WHO DRUG INFORMATION - World Health Organization

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W HO D R UG
I N F O R M A T I ON
V O L U ME 1 1- N U M B ER 3 • 1 9 97
R E C O M M E N D ED I NN L I ST 38
I N T E R N A T I O N AL N O N P R O P R I E T A RY N A M E S
F O R P H A R M A C E U T I C A L S U B S T A N C ES
W O R LD H E A L TH O R G A N I Z A T I ON • G E N E VA
Volume 11, Number 3, 1997 World Health Organization, Geneva
WHO Drug Information
Contents Essential Drugs
WHO Model Formulary
Antiprotozoal drugs
General Policy Issues
Drugs used in amoebiasis 144
The dangers of counterfeit and substandard Diloxanide 144
active pharmaceutical ingredients 123 Drugs used in giardiasis
Metronidazole 145
Drugs used in leishmaniasis 145
Quality Assurance Issues
Meglumine antimoniate &
The importance of analytical procedures sodium stibogluconate 146
in regulatory control 128 Pentamidine 147
Amphotericin B 148
Drugs used in trypanosomiasis 148
Reports on Individual Drugs
Melarsoprol 148
Simplified treatment for leprosy 131 Pentamidine 149
Should antibiotics be indicated for children Suramin sodium 149
with acute otitis media? 131 Eflornithine 151
Acetylsalicylic acid: confirmed efficacy Drugs used in American trypanosomiasis 151
after stroke 132 Benznidazole 151
Antiretroviral therapy for HIV: latest guidelines 134 Nifurtimox 152
General Information ATC/DDD Classification
Biological standardization: report of the (temporary) 153
Expert Committee 138
Recent Publications and Documents
Regulatory Matters
Drugs for the elderly 155
Irinotecan-associated mortality 141 Rapid examination methods against counterfeit
HIV protease inhibitors associated with and substandard drugs 155
diabetes 141 Countering counterfeiting 155
Valvular heart disease associated with Malaria: a manual for community health
fenfluramine and phentermine 141 workers 156
Withdrawal of antidiarrhoeal paediatric product 142 Guidelines for the management of
Dangerous products promoted on the Internet 142 drug-resistant tuberculosis 156
Health risks of herbal products containing
ephedrine 142
Photoallergic and phototoxic reactions Recommended International
associated with fibrates 143 Nonproprietary Names: List 38
Restriction on sale of high-dose vitamin B6 157
products 143
First-year safety reports with triple component
pertussis vaccine 143
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WHO Drug Information Vol. 11, No. 3, 1997
General Policy Issues
The dangers of counterfeit In countries where there is strong regulation,
counterfeits are fewer in number, but highly
and substandard active
sophisticated. Where the risk of detection is lower,
pharmaceutical ingredients the infringements increase in number and the
misrepresentations become more crude. In the
WHO was first alerted to the circulation of counter- developing countries, it is the essential life-saving
feit pharmaceuticals at the Conference of Experts drugs such as antibiotics and antiparasitics that are
on the Rational Use of Drugs held in Nairobi, in most commonly counterfeited. Many developing
1985. Since then, concern about the situation has countries are heavily reliant on imports of finished
been voiced repeatedly by delegations at the World dosage forms and active pharmaceutical ingredi-
Health Assembly and this has been reflected in ents. As a result of the attention that has repeatedly
several resolutions. The most important was been drawn to the extent of counterfeit and
adopted in May 1988 (1) and requested WHO "to substandard products, including APIs, circulating
initiate programmes for the prevention and within these countries, the WHO Certification
detection of the export, import and smuggling of Scheme is being extended to include active
falsely labelled, spurious, counterfeited or pharmaceutical ingredients.
substandard pharmaceutical preparations and to
cooperate with the Secretary-General of the United It must be underscored that, at present, the legal
Nations in such cases when the provisions of status of APIs differs fundamentally from that of
international drug treaties are violated". finished dosage forms. APIs are not subject to
marketing authorization, although they are regulat-
The WHO Secretariat has implemented these ed indirectly through the drug master file (DMF).
resolutions through its normative activities as well However, this mechanism is only applied in highly
as in the formulation of guidelines. It has set out to developed countries and, even there, marketing
stimulate collaboration between regulatory authori- and labelling are not always regulated. Finished
ties, and a data base has been created within WHO dosage forms, on the other hand, are subject to
which contains some 700 case reports on counter- marketing authorization, and their labelling is strictly
feit finished dosage forms. Information and news regulated and requires display of the marketing
are exchanged regularly with other interested authorization holder, even when this is not the
parties and drug alerts are circulated to drug manufacturer.
regulatory authorities. Particular importance is
placed on the promotion of training for drug Because of the present lack of regulation of APIs, it
regulators and inspectors in those countries which is unclear whether the definition manufacture and
are most vulnerable to counterfeiting and related
manufacturer — as set out, for example, in the
activities.
WHO/GMP text (3) and in Directive 75/319/EEC —
The report of a WHO/IFPMA workshop held in 1992 also covers APIs. If it does, the opportunity arises
(2) defines a counterfeit medicine as one which is for a company or an individual involved in “partial
deliberately and fraudulently mislabelled with manufacture” — perhaps only repackaging — to
respect to identity and/or source. This definition is place their name on the label without further
also relevant to active pharmaceutical ingredients reference to the manufacturer responsible for the
(APIs) and underscores the need to establish their chemical synthesis. In many instances, this practice
true origin and to have this information reflected on provides a means to deliberately obscure the true
the label. Furthermore, it has become evident that provenance and quality of the material.
both developed and developing countries alike are
Case reports
confronted with similar problems. Counterfeits can
range from highly sophisticated copies which are The following reports on counterfeit APIs have been
almost indistinguishable from the authentic branded provided to WHO, and several of them clearly
product, to potentially dangerous substandard or illustrate the problem of labelling.
spurious preparations sold under branded or
generic labels.
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General Policy Issues WHO Drug Information Vol. 11, No. 3, 1997
Australia that the value-added nature of the work conducted
In February 1997, the Therapeutic Goods Ad- in Western Europe was greater than 50% of the
ministration of Australia drew the attention of the cost of the drug provided to Australia and hence the
Pharmaceutical Inspection Convention (PIC-PIC/S) company was entitled to claim that it was “made” in
Committee of Officials (4) to the practice of sub- that particular country. No action could be taken
stitution. The following cases, concerning APIs since the Australian companies had not committed
manufactured and supplied from Asia, are drawn an offence, and no prosecution of the overseas
from the evidence provided. companies from within Australia was possible.
However, because of lack of regulation of either the
An API, sulfamethoxazole, manufactured in India
manufacturing process, de novo synthesis, or
and delivered to an Australian firm, was partially
repackaging, and the routing of subsequent
substituted with sugar in the same particle size. The
exports, it is unlikely that the authorities in any of
substitution involved three of every 10 containers in
the countries involved would have had a basis for
the delivery. In another incident, inferior grade and
legal intervention.
rejected APIs were deliberately being placed at the
bottom of every third or fourth drum. During sub-
Many similar cases involve substitution, dilution or
sequent investigations, it came to light that this
adulteration, including the addition of subpotent
substitution often takes place immediately following
material to normal material in such a way as to be
departure of the consignment from the premises of
just able to pass pharmacopoeial specifications,
the legitimate manufacturer. Substitution racket-
and the switching of technical grade for pharma-
eers also gain access to sophisticated packaging
ceutical grade substances.
technology, including access to “tamper-proof”
security devices through co-opting company
United States of America
employees into providing packaging information, or
Information has also been received from the US
examples of the security, or the actual packaging
Food and Drug Administration's Office of Criminal
material from either the manufacturing plant or the
Investigation (5) regarding recent cases involving
printer of the labels.
APIs. The following investigation was carried out
Information on this particular situation was passed jointly with the US Customs Service.
on to all members of the PIC-PIC/S, and inspector-
ates were requested to report any similar problems In 1991, chemists at SmithKline Beecham Labora-
occurring in their own country. They were also tories notified the FDA of the delivery of counterfeit
asked whether a provision for “top, middle and oxytetracycline at their Animal Health Facility in
bottom” sampling of each container of API received Nebraska. Investigations discovered a conspiracy
from specified countries should be implemented. to import and distribute counterfeit bulk drugs. As a
consequence, a company and three individuals
The Therapeutic Goods Administration has also were fined for drug counterfeiting and money
investigated the following cases. laundering.
• An antibiotic API exported to Australia from a The investigation determined that company
country in Western Europe was in fact manu- employees were switching national drug codes
factured in Central America, then sent to the (NDCs) and producing counterfeit certificates of
European company where it was repackaged, analysis (COAs) reflecting false codes, false
reanalysed and issued with a new certificate of manufacturers and false batch-code information. In
analysis before being shipped to an affiliate in essence, the legitimate API was replaced with
Australia. The label and documentation gave the counterfeit API, or repackaged into drums that were
impression that the API originated in Europe. The different from those used by the legitimate manu-
Australian company only discovered the origin of facturer. The legitimate drug was therefore replaced
the product after an investigation. with a drug which purported to be the approved US
API, when in fact it was not.
• An orphan drug API, documented as originating
from a Western European country, was actually
Surprisingly, legitimate firms receiving the counter-
produced in Eastern Europe. The practice went
feit products did not bother to challenge the
undetected by the Australian affiliate company for
deliveries, even when they observed unusual or
about a decade until the Western European plant
mismatched drums. The drugs involved were
was closed down and information was disclosed.
chlortetracycline, oxytetracycline, tetracycline,
The argument provided by these companies was
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WHO Drug Information Vol. 11, No. 3, 1997 General Policy Issues
chloramphenicol, gentamicin, neomycin sulfate, Agency can request courts to confiscate property,
sulfadimidine, and methyldopa. money and other assets. Consignments of
pharmaceutical products are also seized. These
United Kingdom actions are intended to make counterfeiting
Examples of prosecuted cases (6) on which activities unrewarding and, as a deterrent, can be
information is provided from the United Kingdom more effective than fines or even imprisonment.
involve pharmaceutical products and not APIs.
However, the way in which they were handled could Contamination with diethylene glycol
equally apply to APIs and the following examples Experience with this compound indicates that
may be of interest. safeguards need to be applied to all materials
included in formulated dosage forms and not just
• A licensed UK wholesale distributor was found to APIs. Contamination or substitution with diethylene
have stocks of pharmaceutical products on pre- glycol in the manufacture of pharmaceutical pro-
mises other than those declared on the licence. ducts has resulted in the loss of over 500 lives —
These products were imports for which the mostly children — in Argentina, Bangladesh, India,
company did not have marketing authorization. Nigeria and, now, Haiti. WHO has sent warnings to
The products had been removed from original drug regulatory authorities in all Member States
containers and repackaged to disguise the origin, following these incidents.
and the expiry dates were extended beyond the
shelf-life. As a consequence of this investigation, Over 80 children died in the Haiti incident last year
the operating licence was withdrawn and the (7), and the case was investigated by the Haitian
company and its owner successfully prosecuted. authorities with the assistance of the US Food and
Drug Administration (FDA), the US Centers for
• An unlicensed trader was found to import large Disease Control (CDC) and WHO/PAHO. A special
quantities of pharmaceutical products from outside workshop on diethylene glycol contamination was
the European Union, and manufactured on subsequently held and a report will soon be issued
unlicensed sites. These were sold to pharmacies with recommendations on this particular problem. It
“from the back of a van”. The trader was arrested will also include simple analytical test procedures
and the stock seized, as were the proceeds of the that allow the detection of diethylene glycol down to
sales. Both the trader and an accomplice were a low content limit.
successfully prosecuted and pharmacists pur-
chasing the products were reported to their Despite the fact that the pharmaceutical company
professional association. in Haiti ordered glycerol from a company in
Germany, the material was originally shipped from
• A licensed wholesaler who substituted batch Xiangang (China) via the free port in Rotterdam
numbers on a substantial quantity of stock he was (Netherlands) to Port-au-Prince. It is clear that
not licensed to sell was successfully prosecuted. throughout a series of complicated and numerous
transactions, vital information on the provenance
Cases still under investigation in the UK involve and nature of the material was obliterated on
illicit manufacture, obtaining APIs from unlicensed documents and product containers.
sites in the Far East, assembling products and
proposing these as the genuine product, and The pharmaceutical company in Haiti used the
assembling products containing only 50% of the product traded in this way for the preparation of
API. paracetamol syrup and oral drops for neonates.
Following the incident, the manufacturer was visited
A counterfeit product in the UK tends to be a by an FDA inspector and found to be in violation of
prescription-only medicine and one for which either basic GMP principles, since the incoming starting
demand and sale price are high, or for which there materials were not being tested, no in-process
is a specialized highly-priced demand. quality control was implemented, and certificates of
analysis were not always available. According to a
Prosecutions generally result in fines and, newspaper article on this case, the manufacturer
occasionally, a prison sentence. United Kingdom stated that he had ordered the material from
legislation permits sequestration of assets gained Germany to be certain of its quality.
by unlawful activity, and the Medicines Control
What can be done?
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General Policy Issues WHO Drug Information Vol. 11, No. 3, 1997
There is now sufficient evidence of the international on GMP, inspection and drug registration.
circulation of counterfeit and substandard APIs and
other starting materials used in the manufacture of Pharmaceutical manufacturers,
medicines. The magnitude of this trade may be wholesalers and traders should:
unknown, but it is certainly far greater than is evi-
dent from the case histories that have filtered • be cautious in the procurement of APIs and
through into the public domain. The range and finished products, and when introducing products
extent of illicit activities, even in highly regulated into the distribution chain.
countries, points to an urgent need for counter-
• maintain vigilance in detecting counterfeiting or
measures which should be coordinated on a global
substitution of dosage forms and APIs.
basis. The following recommendations may provide
ways to consolidate efforts against unlawful and • share information with regulatory authorities. This
dangerous activities. information should be handled with due discretion
to avoid loss of confidence in legitimate products.
Drug regulatory authorities should:
• rigorously implement GMP in the manufacture of
• extend their regulatory mandate to cover manu-
APIs (3).
facturers of APIs — particularly with regard to
inspection of GMP compliance, and impose Manufacturers of finished dosage forms
rigorous requirements for labelling and certificates
should:
of analysis for consignments moving in interna-
tional commerce. • buy APIs, whenever possible, from the original
manufacturer or, when through traders, insist on
• introduce regulations that require APIs and all
transparent and full documentation concerning the
other starting materials intended for the formu-
origin, and demand certificates of analysis.
lation of medicinal products to be clearly labelled
“for pharmaceutical use” or with a suitable
• be aware of their responsibility and liability in
pictogram.
assessing and ensuring the quality of the APIs
• establish within the regulatory authority a multi- and other starting materials that they use, and the
disciplinary group to investigate illicit activities rigorous conditions, as outlined in GMP (3), to be
promptly and professionally. applied in those exceptional situations where
reliance is vested in the supplier’s certificate of
• monitor free ports and strengthen collaboration
analysis in place of a full re-analysis.
with law enforcement agencies including customs
officials, and offices of criminal investigation, at
Interested parties must decide to what extent these
national and international level.
recommendations are realistic. The impact of
• seek to enact legislation that permits seques- additional laws and regulations will depend on their
tration of assets gained by unlawful activity and implementation, and this will require increased
seizure and destruction of products involved. inspection capacity and more resources. The full
responsibility of the manufacturer cannot be
WHO should: overstressed and the supplier must inform the
manufacturer of the true origin of the API. Many
• develop a network of technically competent small manufacturers in developing countries may
officials within national drug regulatory authorities have little bargaining power to insist on this trans-
with a view to ensuring timely exchange of parency, and action needs to be considered with
information, both on cases of counterfeiting and urgency to protect all concerned.
on any countermeasures taken at national level.
References
• act as a clearinghouse for the exchange of
information on counterfeit pharmaceuticals and 1. World Health Assembly resolution WHA 41.16.
APIs.
2. World Health Organization. Counterfeit drugs: report of
• develop guidelines for the certification of APIs
a joint WHO/IFPMA workshop. WHO/DMP/CFD/92. WHO,
moving in international commerce and strengthen Geneva 1992.
GMP.
• continue to promote the use of WHO guidelines
3. WHO Expert Committee on Specifications for Pharma-
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WHO Drug Information Vol. 11, No. 3, 1997 General Policy Issues
ceutical Preparations, Thirty-second Report. WHO tions addressed to WHO dated 28 February and 7 April
Technical Report Series, Number 823, WHO, Geneva, 1997.
1992.
6. Letter from Medicines Control Agency, United Kingdom
4. Note from the Therapeutics Goods Administration to WHO dated 2 June 1997.
(TGA) entitled Substitution of Active Pharmaceutical
Ingredients, distributed during PIC-PIC/S meeting of 7. Pan American Health Organization. Deaths in Haiti
officials in Geneva in February 1997. Communication from renal failure epidemic. PAHO News Release, 7 August
the TGA addressed to WHO dated 3 and 25 March 1997. 1996.
5. Letters from the US FDA Office of Criminal Investiga-
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WHO Drug Information Vol. 11, No. 3, 1997
Quality Assurance Issues
The importance of analytical Once drug registration has been established,
compliance of the approved products with quality
procedures in regulatory control
standards must be sought. In some instances,
where a country depends largely on imported
Thomas Layloff
finished products, a regulatory authority will apply
Division of Drug Analysis the same methods of analysis and quality
United States Food and Drug Administration standards as those in the country of product origin.
St Louis, MO, USA Since little harmonization has so far taken place
among the major pharmacopoeias, this could give
A regulatory authority responsible for the quality of
rise to a situation where several different quality
the pharmaceutical products distributed within its
standards and methods of analysis are in use for
jurisdiction is confronted with many challenges in its
the same product within a given country or market
efforts to assure the public health of its citizens.
area.
One of the primary tasks of regulation is to deter-
mine which products can safely be allowed onto the
The multiplicity of standards and methods applic-
market. This is usually accomplished through a
able to the same product can result in an extremely
drug registration system.
complicated situation for the regulatory control
services, such as the need to have access to each
The laboratory resources needed to support the
pharmacopoeia and the specific equipment and
regulation of any given market will depend heavily
reagents used in the country of origin. In an effort
on whether or not the products are manufactured
to remedy this situation, it has been suggested that
within that market area or whether they are largely
the establishment of a unique analytical monograph
imported. Consequently, if the market is important
for registration purposes and an accompanying
and handles large quantities of products, the official
quality standard for each finished dosage form
laboratory will need sufficient resources to provide
would help to ensure that the approved product
an analytical service which will assure the quality of
conforms to the same standards. However, this
these products. This is especially important when
undertaking would constitute an immense task, and
products proposed for entry into the area have
an easier solution may be the adoption of specific
been manufactured in facilities which have not had
monographs and quality standards for each
direct inspection for compliance with good manu-
approved product based on existing pharmaco-
facturing practice (GMP).
poeias.
In many developing countries, however, an
When a pharmaceutical product is received at a
unfortunate combination of two factors exists. On
port of entry, it is subject to controls to determine its
the one hand, there is a predominance of imported
marketing status, labelling, and claimed ingredients.
finished products and on the other, a lack of
These determinations should be made on all
adequate analytical services. Product quality can
products entering the market area. In order not to
be better assured if an inspection force is available
hold up shipments, analytical tests to substantiate
to periodically visit manufacturing sites and review
the claimed product characteristics are needed
production records. Although the United States
rapidly and as near to the port of entry as possible.
market is supplied mainly by manufacturers
However, this is not always possible, since a
operating within its borders, the number of finished
market area can very often be serviced by multiple
dosage forms entering the country is steadily
ports of entry and standard laboratory services are
increasing. It is furthermore expected that the
not necessarily available at all of them. In this
current globalization of the pharmaceutical market
situation, a preliminary screening can be made of
will also give impetus to increased trading in
the product to ascertain the presence of the active
finished dosage forms and this situation will
ingredient and the claimed amount. In order to be
demand even greater efforts by inspection and
effective, this analysis must be carried out before
laboratory services.
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WHO Drug Information Vol. 11, No. 3, 1997 Quality Assurance Issues
release of the goods. If this is not the case, the Unfortunately, in the case of the LRM, several days
products will be distributed throughout the country or weeks may be needed to set up the analytical
and regulatory controls would be ineffective in the equipment and prepare the reagents. In addition,
event that a product needs to be withdrawn. An many LRM use liquid chromatography (LC) or gas-
array of chemical methods of analysis are available liquid chromatography (GLC) methods. The United
to provide information on the quality of a product States Pharmacopeia, for example, contains over
and ensure that it complies with the regulatory 800 monographs requiring LC and 150 monographs
requirements in force. This availability is, however, requiring GLC. As can be imagined, equipment for
dependent on many factors such as funding and this type of analysis requires a relatively large
the extent to which these services are required. capital investment, with the related costs for trained
Consideration must additionally be addressed to operators and maintenance staff. In the United
sources of funding for staff, training, equipment, States, a high-performance liquid chromatograph
maintenance, supplies and running costs. will cost approximately $25 000 to $65 000
depending on the accessories and attachments,
A preliminary screening at a port of entry will and a gas-liquid chromatograph will cost between
provide information on whether a product is $15 000 and $70 000, although less expensive
approved for distribution, is properly labelled, equipment may be available in other regions of the
contains the correct ingredient in the claimed world. In order to keep the equipment operational
amount and complies with legal specifications. It is and to replace worn parts, a laboratory will need an
at this point that counterfeit products can most additional 5–10% of the initial cost for maintenance.
conveniently be identified. Screening techniques It is important to have easy access to parts and
include WHO basic tests, and other simple test circuit boards in addition to the necessary reagents,
methods. However, the use of thin layer chroma- reference standards and supplies, the cost of which
tography (TLC) has been shown to be particularly may represent a further 5–10% of the initial outlay.
useful during this preliminary screening phase. The Furthermore, operation of the equipment can be
tests are cheap and quick, require a low capital affected by environmental factors such as
investment and have low operating costs. TLC temperature and humidity.
requires minimum laboratory resources and analyst
Experience with running an LRM facility suggests
skills, which means that competent personnel can
that, in order to be efficient, it should be equipped
be easily trained in their use. Any sample found to
and staffed at a level over and above minimum
fail the necessary tests using this method could
requirements and it is often preferable to have three
then be subjected to analysis according to the legal
or more units of identical equipment so that aber-
reference methods (LRM) carried out by the
rant results can be confirmed by a second appara-
regulatory control laboratory. Notwithstanding the
tus. Also, modules can be switched around or
simplicity of the method, TLC is reliable enough to
exchanged when defective parts are identified.
support decisions on whether entry should be
Multiple units of identical apparatus will also reduce
denied for products which fail significantly.
the need for space to house spare parts and
consumable supplies required to keep the equip-
Once a product has entered the market and has
ment operational.
been distributed, it falls within the jurisdiction of that
market. This generally means that any regulatory The acquisition of expertise is also an important
action taken against the product must be based on factor if the laboratory is to be run successfully. In
LRM as determined by legislation. Thus, in addition contrast to the minimum skills needed for applying
to providing preliminary screening of imported the preliminary testing methods, personnel carrying
products, regulatory authorities must maintain, or out LRM need higher levels of training. In the more
have access to, facilities suitable for conducting complex laboratory environments, it is useful to
LRM which will confirm or refute the preliminary have several persons skilled in the same tech-
screening results. These facilities are also useful for niques working together in order to stimulate the
carrying out special surveillance activities. Prelimi- functioning of the laboratory and discuss details of
nary screening, with possible confirmatory LRM the work. This strengthens the analytical capability
activities, is therefore essential before a product of the services provided and assists in the applica-
can be released into the market area, and to ensure tion of the more complicated instrumental
that the product will comply with the claimed expiry techniques.
date and required quality standards.
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Quality Assurance Issues WHO Drug Information Vol. 11, No. 3, 1997
Because of the costs involved, LRM testing can circulating within its boundaries and those entering
only be performed on a fraction of the products the market area from other parts of the world. This
actually in circulation and in many cases this is can only be achieved through a three-tiered system
below 1% of the total. For example, in a country of preliminary and legally required methods (LRM)
where 35 000 prescription-only medicines and backed up by advanced analytical methods. This
115 000 over-the-counter products are on the will enable large numbers of products to be
market, there would be 150 000 batch samples to screened to ensure identity and content amount,
be collected and analysed. For each product, with an LRM level to validate the results of these
analysis would include assay, content uniformity, techniques, confirm marginal findings and
release rate and identity and an approximate total determine conformity with legal requirements.
of 30 analytical results would eventually be Advanced analytical methods will be relied on when
produced taking approximately one week per sophisticated counterfeit products need to be
sample to complete. For the sake of statistics, it identified or to confirm or refute circumstances of
may be worth while for a regulatory authority to product-related, epidemiological events.
collaborate with industry in estimating the number
of batches manufactured annually within the Further reading
territory in order to compare these figures with the
number of batches tested for compliance. 1. Vincent-Ballereau, F. et al. Contrôle de qualité des
médicaments essentiels dans les pays en développe-
ment. Méthodes standardisées (Standardized methods for
In some special cases, a product may need further
the quality control of essential drugs in developing
testing using advanced analytical methods. For
countries). GEEP, Centre Hospitalier, Villeneuve St-
example, in the case of an epidemiological
Georges, France, 1993.
aberration associated with a specific product or in
detection of counterfeit or spurious products. These 2. World Health Organization. Basic tests for
methods will also provide a means of verification of pharmaceutical substances. WHO, Geneva, 1986.
the techniques proposed by manufacturers in the
registration dossiers and may assist in carrying out 3. World Health Organization. Basic tests for
research into detecting unexpected impurities, pharmaceutical dosage forms. WHO, Geneva, 1991.
undeclared or substituted excipients or other
4. Drug identification and assay sheets, 1988—1991.
characteristics which need examination. In this
Syndicat National de l’Industrie Pharmaceutique (SNIP),
case, mass spectrometric, nuclear magnetic
France, 1992.
resonance, or X-ray powder diffraction analysis
may be required. This can only be carried out by 5. Ministry for Health, Cairo, Egypt. Analytical mono-
skilled staff backed by an armamentarium of graphs of essential drugs. Pharmaco Information Centre,
sophisticated equipment normally available only at National Organization for Drug Control and Research
universities and research institutes. Access to this (NODCAR), Ministry for Health, Cairo, Egypt, 1994.
expertise should be facilitated whenever possible
6. Kenyon, T.A., Kenyon, A.S., Sibiya, T. Drug quality
by the authorities.
screening in developing countries: Establishment of
an appropriate laboratory in Swaziland. Bulletin of the
It is therefore important that the regulation of
World Health Organization, 72: 615–620 (1994).
pharmaceutical products in every country should
include responsibility for the quality of products
130