Antony Fake PhD WHO Medicines Prequalification Programme 1
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Abbreviations API Active Pharmaceutical Ingredient FPP Finished Pharmaceutical Product API PQ API Prequalification APIMF Active Pharmaceutical Ingredient Master File (DMF) CPQ Confirmation of API PQ Document SRA Stringent Regulatory Authority GMP Good Manufacturing Practice PQP Prequalification of Medicines Programme
Overview Outline the API PQ procedure Updated statistics API related changes 4
Prequalification of Medicines Programme The is an initiative within the existing Prequalification of Medicines Programme. Prequalification of medicinal products. Prequalification of Quality Control Laboratories. Capacity building activities. Prequalification of Active Pharmaceutical Ingredients. 5
Two uses of APIMFs in PQP APIMF Procedure APIMFs API Prequalification APIMFs are used to support FPP Prequalification and API prequalification. 6
APIMF Procedure FPP Manufacturer API Manufacturer + AP RP + APIMF assessment is conducted in conjunction with an FPP application 7
What is API Prequalification? It is a scheme for API manufacturers only API Prequalification API Manufacturer There is no involvement by FPP manufacturers 8
What is API Prequalification? It is a scheme for manufacturers of APIs that are used in medicinal products for HIV, TB, Reproductive Health and Malaria. It seeks to verify and identify APIs that are of good quality and manufactured in compliance with GMP. It commenced as a pilot project in October 2010. It is part of the Prequalification of Medicines Programme, WHO based in Geneva. 9
Prequalification of Medicines website http://www.who.int/prequal 10
Why is needed? There is a need to identify sources of good quality API for use in medicinal products for HIV, TB, malaria and reproductive health. Primarily for use in medicinal products procured by UN agencies and other international procurers, but Also for use in medicinal products procured by countries with limited regulatory capacity. 11
Why is needed? Medicine manufacturers involved in the PQ programme (and in general) have difficulties in finding sources of quality APIs for malaria, HIV, reproductive health and TB, because: There is a relative scarcity of API. There are significant geographical distances between API and FPP manufacturers, i.e. between China and India. The quality of the API manufacturer may not be clear. This creates basic problems for FPP manufacturers to find and establish contact with potential API manufacturers. 12
Benefits to API manufacturers Recognition as a source of quality API, manufactured in compliance with GMP. Serves as a point of difference between good quality and poor quality APIs. Opportunities to verify compliance with GMP. Opportunities to compile, revise and refine their regulatory documentation, leading to quicker acceptance by other national regulatory agencies. There is no fee. 13
Benefits to FPP manufacturers Ease of identifying potential sources of quality API. Identifying API manufacturers with robust quality systems in place. Identifying API manufacturers that maintain good regulatory documentation, which may be used in regulatory submissions. Reduced API assessment requirements (PQP) There is no fee. 14
How are APIs Prequalified Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 15
3 rd Invitation for EOI Not all APIs are invited to apply for prequalification. APIs are publicly invited through a published invitation for expression of interest (EOI). A 3 rd invitation for Expressions of Interest (EOI) has now been announced. It essentially covers those APIs listed in the associated FPP EOIs for HIV, anti-tb, Malaria, reproductive health neglected tropical diseases. See website for the invitation: http://www.who.int/prequal/info_applicants/api_info_applicants.htm 16
3 rd Invitation for EOI Therapeutic area HIV Anti-malarial Anti-tuberculosis Invited Active Pharmaceutical Ingredient Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Sulfadoxine, Pyronaridine Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone Reproductive health Neglected Tropical Diseases Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, Oxytocin Diethylcarbamazine, Mebendazole 17
Application Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 18
Application An application for API Prequalification is made by the API manufacturer, or agent. An applicant does not need to be supplying API to a WHO Prequalified FPP to seek API prequalification. 19
Application An application should consist of: The PQ application form. An APIMF (if not previously provided). A Site Master File (if not previously provided). Any further evidence of GMP at the facility (optional). 20
Assessment Quality (APIMF) Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 21
APIMF submission There are four options when submitting an APIMF in support of PQ. Option 1 New APIMF (PQP only) A new APIMF, with a unique version number is submitted as part of the application. 22
APIMF submission Option 2 The APIMF is intended for API PQ use only. The technical content of the submitted APIMF is the same as the APIMF submitted for the APIMF procedure and subsequent amendments. A new APIMF is submitted using a version number differing from that used in APIMF procedure. Information in the two APIMFs may diverge over time. 23
APIMF submission Option 3 The APIMF is intended for both API PQ and APIMF procedure. The technical content of the submitted APIMF is the same as the APIMF submitted for the APIMF procedure and subsequent amendments. A new APIMF is submitted using a version number differing from that used in APIMF procedure. The same APIMF will be used in both procedures. It replaces the existing APIMF used in the APIMF procedure. 24
APIMF submission Option 4 No APIMF is provided. An existing APIMF already held for the APIMF procedure is referred to. The existing APIMF will be used for API PQ and APIMF procedure The existing APIMF must met all current requirements. 25
APIMF - Technical content Excellent technical guidance can be found in the module 3.2.S sections (pages 11 to 31) of the recently published guideline : Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part. http://www.who.int/prequal/info_general/documents/generic_guide/generi cguideline_quality.pdf 26
The submitted APIMF should: be prepared in CTD format. APIMF Presentation be separated into open (applicant) and closed (restricted) sections. be paginated throughout the entire document. Restarting page numbers for each subsection section is not permitted. include a contents page with page number references to each of the CTD subsections. be assigned a manufacturer's version number that should be present in the footer or header of each page of the APIMF. 27
APIMF Presentation The submitted electronic APIMF should: have separate files for the open and closed sections. single files should not exceed 30 MB in size. be provided in text-selectable PDF format. have document bookmarks for each of the CTD subsections. In additional the use of hyperlinks within the body of the text is encouraged. Scanned copies of supporting documents such as Certificates of Analysis, authorized specifications, signed protocols, etc are permitted. 28
Assessment - GMP Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 29
Assessment GMP There are two ways to demonstrate GMP compliance at the API manufacturing facility. By providing evidence of current compliance: GMP certificates, inspection reports, CAPAs, the most recently completed Product Quality Review (PQR) report. or By inspection by the WHO. 30
Assessment GMP Assessment of GMP compliance at the site of API manufacture takes into account: Inspections performed previously by WHO, a member of PIC/S, or an SRA. Inspection must have occurred within 3 years of application. Inspections must be API specific. The WHO will perform an inspection if, after assessment and requests for information, GMP compliance can not be established. 31
Assessment of GMP An SRA is a medicines regulatory authority in a country that is: a member of the ICH: Japan, USA, EU member; or an ICH Observer, e.g. Swissmedic, Health Canada; or associated with an ICH member through a legally binding mutual recognition agreement, e.g. Australia, Iceland, Liechtenstein, Norway etc. 32
WHO GMP Certificates There is no such thing. The WHO does not issue GMP Certificates. There are many certificates circulating that appear to be issued by the WHO, but they are not. Certificates might be issued in the WHO format, or the inspection may have occurred against WHO criteria, but this is not a WHO inspection. Successful inspections conducted by the WHO are published in WHOPIR that can be found at this link: http://www.who.int/prequal/whopir/pq_whopir.htm 33 Prequalification of APIs 1 October 2011, Mumbai Malaysia September 2012
Decision Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 34
Decision Once the APIMF is accepted the applicant will receive an Letter of APIMF acceptance. This is not prequalification. Typically a final conclusion over GMP status may still be required, if this has not been achieved already. Once both the APIMF and GMP status is accepted the application is considered for sign-off. The applicant will be contacted by WHO to confirm final details for publishing. Expressions of storage statement may differ to meet WHO requirements. 35
Publishing Invitation Application Assessment (GMP) Assessment (Quality) Decision Publishing 36
Publishing List of PQ APIs Website (Public) + WHOPIRs Website (Public) Confirmation Document (Private) 37
Publishing The date of prequalification is the date when the API is published on the WHO List of Prequalified Active Pharmaceutical ingredients. http://www.who.int/prequal/info_applicants/api_pq-list.htm 38
WHO List of Prequalified APIs Publically available WHO application number. INN name. Date of prequalification. Name of the applicant Sites of API manufacture. The APIMF version number. The API specification version number. The primary and secondary packaging components. The assigned re-test period. The recommended storage conditions. Confirmation of API PQ document issue date Intended for: UN agencies, National medicine authorities, FPP manufacturers, public 39
Confirmation of API PQ document Provided to the API manufacturer for distribution at their discretion The assigned WHO application number. The INN name of the active pharmaceutical ingredient. API manufacturer company name. The API specification version number. A copy of the API specifications. The assigned re-test period. The recommended storage conditions. A copy of the assay and related substances test methods. Intended for: UN agencies, National medicine authorities, FPP manufacturers 40
API-PQ Procedure + API Manufacturer FPP Manufacturer
Confirmation of API PQ document (CPQ) It is intended that the CPQ is circulated to relevant parties, such as FPP manufacturers. Wider recognition of API-PQ is a long term goal. Manufacturers of a PQ d API currently participating in the APIMF procedure should circulate the CPQ to associated FPP manufacturer s. Normally the FPP manufacturer will then submit the CPQ and withdraw from the APIMF procedure. FPP manufacturers need to actively request this change. This will have post-prequalification benefits in terms of the number of variations they will need to file. 42
API Prequalification Performance 1 April 2011 1 November 2011 1 Sept 2012 Total number of applications 8 29 62 Number of PQ APIs 2 5 18 There is positive feedback from FPP manufacturers whenever PQ of APIs is discussed. Applications and the number of prequalified APIs continues to increase. 43
API Prequalification Performance APIs have been prequalified for HIV (2), Malaria (15), and TB (4). 8 manufacturers have successfully PQ d one or more APIs: Anuh Pharma Ltd (1) Calyx Chemicals & Pharmaceuticals Ltd (4) Ipca Laboratories Ltd (3) Laurus Labs Pvt Ltd (2) Lupin Ltd (1) Mangalam Drugs & Organics Ltd (7) Mylan Laboratories Ltd (1) Sequent Scientific Ltd (2) 44
Changes to API Details Changes to API details must be announced to the PQP. There are two phases to this process 1.The APIMF holder submits an amendment to PQP for the change. 2.Prequalified FPP manufacturers submits a variation to PQP for the change. This is placing an increasing burden on both PQP and manufacturers. This is true for API manufacturers using the APIMF procedure or a Prequalified API 45
Changes to API Details The proposed PQP guidance on the submission of variations in support of Prequalified FPP was circulated this year for comment and is in the final stages of drafting. This guidance refers in many cases to the submission and acceptance of APIMF amendments. It also introduces the use of CPQ documentation 46
Changes to API Details The Variation Guidance being finalised proposes that: FPP manufacturers using a Prequalified API will only submit a variation if a new Confirmation of API PQ document is issued. Similarly, when an FPP relies upon a CEP or a Prequalified API, FPP applicants are required to notify WHO PQP only when the associated CEP or Confirmation of API Prequalification document has been revised This is a distinct advantage for FPP manufacturers. 47
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Current focus: Improving the API PQ process The introduction of the FPP Variation and APIMF Amendment guidance. Introduction of mandatory documentation requirements. Reduction of assessment backlogs Next: Discontinuation of paper submissions. Wider recognition and use of CPQs in national authorities. However! Feedback on how the assessment process can be improved and API PQ value enhanced are welcome at any time. 49
Further information The PQ website is a good source of information, please read. http://www.who.int/prequal/info_applicants/api_info_applicants.htm AND, ALSO Please email me (or visit) if you have any questions. Fakea@who.int One email could save you a lot of time. 50