the value of the certificate of pharmaceutical product in registration ...

Drug Information Journal, Vol. 36, pp. 163–167, 2002 0092-8615/2002
Printed in the USA. All rights reserved. Copyright © 2002 Drug Information Association Inc.
THE VALUE OF THE CERTIFICATE
OF PHARMACEUTICAL PRODUCT
IN REGISTRATION OF
MEDICINAL PRODUCTS
ALISTAIR DAVIDSON, BAGR
Vice President & Regulatory Director, GlaxoSmithKline Asia-Pacific, Singapore
ANTHONY J. GRACE, BSC, PHD
Executive Director, Intercontinental and Licensing Strategy & Registration, Pfizer Limited, Kent, England
ECKART W. SCHWARZ, MB,CHB, MPHIL
Vice President, International Regulatory Affairs, GlaxoSmithKline plc, Middlesex, England
COLIN VICKERS, BSC
Senior Director, Intercontinental Strategy & Registration, Pfizer Limited, Kent, England
This article reviews the value and importance of the World Health Organisation Certificate
of Pharmaceutical Product (CPP) scheme. The scheme has largely streamlined a part
of the registration procedure associated with imported medicines. It provides a significant
assurance to regulatory authorities that imported medicines have been evaluated against
rigorous and publicly-defined standards of quality, safety, and efficacy and have been
approved for marketing. It also provides confirmation that the product is manufactured
in accordance with the requirements of Good Manufacturing Practice.
A more effective use of the scheme may provide drug regulatory authorities with an
opportunity to deploy their resources to other areas of medicines regulation to the greater
benefit of the public health. Six recommendations are made regarding how use of the
scheme could be enhanced to improve patients’ access to new medicines more rapidly:
1. CPPs should be required at the regulatory approval stage rather than at submission
of the application; 2. Regulatory agencies should develop goals to approve products
within one month after receiving the CPP; 3. CPPs should be acceptable from nonsource
countries, that is, a selection of issuing authorities recognized for their highly developed
regulatory review processes; 4. CPPs should be accepted from recognized authorities
regardless of marketing status in that country; 5. Health authorities with limited resources
should consider approving the product on the basis of a CPP alone; and 6. Legalization
of CPPs should not be required.
Key Words: Certificate of Pharmaceutical Product (CPP); World Health Organisation;
Importation; Medicines; Regulatory
Reprint address: Dr. A. J. Grace, IPC 001, Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United
Kingdom.
163

164 A. Davidson, A. J. Grace, E. W. Schwarz, and C. Vickers
INTRODUCTION In addition to the requirement for a scien-
THE WORLD HEALTH Organisation at-
tempts to ensure and support the safe use of
effective, high-quality medicines in countries
tific dossier, many regulatory authorities have
developed two regulatory strategies to deal
with the approval of imported medicines:
around the world where drug regulatory systems
are less well developed than, for example,
in Europe and North America. It sup-
ports this activity with a series of guidelines,
training for members of appropriate drug regulatory
authorities, and an essential drugs
list, to name a few examples. From the point
of view of the pharmaceutical industry, which
includes generic drug manufacturers, over-
1. They require samples so that they can analyze
each medicine to ensure that it complies
with the specification included in the
application for approval to market, and
2. They demand evidence that each medicine
has been approved and marketed in one
or more countries with highly developed,
well-resourced regulatory systems.
the-counter consumer health care suppliers,
and the research-based companies, one of the
major innovations by the World Health Organisation
toward the end of the twentieth century
was the introduction of the CPP (1). This
brief paper evaluates the value and utility of
the CPP in relation to both the regulatory
authorities and the pharmaceutical industry.
Such evidence of approval and marketing,
which used to be called a Certificate of Free
Sale, historically was highly variable in for-
mat and content depending on the country
which provided it. In many cases, it also was
in a language that the regulatory authorities
in importing countries did not necessarily
understand. In consequence, the regulatory
HISTORICAL PERSPECTIVE
authorities generally required that each Certificate
of Free Sale be legalized by their em-
Governments have a duty to their citizens to bassy or consulate in the issuing country in
protect and promote public health. One aspect order to provide the authorities with an assur-
of that duty is to ensure, as far as possible, ance that it was a valid document. The World
that commercially available medicines are Health Organisation developed the CPP in or-
effective and of acceptable safety and quality. der to simplify and improve this process.
Most countries thus have regulatory authori- CPPs are intended to be issued in a stanties
to regulate market entry of new products. dard format such that they are more user-
Often they also control advertising, inspect friendly for recipient regulatory authorities.
pharmacies, ensure that local pharmaceutical
manufacturers use Good Manufacturing Prac-
They provide the following information:
tice (GMP), and so on. Many countries have • Confirmation that the regulatory authority
limited resources to support the approval pro- has reviewed the application and deemed
cess for new, research-based medicines, line it satisfactory, on the basis of quality,
extensions (additional formulations or clini- safety, and efficacy to be placed on the
cal indications), or manufacturing changes. market,
The same applies to consumer health medi- • Details of the date of approval and the regcines,
generic medicines and, indeed, to tra- istration number,
ditional or herbal medicines.
• Confirmation that the medicine is manufac-
The issue is particularly acute, however, tured in accordance with the requirements
in relation to imported medicines. The regu- of GMP,
latory authorities concerned have few or no • The formulation of the medicine,
resources to inspect foreign manufacturers • Information on whether the product is mar-
and thus there is the potential risk that im- keted. A CPP may be issued in those cases
ported medicines may not have been manu- where a medicine is not marketed in the
factured to a high quality in accordance with country providing the CPP. This may occur,
GMP.
for example, when the medicine is for a

The Value of the Certificate of Pharmaceutical Product 165
tropical disease although the manufacturer at any time after the supply of a CPP, or if
is in a temperate country, and
an issue of safety arose. The availability of
• In many cases, the issuing country will also a CPP, however, provides an element of
attach a copy of the authorized product in- choice for regulatory authorities that preformation.
viously was not present. That choice is how
best to deploy their resources in order to pro-
THE VALUE OF CPPS
tect and promote the public health.
Is it necessary, therefore, for regulatory
A CPP provides definitive evidence, in a rela- authorities in importing countries to undertively
standard format, that a particular medi- take an independent scientific and medical
cine has been evaluated and approved for mar- evaluation of a dossier of data on a medicine?
keting in the country that issued the CPP. In the This question does not suggest that regula-
case of a CPP from the European Medicines tory authorities should not fulfill their duty
Evaluation Agency, which is a transnational of care in relation to public health and medi-
authority, the document indicates that the medicines, as mentioned earlier.
cine concerned is approved for marketing in all Also, is a full scientific and medical eval-
of the Member States of the European Union uation of a registration dossier going to add
(currently Austria, Belgium, Denmark, Fin- value relative to the assurances of quality,
land, France, Germany, Greece, Ireland, Italy, safety, and efficacy provided by a CPP? It is
Luxembourg, Netherlands, Portugal, Spain, unlikely, unless there are clear reasons why
Sweden, and the United Kingdom).
a medicine should affect a particular commu-
The majority of CPPs are issued by terri- nity of patients in a manner different than
tories involved in the International Confer- those in the territory providing the CPP, for
ence on Harmonization (ICH) process (Ja- example, due to significant differences in diet
pan, the European Union, and the United or the local practice of medicine.
States) or by countries such as Canada and Similarly in terms of regulatory samples,
Australia that rapidly adopt final ICH guide- is it a valuable use of regulatory authorities’
lines. As such, the standards for development resources to analyze them during the approval
and approval of medicines in these territories process? A more valuable utilization of regu-
are well established and publicly available. latory agency resources would be to monitor
Regulatory authorities in importing countries the quality of products placed on the market
thus can have an extremely clear vision of after approval, to ensure that the quality is
the standards of Good Laboratory Practice, maintained over time and that counterfeit
Good Clinical Practice, and GMP to which medicines are not being sold. The choice faca
CPP relates for a particular medicine. In ing regulatory agencies in importing coun-
essence, such a CPP indicates that the medi- tries thus is whether to continue to provide
cine concerned is effective, of satisfactory resources, effectively duplicating a regula-
safety and quality, and that it was developed tory evaluation that has taken place else-
in accordance with the current requirements where, or to rely on the assurances provided
of medical science. by CPPs and redeploy those resources to
A regulatory authority or agency which other areas of medicines regulation. Such
issues CPPs is obliged by the World Health other areas of importance for public health
Organisation guideline to notify all of the purposes may include regulation and inspecrecipient
countries of a CPP for a particular tion of local manufacturers, regulation and
medicine should it subsequently be consid- inspection of storage and distribution of medered
that that medicine may no longer be icines, ongoing evaluation of information
acceptable for marketing. Thus, regulatory provided with medicines by manufacturers,
authorities in importing countries would be control of advertising to ensure that it is in
informed, for example, should a manufac- compliance with the marketing authorizaturer
fail to comply with GMP requirements tion, regulation and inspection of pharma-

166 A. Davidson, A. J. Grace, E. W. Schwarz, and C. Vickers
cies, planned surveillance and sampling of thorities that do not need a CPP for submis-
the quality of marketed products, and pharsion or approval.
macovigilance. This list is not intended to be The impact of this is to delay the availabildefinitive,
it is simply an example of other ity of new medicines to patients. As the regu-
activities that help ensure and protect public latory evaluation process in the ICH-associ-
health and which must be managed by the ated territories, for example, can take more
appropriate government authorities. than a year, this time period must be added on
In the pharmaceutical industry there is a to the time taken for approval of medicines in
clear understanding that any regulatory agency importing countries where a CPP must be
in any country has the right to request sam- supplied with the application for marketing
ples of a medicine as part of an application to authorization. This appears to be an unneces-
market, and also to raise scientific and medical sary impediment to marketing approval and
queries when there are concerns regarding adds nothing to the protection and promotion
the impact of that medicine on the public of public health. Furthermore, as the success
health. The advent of the CPP and its wide- rate of all applications in ICH regions is im-
spread usage during recent years, however, proving—over 95% of all applications are
suggest that its major value to regulatory agen- approved (3), regulatory authorities should
cies in importing countries may be to allow have confidence in commencing review prior
them to focus scarce resources more effec- to CPP availability.
tively to the benefit of public health.
Another issue facing those wishing to gain
The World Health Organisation recom- marketing authorizations is that some regula-
mends a standard format for the CPP. Unfortory agencies insist that a CPP for a medicine
tunately, however, there are some regulatory should be provided from the country where
agencies in importing countries that still in- it is manufactured. In fact, the requirement
sist on legalization, even though the World is now irrelevant and should be discontinued.
Health Organisation guideline does not men- A country that does issue a CPP will have
tion that this is necessary. This situation leads assured itself of the medicine’s quality, safety,
to confusion and thus, more significantly, has and efficacy and that it is manufactured in
the potential to delay access to new medi- accordance with GMP. This will be either by
cines. For example, a recent survey of a num- direct inspection of the manufacturing site(s)
ber of companies in Europe indicated signifi- or by mutual recognition of a satisfactory
cant variation in their understanding of CPP inspection carried out and reported by an-
legalization requirements across a range of other competent regulatory authority.
80 countries (2).
As such, therefore, a requirement for a
The utility of CPPs in support of applica- CPP from the manufacturing source country
tions to market medicines is variable depend- adds no value or additional assurances as to
ing on the importing country concerned. In the medicine’s quality, safety, and efficacy.
some countries, the regulatory agency will In addition there is no consistent definition
accept an application for marketing authori- of site of manufacture and, as manufacturing
zation in the absence of a CPP, on the basis strategies develop and manufacturing sites
that one must be provided before the applica- become more specialized, it becomes even
tion is finally approved. Other regulatory au- more important to rely on global GMP stanthorities,
however, will not accept a dossier dards. An example would be the secondary
unless it is accompanied by a CPP at the packaging of a variety of products not neces-
time of submission. Even then, the time to sarily manufactured at a particular site but
complete evaluation (often there are long packaged and quality released at the site. Fi-
queues for the assessment in regulatory agen- nally, certification confirms that the regula-
cies) is a lot longer and much less predictable tory authority has evaluated the application
than those established by the regulatory au- and approved it on the basis of quality, safety,

The Value of the Certificate of Pharmaceutical Product 167
and efficacy. Issuing a CPP confirms quality, such as one month, after receiving a CPP.
safety, and efficacy and is not linked to mar- This would be of value from a public health
keting status (ie, whether a product is sold point of view,
in a given market.)
• CPPs from recognized health authorities
(eg, European Union and Member States,
CONCLUSIONS
The World Health Organisation’s CPP scheme
has largely harmonized a part of the registration
process for medicines that are being imported
from another country. The major value
of a CPP to an importing country is that it
provides significant assurance that the medicine
to which it relates has been rigorously
evaluated to defined, published standards,
and that it has been approved for placing it
on the market. By relying more heavily on
this assurance, rather than repeating a scientific
and medical assessment of data, regulatory
agencies in the importing countries have
an opportunity to refocus scarce and valuable
resources onto other aspects of medicines regulation
to the greater benefit of the public health
United States, Japan, Canada, Australia)
and not only the source country should be
acceptable,
• CPPs should be accepted from recognized
authorities regardless of marketing status
in that country,
• Regulatory agencies with limited resources
for reviewing the application should con-
sider approving the product on the basis of
a CPP alone, keeping technical data pro-
vided for future reference, and
• As recommended by the World Health Or-
ganisation, legalization of CPPs should not
be required. Legalization adds no value and
increases the duration of the registration
process.
and safety.
REFERENCES
Furthermore, the use of CPPs could significantly
benefit both regulatory agencies
and patients based on the following recom-
1. World Health Organisation Expert Committee on
Specifications for Pharmaceutical Preparations 34th
Report. WHO Technical Report Series No. 863. Ge-
mendations:
neva, Switzerland: World Health Organisation; 1996:
155–177.
• CPPs should be required before approval
to market is granted, not at the time of
application. This will reduce the time to
2. Transnational Regulatory Affairs Group, Association
of the British Pharmaceutical Industry. Survey of
member companies regarding use of Certificates of
Pharmaceutical Product. London, England: Associa-
market, potentially by a year or more, and tion of the British Pharmaceutical Industy; April 2000.
thus, is of benefit to patients, health care 3. Walker S. Trends in Pharmaceutical Research and
professionals, and public health,
• Regulatory agencies ideally should develop
goals such that they aim to approve each
Development, DIA Regulatory Forum—Harmoni-
sation of Drug Regulations in Latin America: The
Road to Quality, Safe, and Effective Medicines, Santi-
ago, Chile. Epsom, England: Center for Medicines
marketing application within a defined time,
Research; May 2001.