2.1
sup,
50–
150
mg
*****
tab,
100–
500
mg
*****
7.1
tab,
300–
500
mg
*****
12.5
tab,
100
mg
*****
aciclovir
6.4.1
tab,
200
mg
*****
aciclovir
(sodium)
6.4.1
pwinj,
250
mg
*****
allopurinol
2.3
tab,
100
mg
*****
aluminium
hydroxide
17.1
osp,
320
mg/
5
ml
tab,
500
mg.174
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
amoxicillin
+
clavulanic
6.2.1
tab,
500
mg
+
125
mg
*****
acidascorbic
acid
27
tab,
50
mg
atropine,
sulfate
17.5
tab,
1
mg
*****
azathioprine
8.1
tab,
50
mg
*****
beclometasone,
25.1
inh,
50
m
g/
dose
*****
dipropionatebenzoic
acid
+
salicylic
13.1
cre,
6%
+
3%
acid
oin,
6%
+
3%
benzoyl
peroxide
13.5
cre,
5%
lot,
5%
benzoyl
benzoate
13.6
lot,
25%
betamethasone,
valerate
13.3
cre,
0.1%
*****
oin,
0.1%
*****
calamine
lotion
13.3
lot
chloral
hydrate
1.3
syr,
200
mg/
5
ml
chloramphenicol,
6.2.2
osp,
150
mg/
5
ml
*****
palmitatechloroquine,
phosphate
6.5.3
syr,
50
mg/
5
mlb,
c
*****
chloroquine,
sulfate
6.5.3
syr,
50
mg/
5
mlb,
c
tab,
100
mg,
b
150
mgb,
c
chlorpromazine,
24.1
syr,
25
mg
/5
ml
*****
hydrochloride
tab,
100
mg
*****
coal
tar
13.5
topsl,
5%
codeine,
phosphate
2.2
tab,
30
mg
*****
17.7.2
tab,
30
mg
*****
colchicine
2.3
tab,
500
m
g
*****.175
cromoglicic
acid,
sodium
25.1
inh,
20
mg/
dose
*****
dextromethorphan
25.2
osl,
3.5
mg/
5
ml
*****
diethylcarbamazine,
6.1.2
tab,
50
mg
*****
dihydrogen
citrate
diethyltoluamide
6.6
topsl,
50%,
75%
digitoxin

tab,
50
m
g,
100
m
g
*****
digoxin
12.4
osl,
50
m
g/
ml
*****
tab,
62.5
m
g,
250
m
g
*****
diloxanide,
furoate
6.5.1
tab,
500
mg
*****
dimercaprol
4.2
oilinj,
50
mg/
ml
*****
dithranol
13.5
oin,
0.1–
2%
*****
ergometrine,
hydrogen
22.1
tab,
200
m
g
*****
maleate ergotamine,
tartrate
7.1
tab,
1
mg
erythromycin,
ethyl
6.2.2
cap,
250
mg
*****
succinate
pwosp,
125
mg
*****
tab,
250
mg
*****
erythromycin,
stearate
6.2.2
cap,
250
mg
*****
pwosp,
125
mg
*****
tab,
250
mg
*****
ethambutol,
6.2.4
tab,
100–
400
mg
*****
hydrochloride ethinylestradiol
+
18.3.1
tab,
35
m
g
+
1.0
mg
*****
norethisterone ferrous
salt,
sulfate
10.1
osl,
equiv.
to
25
mg
iron/
ml
tab,
equiv.
to
60
mg
iron
ferrous
salt
(sulfate)
+
10.1
tab,
equiv.
to
60
mg
iron
+
folic
acid
250
m
g
folic
acid
folic
acid
10.1
tab,
1
mg,
5
mg
*****
gentamicin,
sulfate
21.1
eyd,
0.3%
*****
glibenclamide
18.5
tab,
2.5
mg,
5
mg
*****.176
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
hydrocortisone,
acetate
13.3
cre,
1%
*****
oin,
1%
*****
17.4
supp,
25
mg
*****
hydrogen
peroxide

sl,
3%
iopanoic
acid
14.2
tab,
500
mg
*****
ipecacuanha
4.1
syr,
0.14%,
as
emetine
isoniazid
6.2.4
tab,
100–
300
mg
*****
isoniazid
+
ethambutol
6.2.4
tab,
150
mg
+
400
mg
*****
levothyroxine,
sodium
18.8
tab,
50
m
g,
100
m
g
*****
magnesium
hydroxide
17.1
osp,
equiv.
to
550
mg/
10
ml
mercaptopurine
8.2
tab,
50
mg
*****
metformin
18.5
tab,
500
mg
*****
DL-
methionine
4.2
tab,
250
mg
*****
methotrexate,
sodium
8.2
tab,
2.5
mg
*****
metrifonate

tab,
100
mg
*****
metronidazole
6.2.2
sup,
500
mg,
1
g
*****
tab,
200–
500
mg
*****
6.5.1
tab,
200–
500
mg
*****
metronidazole,
benzoate
6.5.1
osp,
200
mg/
5
ml
*****
morphine,
hydrochloride
2.2
osl,
10
mg/
5
ml
morphine,
sulfate
2.2
osl,
10
mg/
5
ml
tab,
10
mg
neomycin,
sulfate
+
13.2
oin,
5
mg
+
500
IU
*****
bacitracin
zinc
nicotinamide
27
tab,
50
mg
norethisterone
18.7
tab,
5
mg
*****
paracetamol
2.1
syr,
125
mg/
5
ml
tab,
100–
500
mg
7.1
tab,
300–
500
mg.177
permethrin
13.6
lot,
1%
pethidine,
hydrochloride
2.2
tab,
50
mg,
100
mg
*****
phenobarbital
5
elix,
15
mg/
5
ml
*****
pilocarpine,
21.4
sl
(eyd),
2%,
4%
*****
hydrochloride
or
nitratepodophyllum
resin
13.5
topsl,
10–
25%
potassium
iodide
18.8
tab,
60
mg
primaquine,
diphosphate
6.5.3
tab,
7.5
mg,
15
mg
*****
promethazine,
1.3
elix,
5
mg/
5
ml
*****
hydrochloride
syr,
5
mg/
5
ml
*****
17.2
elix,
5
mg/
5
ml
*****
syr,
5
mg/
5
ml
*****
tab,
10
mg,
25
mg
*****
propyliodone
14.2
oilsp,
500–
600
mg/
ml
*****
propylthiouracil
18.8
tab,
50
mg
*****
pyridoxine,
hydrochloride
27
tab,
25
mg
quinidine,
sulfate
12.2
tab,
200
mg
*****
quinine,
bisulfate
6.5.3
tab,
300
mg
quinine,
sulfate
6.5.3
tab,
300
mg
reserpine
12.3
tab,
100
m
g,
250
m
g
*****
retinol,
palmitate
27
cap,
200
000
IU
(110
mg)
oosl,
100
000
IU/
ml
sgtab,
10
000
IU
(5.5
mg)
wminj,
100
000
IU/
2
ml
(55
mg)
riboflavin
27
tab,
5
m
g
salbutamol,
sulfate
22.2
tab,
4
mg
*****
25.1
inh,
100
m
g/
dose
*****
respsl,
5
mg/
ml
*****
syr,
2
mg/
5
ml
*****
tab,
2
mg,
4
mg
*****
salicylic
acid
13.5
topsl,
5%.178
Table
1
(continued)
Pharmaceutical
name
Section
Dosage
forms
and
Comparator
pharmaceutical
products
no.
strengths
Trademark
Primary
market
Manufacturer
senna
(sennoside)
17.6
tab,
7.5
mg
silver
nitrate
21.1
sl
(eyd),
1%
sodium
fluoride
27
any
spironolactone
16
tab,
25
mg
*****
sulfadiazine
6.2.2
tab,
500
mg
*****
sulfadimidine

osp,
500
mg/
5
ml
*****
tab,
500
mg
*****
tetracaine,
hydrochloride
21.3
sl
(eyd),
0.5%
*****
tetracycline,
21.1
eyo,
1%
*****
hydrochloridethiamine, hydrochloride
27
tab,
50
mg
thioacetazone
+
isoniazid
6.2.4
tab,
50
mg
+
100
mg,
150
mg
*****
+
300
mg
trimethoprim
6.2.2
tab,
100
mg,
200
mg
*****
urea
13.5
cre,
10%
oin,
10%
valproic
acid,
sodium
5
encotab,
200
mg,
500
mg
*****
warfarin,
sodium
10.2
tab,
1
mg,
2
mg,
5
mg
*****
zidovudine
6.4.2
cap,
100
mg,
250
mg
*****
osl,
50
mg/
5
ml
*****
zinc
oxide

creoin
a
For
instructions
on
the
use
of
the
list,
see
pages
164–
167.
b
For
curative
treatment.
c
For
prophylaxis..179
Authors
This guidance was discussed during two meetings convened by the
Division of Drug Management and Policies and the Department of
Essential Drugs and other Medicines, World Health Organization,
Geneva, Switzerland, from 12 to 13 February 1996 and from 8 to 9
February 1999. The meetings were attended by the following people:
Mr M.N. Dauramanzi, Drugs Control Council, Harare, Zimbabwe
Dr M. Holz-Slomczyk, Federal Institute for Drugs and Medical
Devices, Berlin, Germany
Professor U. Gundert-Remy, University of Göttingen, Göttingen,
Germany
Mrs M. Ikeda, Ministry of Health and Welfare, Tokyo, Japan
Dr K. Morimoto, Pharmaceuticals and Medical Devices Evaluation
Centre, National Institute of Health Sciences, Tokyo, Japan
Ms A. Poompanich, Division of Drug Analysis, Ministry of Public
Health, Nonthaburi, Thailand
Dr R. Williams, Center for Drug Evaluation and Research, Food and
Drug Administration, Rockville, MD, USA
Secretariat
Mrs K. Bremer, Quality Assurance and Safety: Medicines, Essential
Drugs and other Medicines, WHO, Geneva, Switzerland
Dr M. Demesmaeker, Quality Assurance and Safety: Medicines,
Essential Drugs and other Medicines, WHO, Geneva, Switzerland
Dr J. Idänpään-Heikkilä, Special Adviser on Quality Assurance and
Safety, Health Technology and Pharmaceuticals, WHO, Geneva,
Switzerland
Dr S. Kopp-Kubel, Quality Assurance and Safety: Medicines, Essen-tial
Drugs and other Medicines, WHO, Geneva, Switzerland
Mr D. Sato, Drug Management and Policies, WHO, Geneva,
Switzerland
Miss M. Schmid, Quality Assurance and Safety: Medicines, Essential
Drugs and other Medicines, WHO, Geneva, Switzerland
Miss A. Wehrli, Regulatory Support, Drug Management and Policies,
WHO, Geneva, Switzerland
Mr Y. Yoshida, Quality Assurance and Safety: Medicines, Essential
Drugs and other Medicines, WHO, Geneva, Switzerland.180
Acknowledgements
Acknowledgement was made by the WHO Secretariat to the following people, for
their valuable contributions to the discussions: Miss M. Cone, International
Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva,
Switzerland; Dr I. Kanfer, International Generic Pharmaceutical Alliances,
Genpharm Inc., Etobicoke, Ontario, Canada; and Dr R. Patnaik, Deputy Director,
Division of Bioequivalence, Center for Drugs Evaluation and Research, Food and
Drug Administration, Rockville, MD, USA.
References
1. Multisource (generic) pharmaceutical products: guidelines on registration
requirements to establish interchangeability. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva,
World Health Organization, 1996, Annex 9 (WHO Technical Report Series,
No. 863).
2. The use of essential drugs. Eighth report of the WHO Expert Committee
(including the revised Model List of Essential Drugs). Geneva, World Health
Organization, 1998 (WHO Technical Report Series, No. 882).
3. The international pharmacopoeia, 3rd ed. Vol. 1. General methods of
analysis; Vol. 2. Quality specifications; Vol. 3. Quality specifications; Vol 4.
Tests, methods, and general requirements. Quality specifications for
pharmaceutical substances, excipients, and dosage forms. Geneva, World
Health Organization, 1979–1994..181
© World Health Organization
WHO Technical Report Series, No. 902, 2002
Annex 12
Guidelines on the use of International
Nonproprietary Names (INNs) for pharmaceutical
substances
1. General introduction
The present guidelines on the use of International Nonproprietary
Names (INNs) provide a general explanation of the INN selection
process. They should be of interest to drug regulatory authorities for
use in the marketing authorization/registration of products, to drug
manufacturers requesting new INNs, and to those using INNs, such as
patent authorities/offices, trademark lawyers and specialists, health
professionals, scientists and teachers, as well as to anyone interested
in nomenclature.
1.1 General information on the INN system
An INN identifies a pharmaceutical substance or active pharmaceuti-cal
ingredient by a unique name that is globally recognized and is
public property. A nonproprietary name is also known as a generic
name.
The INN system as it exists today was initiated in 1950 by World
Health Assembly resolution WHA3.11 (see section 5.1) and began
operating in 1953, when the first list of INNs for pharmaceutical
substances was published. The cumulative list of INNs now stands at
some 7000 names designated since that time, and this number is
growing every year by some 120–150 new INNs.
Since its inception, the aim of the INN system has been to provide
health professionals with a unique and universally available desig-nated
name for each pharmaceutical substance. The existence of an
international nomenclature for pharmaceutical substances, in the
form of INNs, is important for the clear identification, safe prescrip-tion
and dispensing of medicines to patients, and for communication
and the exchange of information among health professionals and
scientists worldwide.
As unique names, INNs must be distinctive in sound and spelling, and
not liable to confusion with other names in common use. To make
INNs universally available, they are formally placed by WHO in the.182
public domain, hence their designation as “nonproprietary”. They can
be used without any restriction whatsoever to identify pharmaceutical
substances.
Another important feature of the INN system is that the names of
pharmacologically related substances were identified by the use of
a common “stem” (see section 3.2). The use of common stems
enables the medical practitioner, the pharmacist, or anyone dealing
with pharmaceutical products to recognize that a particular substance
belongs to a group of substances of similar pharmacological activity.
For example, all iodine-containing contrast media are given the
prefix io-, while all b -adrenoreceptor antagonists have the suffix
-olol.
The extent of utilization of INNs is expanding with the increase in the
number of pharmaceutical names. Their wide application and global
recognition are also due to close collaboration in the process of INN
selection with numerous bodies concerned with drug nomenclature.
The increasing coverage of drug names by INNs has led to a situation
whereby the majority of pharmaceutical substances used today in
medical practice are designated by an INN. The use of INNs is already
common in research and clinical documentation, while their impor-tance
is growing further as a result of the expanding use of generic
names for pharmaceutical products.
The names which are given the status of an INN are selected by
WHO on the advice of experts from the WHO Expert Advisory
Panel on the International Pharmacopoeia and Pharmaceutical
Preparations. The process of INN selection consists of three main
steps:
1. A request/application is made by the manufacturer or inventor.
2. After a review of the request, a proposed INN (prop. INN) is
selected and published for comments.
3. After the period allowed for objections has lapsed, the name ob-tains
the status of a recommended INN (rec. INN) and is published
as such.
The procedures relating to each of these steps are described in detail
in sections 2.1 and 2.2.
INNs are selected in principle only for single, well-defined substances
that can be unequivocally characterized by a chemical name (or for-mula).
It is the policy of the INN programme not to select names for
mixtures of substances, while substances that are not fully character-ized
are included in the INN system in exceptional cases only.
INNs are not selected for herbal substances (vegetable drugs) or for.183
homeopathic products. It is also the policy of the INN programme not
to select names for those substances that have a long history of use for
medical purposes under well-established names, such as alkaloids
(e.g. morphine, codeine), or that have well-known trivial chemical
names (e.g. acetic acid).
An INN is usually assigned to the active part of the molecule only, to
avoid the multiplication of entries in cases where several salts, esters,
etc., are actually used. In such cases, the user of the INN can create a
modified INN (INNM) (see section 2.4), e.g. mepyramine maleate
for the mepyramine salt of maleic acid. When the creation of an
INNM would require the use of a long or inconvenient name for the
radical (or group) part of the INNM, the INN programme will select
a short name for such a radical (or group) (e.g. mesilate for
methanesulfonate; see section 2.3).
Names of pharmaceutical preparations, such as those used in titles of
pharmacopoeial monographs, usually consist of two elements, the
first designating the active substance (for which an INN is used), and
the second designating the dosage form of the product. Rules for
creating such names fall outside the scope of the INN programme and
are not discussed here.
In the process of INN selection, the rights of existing trademark
owners are fully protected. If, in a period of 4 months following the
publication of a proposed INN, a formal objection is filed by an
interested person who considers that the proposed INN is in conflict
with an existing trademark, WHO will make every effort to persuade
the person concerned to withdraw their objection or will reconsider
the proposed name. As long as the objection to the name exists,
WHO will not publish it as a recommended INN.
With the growing number of INNs and trademarks, the possibility of
conflicts between the two has gradually increased, even though the
rights of existing trademarks are fully protected. The main source of
conflict is usually an attempt by a manufacturer to propose a new
trademark containing stems established in the INN programme. If
protection were granted to such a name, that might limit the freedom
of the INN programme in selecting further INNs for the same group
of substances. To prevent such occurrences, the matter was taken
up in resolution WHA46.19 of the World Health Assembly (see
section 4).
1.2 Use of INNs
Nonproprietary names are intended for use in pharmacopoeias,
labelling, product information, advertising and other promotional.184
material, drug regulation and scientific literature, and as a basis for
product names, e.g. for generics. Their use is normally required by
national or, as in the case of the European Community, by interna-tional
legislation. As a result of ongoing collaboration, national
names such as British Approved Names (BAN), Dénominations
Communes Françaises (DCF), Japanese Adopted Names (JAN) and
United States Accepted Names (USAN) are nowadays, with rare
exceptions, identical to the corresponding INNs.
Some countries have defined the minimum size of characters in which
the generic nonproprietary name must be printed under the trade-mark
labelling and advertising. In several countries the generic name
must appear prominently in type at least half the size of that used for
the proprietary or brand name. In some countries it must be in larger
type than the trademark name. Certain countries have even gone so
far as to abolish trademarks within the public sector.
To avoid confusion, which could jeopardize the safety of patients,
trademarks cannot be derived from INNs and, in particular, must not
include their common stems. As already mentioned, the selection of
further names within a group of substances would be seriously
hindered by the use of a common stem in a brand name.
2. Elements in the INN system
2.1 Proposed INNs
The selection of a new INN follows a strict procedure. On receipt
of an INN request form, the INN Secretariat examines the sug-gested
names for conformity with the general rules, and for similari-ties
with published INNs and potential conflicts with existing
names, including published INNs and trademarks. A note summariz-ing
the result of this examination is added, and the request is then
forwarded to the INN experts for comments. As soon as all the
experts agree on a name, the applicant is informed of the selected
name.
Newly selected, proposed INNs are then published in WHO Drug
Information, after which a period of 4 months is allowed for com-ments
on and/or objections to them to be made. The reasons for any
objection must be clearly stated and will be evaluated by the experts.
Users are requested to refrain from using the proposed name until it
becomes a recommended INN, in order to avoid confusion should the
name be modified.
Two lists of proposed INNs are published yearly. An example is
shown in Figure 1..185
2.2 Recommended INNs
The final stage of the selection process is the recommended INN.
Once a name has been published as a recommended INN it will not
normally be modified further and is ready for use in labelling, and in
publications and drug information. It will serve to identify the active
pharmaceutical substance during its lifetime worldwide. Since the
name is available in the public domain it may be freely used. It should
not be registered as a trademark, since this would prevent its use by
other parties (see also section 4).
Recommended INNs are published in WHO Drug Information after
the completion of the procedure for dealing with proposed INNs (see
section 2.1). As from 1997, two lists of proposed INNs are published
yearly, and as from list 37 of recommended INNs, graphic formulae
are also included to facilitate identification of the substances.
An example of an entry in the list is shown in Figure 2.
2.3 Names for radicals and groups
During the twentieth meeting of the WHO Expert Committee on
Nonproprietary Names for Pharmaceutical Substances (1), the ex-perts
discussed the issue of INNs for salts and esters and noted that
requests had frequently been received for INNs for salts, esters, or
combination products of substances for which INNs already existed.
At that time, the experts decided that INNs for simple salts and esters
should be derived from the INNs in conformity with normal chemical
practice.
Figure 1
A proposed INN
acidum iocanlidicum (
123
I)
iocanlidic (
123
I) acid 15-( p-[
123
I]iodophenyl)pentadecanoic acid
radiodiagnostic agent
acide iocanlidique (
123
I) acide 15-(4-[
123
I]iodophényl)pentadécanoïque
produit à usage radiodiagnostique
ácido iocanlídico (
123
I) ácido 15-( p-[
123
I]iodofenil)pentadecanoico
agente de radiodiagnóstico
C21 H33
123
IO2 74855-17-7
CO2 H
123 I.186
Some of the radicals and groups involved are, however, so complex
that it is inconvenient to use the chemical nomenclature. It was there-fore
decided that, in such cases, shorter nonproprietary names should
be selected for these active moieties and published in the list of
proposed INNs under the title “Names for radicals and groups”.
Separate names for salts and esters derived from this procedure are
not published. If a “radical and group name” is used in conjunction
with an INN, it is referred to as an International Nonproprietary
Name (Modified) or INNM (see section 2.4).
A comprehensive list of radicals and groups, which is regularly up-dated,
may be obtained from Marketing and Dissemination
1
or the
INN Secretariat (2).
2.4 Modified INNs (INNMs)
As previously mentioned, INNs are usually selected only for the
active part of the molecule, which is usually the base, acid or alcohol.
In some cases, however, the active part needs to be extended for
various reasons, e.g. for formulation purposes, or to increase the
bioavailability or absorption rate of the substance. At its twentieth
meeting in 1975, the WHO Expert Committee on Nonproprietary
Names for Pharmaceutical Substances (1) decided to adopt a new
policy for naming such molecules. As a result, names for different
N H3 C
OCH3
O
H
Figure 2
A recommended INN
agomelatinum
agomelatine N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide
agomélatine N-[2-(7-méthoxynaphtalén-1-yl)éthyl]acétamide
agomelatina N-[2-(7-metoxi-1-naftil)etil]acetamida
C15 H17 NO2
1
Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211
Geneva 27, Switzerland..187
salts or esters of the same active substance should differ only with
regard to the inactive moiety of the molecule. For example, oxacillin
and ibufenac are INNs and their salts are named oxacillin sodium and
ibufenac sodium. The latter are called modified INNs (INNMs).
Before the introduction of this rule, some INNs were published for
salts. In such cases, the term “modified INN” may also be used for a
base or acid. For example, levothyroxine sodium was published as an
INN and levothyroxine may thus be referred to as an INNM.
2.5 Cumulative list
All names selected as proposed and recommended INNs are pub-lished
in a cumulative list (3), which is updated periodically. The
generic names are listed in alphabetical order by Latin name. Each
entry includes:
— the equivalent nonproprietary names in Latin, English, French,
Russian and Spanish;
— a reference to the INN list in which the name was originally
proposed or recommended, or last amended;
— a reference to names of substances that have been abandoned or
never marketed;
— a reference to national nonproprietary names;
— a reference to pharmacopoeial monographs or similar official
publications;
— a reference to names established by the International Organiza-tion
for Standardization (ISO);
— a reference to the Convention on Psychotropic Substances (4), if
applicable;
— a reference to the List of Narcotic Drugs under International
Control (5), if applicable;
— the molecular formula;
— the Chemical Abstracts Service (CAS) number.
The information contained in the cumulative list of INNs (3) is pre-sented
as shown in Figure 3.
3. Principles for selection of INNs
3.1 General rules
General rules were established at the beginning of the INN
programme in order to guide the members of the INN committee and
to allow health professionals to understand the rationale for a number
of new names. At first, some countries used shortened chemical
names as generic names, but this system was found to be of very
limited use, since many molecules contain similar elements and.188
Figure 3
Example of an entry from the Cumulative list
* An asterisk in place of a recommended list number signifies that an objection has been raised to the
proposed name.
Note: Cross-references are provided for entries corresponding to (a) English, French and Spanish
INN that appear in different alphabetical positions from the Latin INN and (b) national names
that differ from the INN. Entries for (a) are printed in lower-case letters (as in the example of
aceburic acid, below) while entries for (b) are printed in capitals (as in the examples of
ACEBUTOLOL HYDROCHLORIDE and ACEBUTOLOLO).
English INN Cross-reference to Latin INN
3377 aceburic acid — acidum aceburicum
3295 ACEBUTOLOL HYDROCHLORIDE — acebutololum
3295 ACEBUTOLOLO — acebutololum
National name(s)
differing from the INN
Request number
List of proposed INN Abbreviations for national
names identical to the INN List of
recommended*
INN INN in English INN in French
INN in Latin
0626 0804 paracetamol
apaueTaMo
paracétamol
paracetamol
paracetamolum
BAN BPC CHP CSP DCF EP INDP
IP MXP USSRP YP
ACETAMINOPHEN
ACETAMINOPHENUM
PARACETAMOLO
USP
JP
DCIT
103-90-2 C8 H9 NO2
INN in Spanish INN in Russian
CAS registry number
Molecular formula National name(s)
differing from the INN
(abbreviation for source of name (left),
and name (right)).189
groups (e.g. phenol, chlor, methyl or benzene rings) in their chemical
structures. In addition, a name that indicates a relationship to a group
of substances having similar pharmacological effects is more mean-ingful
to users.
The general principles for devising INNs and the procedures for
selecting them were reviewed by the WHO Expert Committee
on Nonproprietary Names for Pharmaceutical Substances at its
twentieth meeting (1).
3.2 Use of stems
An INN usually consists of a randomly chosen prefix and a common
stem (see Appendix 1); the latter shows that the substance concerned
belongs to a group of pharmacologically related substances. Substems
are sometimes established to differentiate between different related
groups of substances, e.g. -teplase for tissue-plasminogen activators
and -uplase for urokinase-type plasminogen activators.
It should be noted that a number of stems have been discontinued
(see Appendix 2).
3.3 Stereoisomers
An INN for a new chemical entity does not routinely specify the
stereoisomeric state of the molecule in the nonproprietary name. If
the stereochemistry has been determined, this information is included
in the chemical name(s) used to identify the substance. An INN can
therefore identify the racemic mixture (e.g. ibuprofen, tetramisole),
the ()-isomer (e.g. amifostine, lofentanil, prenalterol, remoxipride,
quadazocine), or the (“´¬–”²ª› )-form (e.g. butopamine). Subsequently, if an
INN is needed for a different enantiomer or for the racemic form, the
following prefixes should be added to the existing INN:
— for the ()-form, the lev-/levo- prefix is used, e.g. levocarnitine,
levamisole;
— for the (“´¬–”²ª› )-form, the dex- prefix is used, e.g. dexamisole, dexi-buprofen;
— for the racemic form, the rac-/race- prefix is used, e.g.
racepinefrine.
3.4 Radioactive compounds
A name for a drug substance containing a radioactive atom should
list, in the following order:
— the name of the substance containing the radioactive atom;
— the isotope number;.190
— the element symbol; and
— the name of the carrier agent, if any.
Examples include cyanocobalamin (
60
Co), technetium (
99m
Tc) bicisate
and technetium (
99m
Tc) sestamibi.
3.5 Specific groups of biological compounds
Because of the complexity of certain new types of pharmaceutical
products, such as those produced by biotechnology, general rules are
not always easily formulated (6). Some of these substances may al-ready
have descriptive names assigned by other institutions such as
the International Union of Biochemistry (IUB), the International
Union of Pure and Applied Chemistry (IUPAC), and the Joint Com-mission
on Biochemical Nomenclature (JCBN). These names may
not be suitable as INNs.
4. Protection of INNs
Lists of both proposed and recommended INNs are sent together
with a note verbale by WHO to its Member States (of which there
are at present 191), to national pharmacopoeia commissions and to
other bodies designated by Member States. The note verbale requests
Member States to take such steps as are necessary to prevent the
acquisition of proprietary rights in the names, including prohibiting
their registration as tradenames or trademarks.
Over the years, the need to maintain the integrity of the INN system
has become urgent. This is reflected in the following extract from the
fifth report of the WHO Expert Committee on the Use of Essential
Drugs (7), which met in November 1991:
The procedure for selecting INNs allows manufacturers to contest names that
are either identical or similar to their licensed trademarks. In contrast,
trademark applications are disallowed, in accordance with the present
procedure, only when they are identical to an INN. A case for increased
protection of INNs is now apparent as a result of competitive promotion of
products no longer protected by patents. Rather than marketing these
products under the generic name, many companies apply for a trademark
derived from an INN and, in particular, including the INN common stem. This
practice endangers the principle that INNs are public property; it can frustrate
the rational selection of further INNs for related substances, and it will
ultimately compromise the safety of patients by promoting confusion in drug
nomenclature.
These concerns were debated during the Sixth International Confer-ence
of Drug Regulatory Authorities (ICDRA) in Ottawa in October
1991..191
On the basis of the recommendations made by the WHO Expert
Committee on the use of Essential Drugs, a resolution on nonpropri-etary
names for pharmaceuticals (WHA46.19) was adopted by the
World Health Assembly in 1993 (8). This requested Member States:
• to enact rules or regulations, as necessary, to ensure that international
nonproprietary names (or the equivalent nationally approved generic
names) used in the labelling and advertising of pharmaceutical products are
always displayed prominently;
• to encourage manufacturers to rely on their corporate name and the
international nonproprietary names, rather than on trademarks, to pro-mote
and market multisource products introduced after the expiry of a
patent;
• to develop policy guidelines on the use and protection of international
nonproprietary names, and to discourage the use of names derived from
them, and particularly names including established stems as trademarks.
Attention is drawn to this resolution concerning the use and protec-tion
of INNs in the note verbale.
As a matter of principle, it may thus be recommended that trade-marks
should not be derived from INNs. In particular, the intentional
incorporation of meaningful INN stems in trademarks should be
avoided.
Similarly, the inclusion of elements from biochemical nomenclature
(e.g. -feron from interferon, or -leukin from interleukin) in trade-marks
is discouraged since these elements are likely to be used as
stems within the INN nomenclature. Their inclusion in trademarks
could thus prevent the logical development of the INN nomenclature.
In accordance with resolution WHA46.19, the registration of an INN
together with a firm’s name is perfectly acceptable as long as it does
not prevent another manufacturer from adopting the same approach.
5. How to apply for an INN
5.1 Procedure for selection of INNs
The selection of INNs is based on the resolution on the procedure for
the selection of INNs for pharmaceutical substances (WHA3.11)
adopted by the World Health Assembly in 1950 (9), and subsequently
adopted and amended by the Executive Board in 1955 (10) and 1969
(11).
In countries with national nomenclature commissions, applications
for INNs can be made through these commissions. In countries
without a national nomenclature commission, requests for INNs may
be forwarded directly to WHO. Applications for INNs should be
addressed to:.192
Secretary of the INN Programme
Quality Assurance and Safety: Medicines
Essential Drugs and Medicines Policy
World Health Organization
20 avenue Appia
1211 Geneva 27
Switzerland
Tel: +41 22 791 0746
Fax: +41 22 791 3636/3660
5.2 INN request form
Before a suggested name can be evaluated by the INN Secretariat,
complete information must be provided on a request form to facilitate
handling of the data and to ensure that pertinent items have not been
omitted. It is important that the information is as comprehensive as
possible. If some of the information is missing or explanations are
unclear or incomplete, the INN Secretariat will request the applicant
to provide the missing data or further explanation. This can result in
delays, because an INN cannot be selected until all the relevant
information is available to the INN experts.
The following explanations will help applicants to complete the INN
form. If additional information is needed, an applicant can contact the
INN Secretariat at the above-mentioned address.
Suggested names in order of preference
An applicant can suggest three names for an INN relating to the acid,
base or alcohol of the chemical entity concerned. The suggested name
should be a single word and not inconveniently long.
Since a nonproprietary name is intended to show the group of phar-macologically
related substances to which the substance concerned
belongs, whenever justified, the suggested name must incorporate the
established common stem. A list of stems (12) is available on request
from Marketing and Dissemination
1
or the INN Secretariat.
Occasionally stems require modification. For example, some drugs
inhibit a -adrenoreceptors as well as b -adrenoreceptors and differ in
structure from the “-olol” prototype. Accordingly, for this type of
drug, one letter in the stem was changed to give “-alol”. The signifi-cance
of this change in the naming of related groups of drugs might
1
Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211
Geneva 27, Switzerland..193
not be apparent to everyone, but would be understood by someone
familiar with the naming conventions of the b -adrenoreceptor antago-nists
and related compounds.
It is imperative that the newly suggested name does not conflict with
existing chemical names, other nonproprietary names or trademarks.
The INN Secretariat therefore requests the applicant to verify the
absence of conflicts with existing chemical names, common names for
insecticides, other nonproprietary names and trademarks. Some firms
routinely perform exhaustive searches for possible conflicts with a
suggested INN and for pharmacologically and chemically related
compounds with already assigned INNs. It would be helpful if the
INN Secretariat could be informed when such searches have been
carried out and be given a summary of the results.
Chemical name and description
The chemical information provided on the request form should be
as complete and as up to date as possible. Information on stereo-chemistry
should be included, if known. The chemical names should
be in accordance with the IUPAC rules of nomenclature, as inter-preted
by the Chemical Abstracts Service (CAS) (8th collective
period); the Chemical Abstracts Index names in their current style
may also be included as additional information. The chemical name
provided by the manufacturer is reviewed for accuracy and to
confirm that its construction follows the accepted rules of chemical
nomenclature.
A description can be used to identify a substance that is insufficiently
defined to be assigned a IUPAC and CAS chemical name. This de-scription
will be superseded by the chemical name when the drug
substance has been fully characterized.
Precautions are taken to ensure confidentiality of the material sub-mitted
to WHO, but an applicant should not attempt to obtain an
INN before all patent procedures are completed and until full chemi-cal
information can be made available to WHO.
Graphic formula
Without a graphic formula, it may be difficult to determine whether
an INN already exists. In addition, a graphic formula is necessary to
relate the new drug to existing compounds in the same chemical
family. Guidelines for drawing structures are available on request
from the INN Secretariat (13).
Molecular formula
A one-line molecular formula constructed in accordance with
accepted chemical practices should be supplied, e.g. C21 H28 N2 ..194
CAS registry number
If a CAS registry number has been assigned to a new compound
before it is submitted to the INN Secretariat, the number should be
included on the request form. If no number has yet been assigned, the
manufacturer should obtain the CAS registry number from the
Chemical Abstracts Services for publication in the INN lists. Proof of
the entry will be required.
Trademarks (known or contemplated)
If a trademark has been issued for the drug, it should be entered on
the form. Any national or international trademarks (and manufactur-ers)
and the name of the country where the trademark is registered
should be listed.
Any other name or code
Sometimes, long before a nonproprietary name or a trademark has
been selected for a new compound, it may have acquired a trivial
name that has been used both in the laboratory and in the scientific
literature. The INN Secretariat would like to be made aware of such
names but requests manufacturers not to create, use or in any way
encourage the creation of trivial names for new drugs. The fact that a
trivial name has become accepted in the literature will not ensure its
adoption as a nonproprietary name and may only cause confusion
when an official nonproprietary name is selected. It is therefore rec-ommended
that codes should be used before a recommended nonpro-prietary
name is published, and that these should be indicated on the
request form sent to the INN Secretariat as an additional reference.
Principal therapeutic use(s) and posology
It is important to know the therapeutic category to which the new
compound belongs as such information may determine the stem se-lected
for the nonproprietary name. Reprints presenting evidence of
the claimed therapeutic use should be included with the application.
A list of terms for the pharmacological action and therapeutic use of
drugs is available from WHO in English, French and Spanish (14).
Pharmacological action
The pharmacological action should be explained in as much detail as
possible, since it may also influence the stem selected for the com-pound.
Again, reprints must be included to support the claimed action
(for terminology, see above).
Date of clinical trial
As a general guide, the development of a drug should have reached
the stage of phase II clinical trials before an application is submitted.195
to the INN Secretariat. The approximate date when clinical trials
began should be indicated as proof that such trials are under way. It
is the belief that if a drug has entered clinical trials, there is a reason-able
expectation that it will be marketed, and thus the name selected
will have been developed for that purpose. If, however, the develop-ment
of the drug is stopped, the manufacturer should inform the INN
Secretariat as soon as possible, in order to halt the selection process.
Availability of suggested names
The originator of the INN request should confirm with his or her
signature that the names are suggested on the understanding that, so
far as is known, none of them have been registered or are awaiting
registration.
Permission to publish the CAS registry number
The applicant must confirm that the CAS registry number sent to the
INN Secretariat is correct and may be used in the INN lists.
Additional comments
This section allows the applicant to make additional comments and/or
provide further information.
References
1. Nonproprietary names for pharmaceutical substances. Twentieth report of
the WHO Expert Committee. Geneva, World Health Organization, 1975
(WHO Technical Report Series, No. 581).
2. INNs: names for radicals and groups, combined summary list.
1
Geneva,
World Health Organization (unpublished document WHO/PHARM S/
NOM1506; available from INN Secretariat, Essential Drugs and Medicines
Policy, World Health Organization, 1211 Geneva 27, Switzerland).
3. International nonproprietary names (INN) for pharmaceutical substances.
Cumulative list no. 9. Geneva World Health Organization, 1996.
4. Convention on Psychotropic Substances, 1971. Vienna, United Nations,
1978.
5. List of narcotic drugs under international control, 41st ed. Vienna, United
Nations, 1999.
6. Definition of INNs for substances prepared by biotechnology.
1
Geneva,
World Health Organization (unpublished document WHO/PHARM S/
NOM1348; available from INN Secretariat, Essential Drugs and Medicines
Policy, World Health Organization, 1211 Geneva 27, Switzerland).
7. The use of essential drugs. Fifth report of the WHO Expert Committee.
Geneva, World Health Organization, 1992 (WHO Technical Report Series,
No. 825).
1
Updated regularly..196
8. Nonproprietary names for pharmaceutical substances. In: Forty-sixth World
Health Assembly, Geneva, 3–14 May 1993. Volume 1. Resolutions and
decisions, annexes. Geneva, World Health Organization, 1993 (unpublished
document WHA46/1993/REC/1):20–21.
9. Nonproprietary names for pharmaceutical substances. In: Handbook of
resolutions and decisions of the World Health Assembly and the Executive
Board. Volume I, 1948–1972. Geneva, World Health Organization, 1973:128.
10. EB15.R1. In: Handbook of resolutions and decisions of the World Health
Assembly and the Executive Board. Volume I, 1948–1972. Geneva, World
Health Organization, 1973:129.
11. EB43.R9. In: Handbook of resolutions and decisions of the World Health
Assembly and the Executive Board. Volume I, 1948–1972. Geneva, World
Health Organization, 1973:130.
12. The use of common stems in the selection of international nonproprietary
names (INNs) for pharmaceutical substances. Geneva, World Health
Organization (unpublished document updated annually; available from INN
Secretariat, Essential Drugs and Medicines Policy, World Health
Organization, 1211 Geneva 27, Switzerland).
13. The graphic representation of chemical formulae in the publications of
international nonproprietary names (INNs) for pharmaceutical substances.
Geneva, World Health Organization, 1995 (unpublished document WHO/
PHARM/95.579; available from INN Secretariat, Essential Drugs and
Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).
14. Pharmacological action and therapeutic use of drugs: a list of terms.
Geneva, World Health Organization, 1996 (unpublished document WHO/
PHARM/96.320; available from Essential Drugs and Medicines Policy, World
Health Organization, 1211 Geneva 27, Switzerland)..197
Appendix 1
List of common stems used in the selection
of INNs
Stem
a
Substem, Definition
if available
-abine see -arabine, -citabine
-ac anti-inflammatory agents, ibufenac derivatives
-acetam see -racetam
-actide synthetic polypeptides with corticotropin-like
action
-adol or -adol- analgesics
-adom analgesics, tifluadom derivatives
-afenone antiarrhythmics, propafenone derivatives
-aj- antiarrhythmics, ajmaline derivatives
-aldrate antacids, aluminium salts
-alol see -olol
-alox see -ox
-amab see -mab
-amivir see vir
andr steroids, androgens ( see also -stan- or -ster-)
-anide
-etanide diuretics, piretanide derivatives
-oxanide antiparasitic, salicylanilides and analogues
-anserin serotonin receptor antagonists (mostly 5-HT2 )
-antel anthelminthics (undefined group)
-apine see -pin(e)
-a(ra)bine arabinofuranosyl derivatives
-arit antiarthritic substances, with a similar
mechanism of action to clobuzarit and
lobenzarit (mechanism different from anti-inflammatory-
type substances, e.g.
-fenamates or -profens)
-arol anticoagulants, dicoumarol derivatives
-arone antiarrhythmics, calcium channel blockers,
uricosurics
-arte- antimalarial agents, artemisinin-related
compounds
-ase enzymes:
-diplase — plasminogen activator combined with
another enzyme
-dismase — with superoxide dismutase activity
-lipase — with lipase activity
-teplase — tissue-type plasminogen activators
-uplase — urokinase-type plasminogen activators
-ast antiasthmatics, antiallergics, not acting
primarily as antihistamines:
-lukast — leukotriene receptor antagonists ( see also
-lubant).198
Stem
a
Substem, Definition
if available
-trodast — thromboxane A2 receptor antagonists,
antiasthmatics
-asteride see -ster
-astine antihistamines
-azam see -azepam
-azenil benzodiazepine receptor antagonists/agonists
(benzodiazepine derivatives):
-carnil — benzodiazepine receptor antagonists/
agonists (carboline derivatives)
-quinil — benzodiazepine receptor partial agonists
(quinoline derivatives)
-azepam diazepam derivatives
-azepide cholecystokinin receptor antagonists
-azocine narcotic antagonists/agonists related to
6,7-benzomorphan
-azolam see -azepam
-azoline antihistamines or local vasoconstrictors,
antazoline derivatives
-azone see -buzone
-azosin antihypertensive substances, prazosin
derivatives
-bactam b -lactamase inhibitors
-bamate tranquillizers, propanediol and pentanediol
derivatives
barb hypnotics, barbituric acid derivatives
-benakin see -kin
-bendan see -dan
-bendazole anthelminthics, tiabendazole derivatives
-betasol see pred
bol anabolic steroids
-bradine bradycardic agents
-brate see -fibrate
-butazone see -buzone
-buzone anti-inflammatory analgesics, phenylbutazone
derivatives
-cain- class I antiarrhythmics, procainamide and
lidocaine derivatives (antifibrillants with local
anaesthetic activity)
-caine local anaesthetics
calci vitamin D analogues/derivatives
-carbef antibiotics, carbacephem derivatives
-carnil see -azenil
-castat see -stat
-cavir see vir
cef- antibiotics, cefalosporanic acid derivatives:
-oxef — antibiotics, oxacefalosporanic acid
derivatives
cell-, -cell- or cellulose derivatives:
cel-.199
Stem
a
Substem, Definition
if available
cell-ate — cellulose ester derivatives for substances
containing acidic residues
-cellose — cellulose ether derivatives
cell-ate see cell--
cellose see cell--
cic hepatoprotective substances with a carboxylic
acid group
-cidin naturally occurring antibiotics (undefined
group)
-cillide see -cillin
-cillin antibiotics, 6-aminopenicillanic acid derivatives
-cillinam see -cillin
-cilpine see -pin(e)
-cisteine see -steine
-citabine nucleoside antiviral or antineoplastic agents,
cytarabine or azarabine derivatives
-clone hypnotic tranquillizers
-cog blood coagulation factors:
(-)eptacog — blood coagulation factor VII
(-)nonacog — blood coagulation factor IX
(-)octacog — blood coagulation factor VIII
-conazole systemic antifungal agents, miconazole
derivatives
cort corticosteroids, except prednisolone derivatives
-crinat diuretics, etacrynic acid derivatives
-crine acridine derivatives
-cromil antiallergics, cromoglicic acid derivatives
-curium see -ium
-cycline antibiotics, tetracycline derivatives
-dan cardiac stimulants, pimobendan derivatives
-dapsone antimycobacterials, diaminodiphenylsulfone
derivatives
-decakin see -kin
-dermin see -ermin
-dil vasodilators
-dilol see -dil
-dipine calcium channel blockers, nifedipine derivatives
-dismase see -ase
-distim see -stim
-dodekin see -kin
-dopa dopamine receptor agonists, dopamine
derivatives, used as antiparkinsonism
drugs/prolactin inhibitors:
-opamine — dopaminergic agents, dopamine derivatives
used as cardiac stimulants/antihypertensives/
diuretics
-dox see -ox
-dralazine antihypertensives, hydrazinephthalazine
derivatives.200
Stem
a
Substem, Definition
if available
-drine sympathomimetics:
-frine — phenethyl derivatives
-dronic acid calcium metabolism regulator, pharmaceutical
adjunct
-dutant see -tant
-dyl see -dil
-ectin antiparasitics, ivermectin derivatives
-elestat see -stat
-elvekin see -kin
-emab see -mab
-entan endothelin receptor antagonists
-eptacog see -cog
erg ergot alkaloid derivatives
-eridine analgesics, pethidine derivatives
-ermin growth factors:
-dermin — epidermal growth factors
-fermin — fibrinoblast growth factors
-filermin — leukaemia-inhibiting factor
-nermin — tumour necrosis factor
-plermin — platelet-derived growth factor
-sermin — insulin-like growth factors
-termin — transforming growth factor
estr- estrogens
-etanide see -anide
-ethidine see -eridine
-exakin see -kin
-exine mucolytic, bromhexine derivatives
-fenamic acid anti-inflammatory, anthranilic acid derivatives
-fenamate — fenamic acid derivatives
-fenin diagnostic aids, (phenylcarbamoyl)methyl
iminodiacetic acid derivatives
-fenine analgesics, glafenine derivatives (subgroup of
-fenamic acid group)
-fentanil narcotic analgesics, fentanyl derivatives
-fermin see -ermin
-fiban fibrinogen receptor antagonists (glycoprotein
IIb/IIIa receptor antagonists)
-fibrate clofibrate derivatives
-filermin see -ermin
-flapon 5-lipoxygenase-activating protein (FLAP)
inhibitor
-flurane halogenated compounds used as general
inhalation anaesthetics
-formin antihyperglycaemics, phenformin derivatives
-fos, -fos- or fos- insecticides, anthelminthics, pesticides, etc.,
phosphorus derivatives
-fradil calcium channel blockers acting as vasodilators
-frine see -drine
-fungin antifungal antibiotics.201
Stem
a
Substem, Definition
if available
-fylline N-methylated xanthine derivatives
gab gabamimetic agents
gado- diagnostic agents, gadolinium derivatives
-gatran thrombin inhibitors, antithrombotic agents
gest steroids, progestogens
-gesterone see -ster
-giline monoamine oxidase inhibitors, type B
-gillin antibiotics produced by Aspergillus spp.
gli antihyperglycaemics, sulfonamide derivatives
-golide dopamine receptor agonists, ergoline
derivatives
-gosivir see vir
-gramostim see -stim
-grastim see -stim
-grel- or -grel platelet aggregation inhibitors
guan- antihypertensives, guanidine derivatives
-ibine see -ribine
-icam anti-inflammatory, isoxicam derivatives
-ifene antiestrogens, clomifene and tamoxifen
derivatives
-igetide see -tide
-ilide class III antiarrhythmics, sematilide derivatives
-imab see -mab
imex immunostimulants
-imod immunomodulators, both stimulant/suppressive
and stimulant
-imus immunosuppressants (other than
antineoplastics)
-ine alkaloids and organic bases
io- iodine-containing contrast media
-io- or iod- iodine-containing compounds other than
contrast media
-iptan serotonin (5HT1 ) receptor agonists, sumatriptan
derivatives
-irudin hirudin derivatives
-isomide antiarrhythmics, disopyramide derivatives
-ium quaternary ammonium compounds:
-curium — curare-like substances
-izine diphenylmethyl piperazine derivatives:
-rizine — antihistamines/cerebral (or peripheral)
vasodilators
-kacin antibiotics, kanamycin and bekanamycin
derivatives (obtained from Streptomyces
kanamyceticus)
-kalant potassium channel blockers
-kalim potassium channel activators, antihypertensive
-kef- enkephalin agonists
-kin interleukin (IL)-type substances ( see also -stim):
-benakin — IL-1 analogues and derivatives.202
Stem
a
Substem, Definition
if available
-decakin — IL-10 analogues and derivatives
-dodekin — IL-12 analogues and derivatives
-elvekin — IL-11 analogues and derivatives
-exakin — IL-6 analogues and derivatives
-kinra — IL receptor antagonists
-leukin — IL-2 analogues and derivatives
-nakin — IL-1 analogues and derivatives
-nakinra — IL-1 receptor antagonists
-octakin — IL-8 analogues and derivatives
-onakin — IL-1 analogues and derivatives
-trakin — Il-4 analogues and derivatives
-kinra see -kin
-kiren renin inhibitors
-leukin see -kin
-listat see -stat
-lubant leukotriene B4 receptor antagonist ( see also -ast)
-lukast see -ast
-mab monoclonal antibodies:
-amab — of rat origin
-emab — of hamster origin
-imab — of primate origin
-omab — of mouse origin
-umab — of human origin
-ximab — of chimeric origin
-zumab — of humanized origin
-mantadine, adamantane derivatives
-mantine or
-mantone
-meline cholinergic agents, muscarinic receptor
agonists/partial antagonists used in the
treatment of Alzheimer disease
-mer polymers
-mesine sigma receptor ligands
-mestane aromatase inhibitors
-metacin anti-inflammatory, indometacin derivatives
-met(h)asone see pred
-micin antibiotics obtained from various
Micromonospora spp.
-mifene see -ifene
-monam monobactam antibiotics
-morelin see -relin
-mostim see -stim
-motine antivirals, quinoline derivatives
-moxin monoamine oxidase inhibitors, hydrazine
derivatives
-mustine antineoplastic, alkylating agents, (-chloroethyl)
amine derivatives
-mycin antibiotics obtained from various Streptomyces
spp. ( see also -kacin).203
Stem
a
Substem, Definition
if available
nab cannabinol derivatives
-nakin see -kin
-nakinra see -kin
nal- narcotic antagonists/agonists related to
normorphine
-naritide see -tide
-navir see vir
-nercept tumour necrosis factor antagonist
-nermin see -ermin
-netant see -tant
-nicate see nico-nico-,
nic- or ni- nicotinic acid or nicotinoyl alcohol derivatives:
-nicate — antihypercholesterolaemic and/or
vasodilating nicotinic acid esters
-nidazole antiprotozoals, metronidazole derivatives
-nidine see -onidine
nifur- 5-nitrofuran derivatives
-nil see -azenil
nitro-, nitr-, nit-, NO2 -derivatives
ni- or -ni--
nixin anti-inflammatory, anilinonicotinic acid
derivatives
-nonacog see -cog
-octacog see -cog
-octakin see -kin
-olol b -adrenoreceptor antagonists:
-alol — aromatic ring –CHOH–CH2 –NH–R related to
-olols
-olone see pred
-omab see -mab
-onakin see -kin
-one ketones
-onide steroids for topical use, acetal derivatives
-onidine antihypertensives, clonidine derivatives
-onium see -ium
-opamine see -dopa
-orex anorectics
-orph- see orphan
orphan narcotic antagonists/agonists, morphinan
derivatives
-ox antacids, aluminium derivatives:
-pirox — antimycotic pyridone derivatives
-xanox — antiallergics, tixanox group
-oxacin antibacterials, nalidixic acid derivatives
-oxan(e) benzodioxane derivatives
-oxanide see -anide
-oxef see cef--
oxepine see -pine
-oxetine antidepressants, fluoxetine derivatives.204
Stem
a
Substem, Definition
if available
-oxicam see -icam
-oxifene see -ifene
-oxopine see -pine
-pafant platelet-activating factor antagonists
-pamide diuretics, sulfamoylbenzoic acid derivatives
-pamil coronary vasodilators, verapamil derivatives
-parcin glycopeptide antibiotics
-parin heparin derivatives including those of low
relative molecular mass:
-parinux — synthetic heparinoids
-parinux see -parin
-pase see -ase
-pendyl see -dil
-penem analogues of penicillanic acid antibiotics
modified in the five-membered ring
perfl(u)- perfluorinated compounds used as blood
substrates and/or diagnostic agents
-peridol see -perone
-peridone see -perone
-perone tranquillizers, neuroleptics, 4¼ñêô-fluoro-4-
piperidinobutyrophenone derivatives:
-peridol — antipsychotics, haloperidol derivatives
-peridone — antipsychotics, risperidone derivatives
-phenine see -fenine
-pidem hypnotics/sedatives, zolpidem derivatives
-pin(e) tricyclic compounds:
-apine — psychoactive
-cilpine — antiepileptic
-zepine — antidepressant/neuroleptic
-piprazole see -prazole
-pirone see -spirone
-pirox see -ox
-pitant see -tant
-plact platelet factor 4 analogues and derivatives
-planin antibacterials obtained from various
Actinoplanes spp.
-plase see -ase
-platin antineoplastic agents, platinum derivatives
-plermin see -ermin
-plestim see -stim
-plon pyrazolo[.]pyrimidine derivatives, used as
anxiolytics, sedatives, hypnotics
-poetin erythropoietin-type blood factors
-porfin benzoporphyrin derivatives
-poride Na + /H + antiport inhibitor
-pramine substances of the imipramine group
-prazole antiulcer, benzimidazole derivatives:
-piprazole — psychotropics, phenylpiperazine derivatives
pred prednisone and prednisolone derivatives:.205
Stem
a
Substem, Definition
if available
-olone — steroids other than prednisolone derivatives
-prenaline see -terol
-pressin vasoconstrictors, vasopressin derivatives
-pride sulpiride derivatives
-pril(at) angiotensin-converting enzyme inhibitors
-prim antibacterials, trimethoprim derivatives
-profen anti-inflammatory agents, ibuprofen derivatives
prost prostaglandins:
-prostil — anti-ulcer
-prostil see prost
-quinil see -azenil
-racetam amide-type nootrope agents, piracetam
derivatives
-relin prehormones or hormone release-stimulating
peptides:
-morelin — growth hormone release-stimulating
peptides
-tirelin — thyrotropin-releasing hormone analogues
-relix hormone release-inhibiting peptides
-renone aldosterone antagonists, spironolactone
derivatives
-restat or -restat- see -stat
retin retinol derivatives
-ribine ribofuranyl derivatives of the “pyrazofurin” type
rifa- antibiotics, rifamycin derivatives
-rinone cardiac stimulants, amrinone derivatives
-rizine see -izine
-rozole aromatase inhibitors, imidazole–triazole
derivatives
-rubicin antineoplastic antibiotics, daunorubicin
derivatives
sal-, -sal or -sal- analgesic, anti-inflammatory salicylic acid
derivatives:
-salan — brominated salicylamide derivatives,
disinfectant
-salazo — phenylazosalicylic acid derivatives,
antibacterial
-salan see sal--
salazine or see sal--
salazide
-salazo see sal--
sartan angiotensin II receptor antagonists,
antihypertensive (non-peptidic)
-semide diuretics, furosemide derivatives
-sermin see -ermin
-serpine derivatives of Rauwolfia alkaloids
-setron serotonin receptor antagonists (5-HT3 ) not
fitting into other established groups of
serotonin receptor antagonists.206
Stem
a
Substem, Definition
if available
som- growth hormone derivatives
-sopine see -pin(e)
-spirone anxiolytics, buspirone derivatives
-stat or -stat- enzyme inhibitors:
-castat — dopamine b -hydroxylase inhibitors
-elestat — elastase inhibitors
-listat — pancreatic lipase inhibitors
-mastat — matrix metalloproteinase inhibitors
-restat or -restat- — aldose reductase inhibitors
-vastatin — antilipidaemic substances, HMG CoA
reductase inhibitors
-steine mucolytics, other than bromhexine derivatives
-ster- androgens/anabolic steroids:
-(a)steride — antineoplastics
-stigmine acetylcholinesterase inhibitors
-stim colony-stimulating factors:
-distim — combination of two different types of
colony-stimulating factor
-gramostim — granulocyte macrophage colony-stimulating
factor (GM-CSF)-type substances
-grastim — granulocyte colony-stimulating factor
(G-CSF)-type substances
-mostim — macrophage colony-stimulating factor
(M-CSF)-type substances
-plestim — IL-3 analogues and derivatives
sulfa- anti-infectives, sulfonamides
-sulfan antineoplastics, alkylating agents,
methanesulfonates
-tant neurokinin (tachykinin) receptor antagonists:
-dutant — neurokinin NK2 receptor antagonist
-netant — neurokinin NK3 receptor antagonist
-pitant — neurokinin NK1 (substance P) receptor
antagonist
-tecan antineoplastics, topoisomerase I inhibitors
-tepa antineoplastics, thiotepa derivatives
-tepine see -pin(e)
-teplase see -ase
-terenol see -terol
-termin see -ermin
-terol bronchodilators, phenylethylamine derivatives
-terone antiandrogens
-tiazem calcium channel blockers, diltiazem derivatives
-tide peptides and glycopeptides (for specific groups
of peptides, see -actide, -pressin, -relin and
-tocin)
-tidine histamine H2 receptor antagonists, cimetidine
derivatives
-tiline see -triptyline
-tirelin see -relin.207
Stem
a
Substem, Definition
if available
-tizide diuretics, chlorothiazide derivatives
-tocin oxytocin derivatives
-toin antiepileptics, hydrantoin derivatives
-trakin see -kin
-trexate folic acid analogues
-tricin antibiotics, polyene derivatives
-triptan serotonin (5HT1 ) receptor agonists, sumatriptan
derivatives
-triptyline antidepressants, dibenzo[ a, d]cycloheptane or
cycloheptene derivatives
-troban thromboxane A2 receptor antagonists,
antithrombotic agents
-trodast see -ast
trop atropine derivatives
-umab see -mab
-uplase see -ase
-ur see -uridine
-uracil uracil derivatives used as thyroid antagonists
and as antineoplastics
-uridine uridine derivatives used as antiviral agents and
as antineoplastics:
-vudine — zidovudine-type antivirals and
antineoplastics
-vastatin see -stat
-verine spasmolytics with a papaverine-like action
vin- or -vin- vinca alkaloids
vir antivirals (undefined group):
-amivir — neuraminidase inhibitors
-cavir — carbocyclic nucleosides
-gosivir — glucoside inhibitors
-navir — HIV protease inhibitors
-virsen antisense oligonucleotides
-vos see -fos
-vudine see -uridine
-xanox see -ox
-ximab see -mab
-yzine see -izine
-zafone alozafone derivatives
-zepine see -pin(e)
-zone see -buzone
-zumab see -mab
a
The hyphens indicate the position of the stem (prefix, infix or suffix) within the INN. If the
hyphen is absent, the stem may be used in any position within the name..208
Appendix 2
Common stems that have been discontinued
Stem
a
Definition
-al(d) aldehydes (deleted from General Principles in 14th report of the
WHO Subcommittee on Nonproprietary Names (1968))
mer- or -mer- mercury-containing drugs, antimicrobial or diuretic (deleted from
General Principles in List 28 of proposed INNs)
mito- antineoplastics, nucleotoxic agents (deleted from General Principles
in List 24 of proposed INNs)
-ol alcohols and phenols (deleted from General Principles in 14th report
of the WHO Subcommittee on Nonproprietary Names (1968))
-quine or quin quinoline derivatives (deleted from General Principles in List 28 of
proposed INNs)
a
The hyphens indicate the position of the stem (prefix, infix or suffix) within the INN. If the
hyphen is absent, the stem may be used in any position within the name..i
Further information on these and other WHO publications can be obtained from
Marketing and Dissemination, World Health Organization, 1211 Geneva 27, Switzerland
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
The international pharmacopoeia, third edition.
Volume 1: general methods of analysis. 1979 (223 pages)
Volume 2: quality specifications. 1981 (342 pages)
Volume 3: quality specifications. 1988 (407 pages)
Volume 4: tests, methods, and general requirements: quality specifications for
pharmaceutical substances, excipients and dosage forms. 1994 (358 pages)
Basic tests for drugs: pharmaceutical substances, medicinal plant materials and
dosage forms.
1998 (94 pages)
Basic tests for pharmaceutical dosage forms.
1991 (134 pages)
Quality assurance of pharmaceuticals: a compendium of guidelines and related
materials.
Volume 1: 1997 (244 pages)
Volume 2: good manufacturing practices and inspection. 1999 (201 pages)
Quality control methods for medicinal plant materials.
1998 (123 pages)
WHO Expert Committee on Specifications for Pharmaceutical Preparations.
Thirty-fifth report.
WHO Technical Report Series, No. 885, 1999 (162 pages)
International nonproprietary names (INN) for pharmaceutical substances.
Cumulative list no. 9.
1996 (898 pages)
The use of essential drugs.
Ninth report of the WHO Expert Committee (including the revised Model
List of Essential Drugs).
WHO Technical Report Series, No. 895, 2000 (66 pages)
WHO Expert Committee on Biological Standardization.
Forty-eighth report.
WHO Technical Report Series, No. 889, 1999 (117 pages).ii
ISBN 92 4 120902 X
This report presents the recommendations of an international
group of experts convened by the World Health Organization to
consider matters concerning the quality assurance of pharma-ceuticals
and specifications for drug substances and dosage
forms. Of particular relevance to drug regulatory authorities and
pharmaceutical manufacturers, the report discusses activities
related to the development of The international pharmacopoeia
and basic tests for pharmaceutical substances and dosage
forms, as well as quality control of reference materials, good
manufacturing practices (GMP), packaging and other aspects of
quality assurance of pharmaceuticals, nomenclature and regula-tory
issues.
The report is complemented by numerous annexes, including
lists of available International Chemical Reference Substances
and International Infrared Reference Spectra, considerations for
requesting analysis of drug samples, guidelines on pre-approval
inspections of pharmaceutical manufacturers, and guidelines for
packaging of pharmaceutical products. Guidance is provided on
the basic elements of GMP and the requirements for sterile
products and for national GMP inspectorates of pharmaceutical
manufacturers. The final annexes provide guidance on the
selection of comparator pharmaceutical products for equiva-lence
assessment of interchangeable multisource (generic)
products and the use of International Nonproprietary Names
(INNs).

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