Sultan Ghani

1. Active Pharmaceutical Ingredient Master File (APIMF) Procedure Sultan Ghani WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E.

2. Ways of presentation of data in PQ Quality dossier for the API Part / Reminder Order of preference A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 of the main generic guide (under revision) and presented in CTD format(see APIMF guideline) Complete submission of data requested in Section 2 2

3. APIMF Procedure Procedure implemented in PQ since January 2007, www.who.int/Prequal/ Adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2007 and recently published in WHO Technical Report Series (TRS) 948 as Annex 4. Inspired from the Active Substance Master File (ASMF)/DMF procedure in use in EU, CPMP/QWP/227/02 Rev 2. Scope only open to APIs # US and Canada DMFs (Drug Master File) Applicable to all types of chemical APIs: pharmacopoeial and non-pharmacopoeial Biological APIs out of scope of the APIMF procedure (like in EU) 3

4. Drug Master File System - International Objective:to permit submission of confidential data to an Authority which can be referenced by a 3rd party such as the sponsor or applicant USFDA was the 1st Authority who has established such procedure US DMF format: a file in one go – no division US DMFs: 5 types Site (type I, no more in use) Drug substance, Drug Substance intermediate and materials used in their preparation, Drug product (type II) Packaging material (type III) Excipient, colorant, flavours and essence (type IV) FDA accepted reference information (type V) 4

5. Drug Master File System - International Canadian DMF established since 1994 (1st guide), new revision published and under comment Canadian DMF: division of format into Sponsor's (Open) and Restricted (Closed) part for DMFs type I and IV Canadian DMFs: 4 types Drug substance or intermediate in the manufacture of DS (type I) Container-closure systems or components (type II) Excipients, colourants, flavours and other additives (type III) Dosage forms and drug product intermediates (e.g. blend of drug substance and excipients (type IV) 5

6. Drug Master File System - International EDMF (EU DMF) established in 1989-1991 Revised in 2005 and became ASMF (Active Substance Master File) after implementation of CTD in EU Applicable only to active substances Biologicals out of scope of ASMF Division of format into open and closed part 6

7. WHO APIMF Procedure Objectives Format and content Steps of the procedure Changes and Updates Recognition of assessment of ICH DRAs Main aspects and conclusion 7

8. APIMF Procedure / Objectives Mainly used when the API manufacturer is different from the FPP manufacturer but also possible when API and FPP manufacturers are the same Allows to protect valuable confidential "know-how" of the API manufacturer While giving the whole informationon manufacture of the API to the WHO PQ team of assessors While giving a part of the information to the applicant to Prequalification/ FPP manufacturer The APIMF procedure is not mandatory but is a possibility offered to applicants and manufacturers of APIs For Prequalification, Permits to avoid multiplication of assessments of one API from one source /centralised handling Lightens the workload of manufacturers (reduces number of deficiencies sent to manufacturers) 8

9. APIMF Procedure / Format and content An APIMF is composed of Restricted part + Applicant's part. It is a whole! Scientific information is physically divided in these 2 parts to fulfil its objectives (similar to EU and Canada DMF) Restricted part (Closed part) Confidential information to be submitted only to the Authority Applicant's part (Open part) Information regarded as to be non-confidential and to be given to the applicant Information to be given also to the authority as part of APIMF 9

10. APIMF Procedure / Format and content (cont’d) An APIMF should be accompanied by a Letter of Access (LoA) The Letter of access is a letter in which the API manufacturer gives authorization to the Authority (WHO team of assessors) to review the confidential part in support of one specific FPP and applicant In addition in the LoA, the API manufacturer commits to ensure batch-to-batch consistency to inform WHO (the Authority) and the applicant of any changes to the manufacturing process and to the APIMF 10

11. APIMF ProcedureContent of the dossier in CTD format/ OPEN Part General information nomenclature structure general properties Manufacture manufacturer(s)/site of manufacture description of the manufacturing process and process controls (Flow sheet of the synthesis and brief outline) Characterization elucidation of structure and other characteristics impurities 11

12. APIMF ProcedureContent of the dossier in CTD format/ OPEN Part (cont’d) Characterization elucidation of structure and other characteristics impurities Control of API specification analytical procedures validation of analytical procedures batch analysis justification of specification Reference standards or materials 12

13. APIMF ProcedureContent of the dossier in CTD format/ OPEN Part (cont’d) Container closure system Stability stability summary and conclusion post-approval stability protocol and stability commitment stability data 13

14. APIMF ProcedureContent of the dossier in CTD format/ Closed part Manufacture manufacturer(s)/site of manufacture detailed description of the manufacturing process and process controls control of materials (Starting material of the API, reagents, solvents, other materials used) control of critical steps and intermediates process validation and/or evaluation manufacturing process development 14

15. APIMF Procedure Steps of the procedure Manufacturer of the API should submit directly to the Authority: Restricted part + applicant's part + Letter of access (LoA) + summaries on each part Manufacturer of the API should make available to the applicant: Applicant's part + Letter of access (LoA) + summary of the Open part The applicant, in its turn, includes the Open part received in its FPP dossier + LoA + summary on the Open part in the PQIF. Submits the whole to the Authority. Submission of the APIMF from API manufacturer should be synchronized with the submission of the 1st concerned FPP dossier referring to this APIMF No need that the API manufacturers submits several time the APIMF to the Authority. Only once suffices. For other FPP dossiers, the API manufacturer has to submit to the authority only LoAs UNLESS there is a change in the APIMF. 15

16. APIMF Procedure Changes and Updates APIMF should be kept up to date on actual synthesis/ manufacturing process Quality control methods kept in line with current regulatory and scientific requirements In case of changes introduced in the APIMF - Those requiring filing a variation by the applicant should be notified to each applicant. - Those not requiring filing a variation are to be submitted to the Authority only and this before implementation. Tabular list summarizing changes Overview comparing the old and new content of APIMF New versions of OP and RP and quality summaries Changes accepted or rejected by Regulatory Authority of ICH participating countries 16

17. APIMF Procedure Recognition of assessment of ICH DRAs A DMF on API assessed by a Drug Regulatory Authority (DRAs) in ICH regions can be accepted without further evaluation, in condition: Full DMF is submitted to WHO PQ Assessment report of the ICH Authority is made available through a mechanism of sharing of information OR Proof that the API is used in an FPP-approved in an ICH regions. e.g. A certificate according to the WHO pharmaceutical starting materials certification scheme (SMACS) issued by the ICH DRA to attest the relevant data covered by the scheme Declaration of the DMF holder that there have been no changes since acceptance in the manufacture of batches of the API to be supplied for WHO PQ In the content of the DMF 17

18. APIMF Procedure Main aspects and Conclusion An APIMF IS NOT an stand-alone, independent dossier of API An APIMF is always submitted ONLY and ONLY in support of a FPP dossier An APIMF is never approved as such, it can be only accepted in support of an FPP dossier The party submitting the APIMF will be considered as holder of the APIMF. Preferably the API manufacturer should be the holder. However it is permissible that APIMF be submitted by another party, then an official letter from the manufacturer is needed. The applicant, as responsible of the medicinal product, has to arrange with its API manufacturer that the Authority (WHO PQ) has access to the whole information. The applicant has to have access to the latest version of the APIMF Open part. Therefore, any changes or update of the Open part should be communicated by the APIMF holder to all the applicants referring to an APIMF. By its divided format and mechanism, the APIMF is meant to a better communication between the API manufacturer and the FPP manufacturer/applicant (like EU and Canadian DMFs) 18

19. . THANK YOU 19