Saturday, June 20, 2009

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 implementation
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 establishing
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
involved included their willingness and commitment to participate,
and the presence of local and multinational pharmaceutical
The Committee endorsed the project and encouraged the Secretariat
to continue work in this area.
Information on the basic elements of GMP in pharmaceutical production
is needed by interested parties and decision-makers at all levels,
and the provision of such information is encouraged. A brief summary,
intended mainly for non-specialists, is given in Annex 5.
5.2 Good manufacturing practices for sterile pharmaceutical
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 guidelines
on the inspection of pharmaceutical manufacturers in Annex 2
of its thirty-second report (19). Conducting inspections before granting
marketing authorization could avoid problems at a later stage in
the evaluation process. This should assist both regulatory authorities
and manufacturers.
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 concerned
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
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 development,
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
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 Committee
(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
(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 governments,
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 circulated
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 different
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 chromatography
(TLC) was a useful method for the rapid screening of
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 minimize
the quantities of any solvents used. This is consistent with current
safety and environmental considerations.
For both the malaria and tuberculosis programmes, the Committee
encouraged the preparation of test manuals to incorporate all relevant
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
8.4 Tuberculosis programme — fixed-dose combinations
The Committee was informed of WHO treatment policies for tuberculosis
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
fixed-dose combination (FDC) tablets to replace single drug tablets
for the treatment of tuberculosis. FDC tablets simplify drug management,
treatment (increased patient and doctor compliance) and distribution.
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 emphasized
that quality assurance should not be compromised. Attention
should be paid to the pharmaceutical aspects of such tablets, particularly
their stability and in vitro dissolution. The development of
monographs on FDC tablets for The international pharmacopoeia was
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 pharmaceutical
products for the equivalence testing and assessment of
interchangeable multisource (generic) products and includes a
decision-tree for use in identifying comparator pharmaceutical products.
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
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 approaching
finalization. It emphasized the importance of communication
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 encouraged
the sharing of information by national regulatory authorities
through the network of liaison officers established to combat counterfeit
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 electronic
Publications (in English, French and Spanish) are available, inter alia,
on basic tests for pharmaceutical substances, dosage forms and medicinal
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.

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