Theo Dekker -- CPH -- Nov |2 | Meeting of WHO PQP with European manufacturers and EU holders of marketing authorisations WHO Prequalification of Generic Medicines approved by Stringent Regulatory Authorities Copenhagen 26 November 2009 Issues related to demonstration of quality and maintenance of prequalification Theo Dekker, D.Sc.

Theo Dekker -- CPH -- Nov |3 | Routes to Prequalification of FPPs Prequalification WHO route Dossier Q/E PQ GMP/GCP PQ SRA route InnovatorsGenerics Simplified procedure new End of 2005: 52 products

Theo Dekker -- CPH -- Nov |4 | PQ of Generics – “WHO route” Quality part of dossier 1.Applicant prepares / submits dossier oGuideline on website oComplete: Pharmaceutical Quality Information Form (PQIF) 2.WHO assessment (6 sessions p/a) oAPI part (in conjunction with FPP) CEP with all annexes (+ information not covered by CEP) APIMF procedure similar to EU ASMF procedure API information filled out by Applicant similar to EU oFPP part 3.Acceptance of quality part of dossier Similar to EU procedures

Theo Dekker -- CPH -- Nov |5 | PQ of Generics – “WHO route” Prequalification Accepted Quality Dossier BEGMP/GCP Prequalification of product

Theo Dekker -- CPH -- Nov |6 | PQ of Generics – “WHO route” Maintenance 1.Variations oVariations guideline 2.Requalification oGuideline accepted by WHO Expert Committee - Oct Every 5 years For other reasons, like fraud or problems with quality of batches Only applicable to products prequalified via WHO route

Theo Dekker -- CPH -- Nov |7 | PQ of Generics – “SRA route” Guideline Guideline on Submission of Documentation for Prequalification of Multisource (generic) Finished Pharmaceutical Products (FPPs) approved by Stringent Regulatory Authorities (SRAs) June 2009

Theo Dekker -- CPH -- Nov |8 | PQ of Generics – “SRA route” Quality aspects Quality Demonstration SRA Maintenance Variations Renewal of MA SRA ? Information Manufacturer yes

Theo Dekker -- CPH -- Nov |9 | PQ of Generics – “SRA route” Demonstration of quality WHO PQP relies on SRA assessment / inspection outcome Marketing authorization: proof oQA-certified copy Manufacturing Authorization: proof oQA-certified copy WHO type CPP o+ SPC/PIL/labelling Assessment report onot required for simplified procedure (TB & malaria FPPs)

Theo Dekker -- CPH -- Nov | PQ of Generics – “SRA route” Demonstration of quality Simplified procedure - applicant to provide justification oNo assessment report, if: Demonstrate that the API(s) of the FPP have owell established medicinal use owith recognized efficacy and an acceptable level of safety by means of a detailed scientific bibliographical or expert evidence oThe FPP (or corresponding FPP) has been in medicinal use throughout at least 30 years before the date of application, including at least 15 years within the ICH regions. Similarity to EC 2003/63/EC directive part II for well-established medicinal use

Theo Dekker -- CPH -- Nov | PQ of Generics – “SRA route” Applicant to provide Evidence of ≥ 5 years continuous & current manufacture oProduct quality review (annual product review) FPP batch sample oall pack types and sizes oCoA of the same batch Main product characteristics oComplete table A of guideline WHO’s core information on the FPP To be used in the letter of Prequalification

Theo Dekker -- CPH -- Nov | Submission accepted – Generic “SRA route” Letter of Prequalification Typical letter (currently for innovators), including inter alia Based on the product is prequalified under the following details: 1.Qualitative and quantitative unit composition 2.Pharmaceutical form 3.Labeling for storage 4.Contents of container 5.Shelf life of Finished Pharmaceutical Product (FPP) 6.Manufacturing site(s) of the API and FPP, etc… (see table A) NOTE. Please provide WHO with a copy of the regulatory acceptance letter of any changes to the above parts of after the variation has been approved by the

Theo Dekker -- CPH -- Nov | PQ of Generics – “SRA route” Maintenance 1.Variations (amendments) WHO does not assess / approve variations oTo be approved by relevant SRA WHO must be informed of all variations – regulatory acceptance letter Rationale oProduct stays in all respects the same as registered with SRA This is basis of the SRA prequalification route Otherwise WHO builds on non-assessed dossiers, specifications, validation data, etc. –No foundation for scientific judgment Risk management

Theo Dekker -- CPH -- Nov | PQ of Generics – “SRA route” Maintenance 2.Renewal of MA (Requalification) Draft WHO Requalification guideline states: Renewal of marketing authorization of products that have been listed by WHO based on approval by a stringent regulatory agency (SRA) remains the responsibility of the relevant SRA Rationale oProduct stays in all respects the same as registered with SRA

Theo Dekker -- CPH -- Nov | Stability and packaging Stability storage conditions for “WHO route” oZone IVB unless justified Global distribution conditions for procurement agencies Shelf-life of preferably 36 months (procurement agencies) oWhat, if not currently approved by relevant SRA? Not mandatory for current “SRA route” Submit data to SRA for approval Inform WHO of change / acceptability Change SPC/PIL/label (with SRA) ? Packaging changes o Ditto – via SRA

Theo Dekker -- CPH -- Nov | Special precautions for storage Examples from EPAR Do not store above 30°C in SPCs: Janumet FC tablets (sitagliptin and metformin, both salts) Ziagen FC tablets (abacavir sulfate) Zerit hard capsules (stavudine) Epivir FC tablets (lamivudine) Viracept oral powder (nelfinavir mesilate)

Theo Dekker -- CPH -- Nov | Thank you