1. 1 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

2. 2 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

3. 3 1. Related background The global position of drug substance industry in China:  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.

4. 4 1. Related background Problems that resulted from inconsistency of laws and regulations:  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 non- drug 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. 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 numberNot accepted. Individual DMF/COS document review Quality system licensing: GMP certificateNot accepted, individual GMP on-site audit/examination

5. 5 2. Differences in legal definition of drug and approval system Difference in drug definition:  Definition of drug in European and American laws: 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.

6. 6 2. Differences in legal definition of drug and approval system Definition of drug in Drug Administration Law of PRC:  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.

7. 7 2. Differences in legal definition of drug and approval system Differences in drug approval system:  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.

8. 8 2. Differences in legal definition of drug and approval system Effect of differences in drug definition and authorization system on drug substance regulatory system in China :  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.

9. 9 2. Differences in legal definition of drug and approval system Modification on legal system of drug administration:  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: 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. 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.

10. 10 3. Difference in regulatory system of drug substances between China and foreign countries Requirements on manufacturing of drug substances in China:  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 on- site examination, obtain GMP certificate and accept the monitoring of on- site 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.

11. 11 3. Difference in regulatory system of drug substances between China and foreign countries Requirements on the usage of drug substances in China :  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.

12. 12 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 :  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.

13. 13 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 :  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 on- site 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.

14. 14 3. Difference in regulatory system of drug substances between China and foreign countries Differences in regulatory system of drug substances between China and European or American countries : Comparison itemsEuropean and American countries China position of manufactures of drug substances Suppliers of active substances Drug manufacturers Application for registration of drug substance Subjected to application of pharmaceutical products Independent application Administration of drug substance products DMF/ repeated reviewDrug approval number Quality monitoring of drug substances Supplier auditing plays a major part Official administration plays a major part

15. 15 4. How to link Chinese and foreign regulatory systems of drug substances Advantages of Chinese regulatory systems of drug substances :  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 :  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. Advantages of European and American regulatory systems of drug substances :  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 :  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.

16. 16 4. How to link Chinese and western regulatory system of drug substances Improvement in the registration process of drug substances in Europe: The Certificate of Suitability to the Monographs of the European Pharmacopoeia (CEP)  The importance of CEP for manufacturers of drug substances More independent, can be applied independently Sufficient protection of intellectual property rights, do not need to provide technical data to manufacturers of pharmaceutical products Repeated approval process for application of DMF can be avoided.  The importance of CEP for manufactures of pharmaceutical products More effective. The registration is more convenient (Replacement of DMF by CEP belongs to IA change, only a record is needed.) There is no need to assume responsibility for technical documents and GMP compliance of drug substances.  The importance of CEP for drug review institutions Avoid repeated application and review. Promote the update of pharmacopeia standard Promote multi-party cooperation and ensure the quality of drug substances

17. 17 The CEP authorization process and Chinese administration process for registration of drug substances had different tunes that rendered with equal skill: Comparison itemsAdministration of drug substances in China CEP authorization of drug substance 1. Applicable scopeAll drug substancesDrug substances that recorded in European pharmacopeia 2. Main applicantAPI manufacturers 3. Approval certificateObtain legal manufacturing qualification 4. On-site examinationSFDAEDQM 5. Use of certificateFor registration of pharmaceutical products Do not need repeated review 6. Information obtained by userNot sufficientSufficient** **: 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. 4. How to link Chinese and western regulatory system of drug substances

18. 18 The necessary improvements for Chinese API system : 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 non- restricted 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. 4. How Chinese API system adapt to western standard

19. 19 5. Summary: the importance of coordinating global regulatory system of drug substances Consistent regulatory systems of drug substances have great importance for ensuring the safety of supplying chain of global drug manufacturers :  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.

20. 20 THANKS! 孙悦平 Mobile: 13910816611 Email: sunyueping@sina.comsunyueping@sina.com