Transcript 中国药用活性成分 （原料药）的管理法规 - World Health Organization

中国原料药的监管体系
The API Regulation System of China
孙悦平 (SUN Yueping)
世界卫生组织TB FDC项目技术顾问
2010年3月
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Contents
1. Related background
2. Differences in legal definition of drug and approval
system
3. Difference in regulatory system of drug substances
between China and foreign countries
4. How to link Chinese and foreign regulatory systems of
drug substances
5. Summary: the importance of coordinating global
regulatory system of drug substances
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1. Related background
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The global position of drug substance industry in China:
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China has become the biggest manufacture and export country of drug
substance in the world. The export amount of drug substance reached 17.58
billion dollar and increased by 30% compared with the same period in the
past year.
The technical documents of drug substance and specifications of
production in many manufacturers have been brought in line with
international practice. Until the end of 2009, the number of Chinese API
DMF that accepted by FDA had reached 840, and the number of CEP
certificates that received by Chinese manufacturers had reached 270.
The quality of drug substance is related with drug safety and China is at
the foremost end of global drug industrial chain. Therefore, the
administration of drug substance in China is related with the establishment
of global drug safety system that including western countries.
However, the drug regulatory system in China is greatly different from
that in western countries. The technical standards and GMP also lack of
mutual acceptance. As a result, how to coordinate Chinese laws and
regulations on drug administration with foreign ones becomes a common
topic for both Chinese and foreign drug authorities.
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1. Related background
The administration on drug substances by Chinese
laws and regulations
The administration on drug substances by European and
American laws and regulations
Certification and licensing of pharmaceutical
manufacturers：Drug Manufacturing Certificate
Not accepted. No special approval is needed.
Drug substance product: registration approval number
Not accepted. Individual DMF/COS document review
Quality system licensing: GMP certificate
Not accepted, individual GMP on-site audit/examination
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Problems that resulted from inconsistency of laws and regulations:
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Manufacturers that do not obtain drug manufacturing certificate in China and API
products that do not have registration approval number can be approved in Europe
and America. Since they are not within the monitoring range of SFDA, they will
induce dispute on monitoring responsibility, if there’s any quality problem or
accident.
The intermediate trader can purchase API products which are produced by nondrug manufacturing enterprise, change the package or label and then sell to final
customers.
It is quite necessary to establish consistent monitoring system on drug substances so
as to ensure the safety of international drug market.
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2. Differences in legal definition of drug and
approval system
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Difference in drug definition:
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Definition of drug in European and American laws:
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EU 2001/83/EC: Any substance or combination of substances
which may be administered to human beings …… is likewise
considered a medicinal product.
USA 21 CFR 314: Drug product means a finished dosage
form, …….
Obviously, drug is only limited to preparations that can be
applied in human body. Drug substance does not belong to
the category of drug and its administration is different
from drug.
Only drug can be marketed, and drug substance can not
be marketed.
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2. Differences in legal definition of drug and
approval system
Definition of drug in Drug Administration Law of PRC:
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Article 102 in bylaws of the 10th chapter of Drug Administration
Law: Drug means a substance that is used for preventing, treating
or diagnosing human diseases, that can regulate physiological
function purposively, and that is specified for indication or
function, usage and dosage, including Chinese crude drugs, cut
Chinese crude drugs, Chinese prepared medicine, chemical drug
substances and their preparations, antibiotics, biochemical drugs,
radiopharmaceuticals, serum, vaccines, blood products and
diagnostic drugs, etc.
The above definition confuses drug substances, such as chemical
drug substances, Chinese crude drugs and serum with final
preparations and does not limit drug to a product range that can
be marketed. As a result, the whole frame structure and concept of
drug administration in China is greatly different from that in
western countries.
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2. Differences in legal definition of drug and
approval system
Differences in drug approval system:
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Marketing authorization (MA): MA holders are allowed to sell
specified preparations. The products must comply with the
specifications in GMP. MA holders can manufacture the products
in their own manufacturing sites, and they can contract out the
manufacture of a product to a Toll Processor.
Manufacturing authorization: Approved preparations must be
produced by certificate holders. Or the certificate holders must
possess production sites that comply with GMP and only when
their production capacity can not meet the requirement of market
can a Toll Processor be out-contracted.
Manufacturing authorization system is practiced in China, while
Marketing authorization system is practiced in European and
American developed countries.
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2. Differences in legal definition of drug and
approval system
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Effect of differences in drug definition and authorization
system on drug substance regulatory system in China :
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Drug substances that can not be marketed can be registered
individually and obtain independent approval number, so the drug
marketing authorization system is hard to be practiced.
The requirements on registration of drug substances are hard to be
brought in line with the CTD format. For example, ask the
manufacturers of drug substances to provide data of clinical trials
on their products.
Although new Measures for the Administration of Drug Registration
require that the source of drug substances of pharmaceutical
products must be fixed, manufacturers of pharmaceutical product
still can not master technical data of drug substances (such as
partially published data of DMF). In addition, manufacturers of
drug substances still do not have the obligation of informing their
final customers changing information about production technology.
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2. Differences in legal definition of drug and
approval system
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Modification on legal system of drug administration:
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The manufacturing authorization system of pharmaceutical products in
China may be changed into marketing authorization system. Related
departments have got prepared to propose opinions on the modification of
“drug administration law”.
The manufacturing authorization system of drug substances in China may
still be maintained, since this system has unique advantages compared with
the regulatory system of drug substances in Europe and America:
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Although drug substances should not belong to marketable products, they
are the most important starting materials in drug production. Therefore, the
practice of manufacturing authorization system is the key point in
strengthening government monitoring.
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Compared with the DMF regulatory system in Europe and America, the
release of manufacturing authorization to drug substance products by
government and on-site GMP examination ensure the reliability of quality
and reduce the auditing pressure assumed by manufacturers of
pharmaceutical products.
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3.
Difference in regulatory system of drug substances
between China and foreign countries
Requirements on manufacturing of drug substances in China:
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First of all, qualification for drug manufacturing is required, i.e.
obtaining drug manufacturing authorization.
Drug substances must pass through registration approval and obtain
approval number for drug manufacturing.
The manufacturing sites of drug substances must pass through GMP onsite examination, obtain GMP certificate and accept the monitoring of onsite examination institution from SFDA.
The manufacturing must be performed according to approved technology.
Major changes can only be practiced after supplementary application has
been proposed to SFDA.
Import drug substances must apply for registration authorization for
import drugs.
In principle, export drug substances should be registered and subjected to
examination or authorization by GMP regulatory system according to the
law and regulation of the import country.
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3. Difference in regulatory system of drug substances
between China and foreign countries
Requirements on the usage of drug substances in China :
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Fixation of suppliers: Drug substances must be purchased from
manufacturers that possess the above qualifications and the source
must be fixed. Additional or changed manufacture of drug
substance can only be adopted after supplementary application
has been proposed to SFDA and been approved.
Auditing of suppliers: Quality auditing should be performed
according to GMP requirements on manufacturers of drug
substances, which is not strict. Formal examination on the
qualification of suppliers is more emphasized. The incoming new
edition of GMP will enhance such requirements.
Technical data of drug substances: It is required in the laws and
regulations that technical data provided by manufactures of drug
substances are only limited to specification, quality standard,
examination methods, etc. Other data should be accumulated by
the manufacturers of pharmaceutical products in their own files
on suppliers.
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3. Difference in regulatory system of drug substances
between China and foreign countries
Requirements on manufacturing of drug substances in
European and American developed countries :
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Drug substances can not be registered individually, and their drug
master files are only a part of the registration files of
pharmaceutical products.
If there is any change in the manufacturing technology of drug
substances, the manufacturers must inform the manufacturers of
pharmaceutical products who use their products to do application
of modification.
Manufacturers of drug substances must organize their production
according to GMP (ICH Q7), accept GMP compliance auditing of
final customers or official examination.
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3. Difference in regulatory system of drug substances
between China and foreign countries
Requirements on use of drug substances in European and American
developed countries :
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Registration: DMF (or called as ASMF) of drug substances should be
included in the marketing application documents of pharmaceutical
products. Only approved sources of drug substances can be used.
Additional or changed suppliers of drug substances can only be used after
changing the registration, providing corresponding DMF and being
approved.
GMP auditing: Manufacturers of pharmaceutical products must do onsite auditing on suppliers for drug substances and assure direct
responsibility for GMP compliance of the manufacturing sites.
Note: FDA has been insisting on official GMP examination on
manufacturing sites of drug substances. Recently, European EMEA has
also strengthened official examination on manufacturing sites of drug
substances. However, GMP auditing by final customers still plays a major
part.
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3. Difference in regulatory system of drug substances
between China and foreign countries
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Differences in regulatory system of drug substances
between China and European or American countries :
Comparison items
position of manufactures of
drug substances
Application for registration of
drug substance
Administration of drug
substance products
Quality monitoring of drug
substances
European and American
countries
China
Suppliers of active
substances
Drug manufacturers
Subjected to application of
pharmaceutical products
Independent
application
DMF/ repeated review
Drug approval number
Supplier auditing plays a
major part
Official administration
plays a major part
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4. How to link Chinese and foreign regulatory
systems of drug substances
Advantages of Chinese regulatory
systems of drug substances :
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Repeated review on documents of drug
substance is avoided during drug
registration
Manufacturing authorization system
can effectively control the legality of the
source of drug substances and reduce
the monitoring responsibility of
pharmaceutical manufactures on the
document and quality of drug
substances.
Disadvantage of Chinese regulatory
systems of drug substances :
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Governmental review and monitoring
blocks the knowledge source on drug
substances of pharmaceutical
manufactures, making the technical
data and their changes lose contact with
the manufacturing of pharmaceutical
products.
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Advantages of European and American
regulatory systems of drug substances :
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The technical data of drug substances are
closely associated with manufactures of
pharmaceutical products, so that the
quality and safe ensurance of
pharmaceutical products is enhanced.
Disadvantages of European and
American regulatory systems of drug
substances :
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DMF of drug substances is repeatedly
reviewed during drug registration.
Manufacturers of pharmaceutical
products assume responsibility for the
validity of documents and auditing of
manufacturing sites of drug substances.
The official monitoring on the source and
quality of drug substances is relatively
weak.
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4. How to link Chinese and western regulatory
system of drug substances
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Improvement in the registration process of drug substances in Europe:
The Certificate of Suitability to the Monographs of the European
Pharmacopoeia (CEP)
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The importance of CEP for manufacturers of drug substances
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More independent, can be applied independently
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Sufficient protection of intellectual property rights, do not need to provide
technical data to manufacturers of pharmaceutical products
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Repeated approval process for application of DMF can be avoided.
The importance of CEP for manufactures of pharmaceutical products
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More effective. The registration is more convenient (Replacement of DMF by
CEP belongs to IA change, only a record is needed.)
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There is no need to assume responsibility for technical documents and GMP
compliance of drug substances.
The importance of CEP for drug review institutions
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Avoid repeated application and review.
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Promote the update of pharmacopeia standard
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Promote multi-party cooperation and ensure the quality of drug substances
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4. How to link Chinese and western regulatory
system of drug substances
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The CEP authorization process and Chinese administration process for registration of
drug substances had different tunes that rendered with equal skill:
Comparison items
Administration of drug substances
in China
CEP authorization of drug
substance
1. Applicable scope
All drug substances
Drug substances that recorded in
European pharmacopeia
2. Main applicant
API manufacturers
API manufacturers
3. Approval certificate
Obtain legal manufacturing
qualification
Obtain legal manufacturing
qualification
4. On-site examination
SFDA
EDQM
For registration of pharmaceutical
products
Do not need repeated review
For registration of pharmaceutical
products
Do not need repeated review
Not sufficient
Sufficient**
5. Use of certificate
6. Information obtained by user
**: CEP authorization only reviews the compliance to items in European pharmacopeia and gives
explanation on items that different from the pharmacopeia. Therefore, the final customers can obtain
sufficient technical information of drug substances.
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4. How Chinese API system adapt to western
standard
The necessary improvements for Chinese API system:
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Although the Chinese “Law of Drug Management” need to be revised on the concept of
drug product and drug authorization system, but I think the manufacture authorization for
APIs should be remained as before.
The technical standards of API registration and GMP for manufacture of APIs should be
harmonized with ICH guidelines.
There should be an regulation to request API manufactures that they should open nonrestricted technical data to their end users, such as powder properties, impurity profile,
synthetic route, stability studies, validation of test methods, etc., and notify when there is
any change to these data. And request API manufactures that they must accept the GMP
audits from end users.
The definition of standard materials of APIs manufacturing is differ between Chinese and
western countries, and synthetic process of many starting materials need to have more
strict quality control. Therefore, Chinese API manufacturers should do more control to the
suppliers of starting materials to ensure the quality of APIs.
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5. Summary: the importance of coordinating global
regulatory system of drug substances
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Consistent regulatory systems of drug substances have great
importance for ensuring the safety of supplying chain of global drug
manufacturers :
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Consistency in technical standards: China should elevate the technical
standards for administration of drug substances so as to comply with its
position as the biggest export country in the world. For example, GMP
standards and document standards for drug substances should be
consistent with ICH guidance document.
Consistency in administration process: Western countries should enhance
the understanding of Chinese regulatory system of drug substances, add
requirements that correspond with Chinese laws and regulations in quality
authorization of drug substance, and enhance monitoring of intermediate
trades so as to prevent the purchase of drug substances from unqualified
manufacturers. In particular, the behavior of manufacturing fake products
by changing package should be attacked.
China should enhance information communication with western countries
in order to cooperate in preventing manufacturing fake products and
ensuring the safety of global drug manufacturing and supplying chain.
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THANKS!
孙悦平
Mobile: 13910816611
Email: [email protected]
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