1. CONCEPTUAL: HUMAN Rosanna Melchior Senior Regulatory Manager Thomson Reuters, Healthcare and Science DIA RA SIAC CMC Working Group, November 18, 2010 CERTIFICATES of PHARMACEUTICAL PRODUCTS

2. AGENDA WHAT IS A CPP REGULATORY HURDLES REGIONAL REQUIREMENTS CONCLUSION Q AND A 2

3. ORIGIN OF CPPs In 1969, the Twenty-second World Health Assembly endorsed requirements for Good Practices in the Manufacture and Quality Control of Drugs. These standards provide the basis for the WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce, an international voluntary agreement to provide assurance to Countries participating in the Scheme about the quality of pharmaceutical products moving in international commerce. The primary document of the scheme is the Certificate of a Pharmaceutical Product 3

4. WHO CERTIFICATION SCHEME The Scheme is an administrative instrument that requires a participating country, on application from a product sponsor, to certify to another country that: a specific product is authorised to be placed on the market within its jurisdiction or, if it is not, the reason why; and the plant in which it is produced is periodically subject to GMP inspections; and, that all aspects of the manufacture of the product are satisfactory. 4

5. CERTIFICATE of PHARMACEUTICAL PRODUCTS (1) From WHO :WHO The Certificate of a Pharmaceutical Product issued by the exporting country, is intended for use by the competent authority within an importing country in two situations: when the product in question is under consideration for a product licence that will authorize its importation and sale; when administrative action is required to renew, extend, vary or review such a licence. 5

6. CERTIFICATE of PHARMACEUTICAL PRODUCTS (2) The applicant should submit the following information for each product to the authority issuing the certificate: name and dosage form of product name and amount of active ingredient(s) per unit dose, name and address of product licence holder and/or manufacturing facility, formula (complete composition including all excipients; also particularly when no product licence exists or when the formulation differs from that of the licensed product), product information for health professionals and for the public (patient information leaflets) as approved in the exporting country, 6

7. CERTIFICATE of PHARMACEUTICAL PRODUCTS (3) All requests for certificates should be channelled through the agent in the importing country and the product licence holder or other commercially-interested party in the exporting country ("the applicant"). The certificate is a confidential document. As such, it can be issued by the competent authority in the exporting country ("the certifying authority") only with the permission of the applicant and, if different, of the product-licence holder. The certificate is intended to be incorporated into a product- licence application in the importing country. Once prepared, it is transmitted to the requesting authority through the applicant and, when applicable, the agent in the importing country. 7

8. FREE SALE CERTIFICATE The regulatory authorities may wish to know whether the products being offered for sale by the manufacturer or wholesaler are in fact registered for use in the country of manufacture. This certificate is supported by a product licence (PL) issued by regulatory authorities in the manufacturing country; the PL is issued for the purpose of marketing and free distribution. However, the WHO certificate of a pharmaceutical product (CPP) is increasingly superseding this document, since many manufacturers tend to produce for export. 8

9. EXPORT CERTIFICATE Depending on Country, a certificate stating that the drug: is not manufactured for local consumption is not sold for consumption in Country, and can legally be exported. 9

10. AGENDA WHAT IS A CPP REGULATORY HURDLES REGIONAL REQUIREMENTS CONCLUSION Q AND A 10

11. TIMING OF SUBMISSION At the time of application Ensures that the product has been reviewed and approved by a recognized regulatory agency (exporting country) The review process in importing country is delayed until an authorization has been granted elsewhere Allows smaller agencies to rely on CPP rather than conducting their own full scientific review Before approval Review process can be started before the formal CPP documentation is available 11

12. COUNTRY OF ORIGIN (1) When the WHO Scheme come into operation, the assumption was that it would operate for pharmaceutical products sold directly from the country of manufacture (origin) to the country of final destination Country A API Country B Excipient Country C FP Country D Importing Country CPP 12

13. COUNTRY OF ORIGIN (2) At present different stages of the manufacturing activities take place in different countries before the product is released Country A Bulk Country B Primary pack Country C Cartoning Country D QP Release CPP 13

14. « NON SOURCE » COUNTRY OF ORIGIN Manufacturing sites may not be in a country where the authority carries out the primary review Country ACountry B Product not registered nor sold Country C No CPP Product registered and sold CPP available 14

15. LEGALISATION It is the traditional method for authenticating public documents to be used abroad. The process involves officials of the country where the document is issued as well as foreign Embassy or Consulate of the country where the document is to be used. Statutory requirement outside the remit of the regulatory Agency Builds additional delay into the submission process. 15

16. APOSTILLE The apostille is an international certificate that authenticates the origin of a public document. Apostilles can only be issued for documents issued in one country party to the Apostille Convention and that are to be used in another country which is also party to the Convention. See Hague Convention Abolishing the Requirement for Legalisation for Foreign Public DocumentsHague Convention Abolishing the Requirement for Legalisation for Foreign Public Documents 16

17. HANDLING VARIATIONS IN CPP- DEPENDENT COUNTRIES EFPIA Position Paper EFPIA Position Paper (October 2009) proposal for improving the management of variations in CPP- dependent countries, located in various geographic areas, e.g. Middle East, Africa, Latin America, Asia, by capitalising on the simplification efforts in the EU in this area. based on the fact that a variation should be approved in a reference country prior to being processed in CPP-dependent countries as per local regulations, the EFPIA supports the following operating principles in CPP-dependent countries: –A notification, i.e. a 'Tell and Do' process for labelling changes that increase the safe use of the drug product and minor quality changes, –A 'Tell, Wait and Do' process for other labelling changes and major quality changes. 17

18. AGENDA WHAT IS A CPP REGULATORY HURDLES REGIONAL REQUIREMENTS CONCLUSION Q AND A 18

19. CPPs IN LATIN AMERICA As issuing autority: Compliant to WHO format (Mexico: upon request) Turnaround time: 10 to 30 days Subject to fee payment (exception: Brazil) Spanish. Multilingual in Argentina and Brazil Validity: 1 year 19

20. ARGENTINA CPP REQUIREMENTS Accepted CPPs are those issued by Health Authorities of the following countries: USA, Canada, Japan, Australia, New Zealand, Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland, UK, Israel, Brazil, Cuba, Chile, Mexico, China CPPs should be legalized (apostille or consular legalization) 20

21. BRAZIL CPP REQUIREMENTS CPPs are required for medicinal products' registration. Without CPP the application may be filed but registration will not be granted. The CPP should be issued by the Health Authority of the country of the manufacturing site. The CPP should be certified and have a legal translation and a notarized copy of the original. 21

22. OTHER LAT AM COUNTRIES REQUIREMENTS Chile CPPs issued by any country of origin are accepted. They should be legalized (consular legalization). Colombia CPPs issued by any country of origin are accepted. They should be legalized (apostille or consular legalization). Mexico CPPs should be issued by the Ministry of Health of the country of origin. They should be legalized. 22

23. ISRAEL As Issuing Authority: Compliant to WHO format Turnaround time: 30 days Subject to fee payment English Validity: 2 year As Requesting Authority: Accepted CPPs are those issued by the health authorities of the following 'recognized' countries: US, Canada, Japan, EU countries (before 2004) or EMA, Iceland, Switzerland, Sweden, Norway, Australia, New Zealand. 23

24. SAUDI ARABIA / ISSUING COUNTRY Issuing autority: Saudi Food and Drug Authority (SFDA) Compliant to WHO format Turnaround time: standard: 2 weeks, fast track: 2-3 days Subject to fee payment English Validity: 2 years Once SFDA has issued the CPP, the applicant applies for its legalization at the Saudi Ministry of Foreign Affairs and from the embassy/consulate of the targeted country (fees vary among target countries ). 24

25. SAUDI ARABIA / REQUESTING COUNTRY CPPs are required for registration, renewal, CMC major change, although not mention nor described in SFDA guidelines. Could also be requested if their is a major package change. Accepted CPPs are those issued by the Country of the MAH. Additional CPPs released by the agencies of the following reference countries (USA, Australia, UK, Sweden, Canada, Japan, Switzerland, Germany) might be needed to support the application. CPPs should be submitted when the MA dossier is filed, however could also be submitted at a later stage upon justification from the applicant. CPPs should be authenticated from the issuing agency and from Saudi Consulate or Embassy. 25

26. SOUTH AFRICA As Issuing Authority Compliant to WHO format Turnaround time: approx. 1 week Subject to fee payment English Validity: 1 year As Requesting Authority For registration purposes, a CPP is not essential but should be included if available, with the application for registration. 26

27. ASIA PACIFIC / ISSUING AUTHORITIES Compliant to WHO format (exception: China) Turnaround time: 1 day (HK, Thailand) – 3/9 months (India) Subject to fee payment (exception: China, India, Thailand, Vietnam) English (EN/Chinese in China, Hong Kong) Validity: 28 days (HK) 1 year (Thailand) 2 years (China, India, Malaysia, Singapore, South Korea, Vietnam) 5 years (Taiwan) 27

28. ASIA PAC COUNTRIES LOCAL REQUIREMENTS (1) China An original CPP (WHO format) issued by the competent authority in the exporting country of origin is required. If a copy of the original CPP is submitted it should be locally notarized and legalized. Hong Kong For generic drugs the CPP of country of origin is satisfactory; for NCE CPPs from both the country of origin and from the list of acceptable countries are needed. It should be legalised. India They should be issued by the Health Authority of the country of origin. Legalisation is not required. 28

29. ASIA PAC COUNTRIES LOCAL REQUIREMENTS (2) South Korea CPP should be issued by the health authority of the exporting country of origin Submitted in original and as a scanned image. Taiwan CPP should be issued by the Health Authority of the exporting country Should be legalised by the Embassy. An application can be filed without CPP however it has to be submitted in time for the product to be approved. Vietnam CPP should be issued by the country of origin or by competent authority of UK, France, Germany, USA, Japan, Australia, Canada or European Medicines Agency. They should be legalised. 29

30. MALAYSIA CPPs shall be issued by the competent authority of the country of origin and should be legalized. CPPs issued by EMA for products registered through the centralized procedure in EU will be accepted; CPPs issued by the manufacturer or other authorities are not accepted. In the event a CPP is not available from the country of manufacture (e.g. where a product is not licensed for sale in said country but manufactured under contract only for product owner from another country), the following alternatives may be considered: GMP Certification/Manufacturing Licence for the manufacturer from the relevant competent authority, together with : (1) CPP from the country of the product owner; or (2) CPP from the country of release, if (1) is not available. If more than one manufacturer is involved, GMP certificates should be available for all the manufacturers. The Drug Control Authority reserves the right to conduct an inspection on any manufacturing site. 30

31. SINGAPORE CPPs are required for abridged NDA and GDA of imported products as a proof of approval certifying the product's registration status (proof of approval and CPPs are not required in case a full dossier is submitted). An application can be filed without CPP however it has to be submitted in time for the product to be approved/renewed. CPPs from the country of manufacture, other than Singapore, are also required for the annual retention of the licence. In cases where the CPP is not obtainable from the relevant regulatory agency because the product is manufactured solely for export, the licence holder may submit a certified true copy of the manufacturer’s GMP certificate or its equivalent in addition to a CPP from another country to which the same product is exported to and sold therein. Original CPPs shall be in the WHO recommended format. A recent CPP (i.e. no more than 6 months old based on the issue date) is required if the CPP previously submitted is more then 2 years old (based on its issue date or expiry date, whichever is earlier). 31

32. AGENDA WHAT IS A CPP REGULATORY HURDLES REGIONAL REQUIREMENTS CONCLUSION Q AND A 32

33. CONCLUSION Requirements for CPP differ in countries The original WHO Scheme needs to adapt to pharmaceutical delocalised manufacturing activities Issues with counterfeit CPP to be taken into account Opportunities for exporting/CPP-dependent countries for more flexible approval processes 33

34. AGENDA WHAT IS A CPP REGULATORY HURDLES REGIONAL REQUIREMENTS CONCLUSION Q AND A 34