Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Pharmaceutical Development Applications for prequalification: Dossier requirements Presenter: János Pogány, pharmacist, PhD pogany.janos@chello.hu WHO expert

3. Pharmaceutical Development Outline and Objectives of presentation • Multisource (generic) products • Products from ICH regions • New products developed bygeneric manufacturers • Main points

4. Guideline on Assessment Procedure Guideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and Tuberculosis [Generic Guideline under revision] Pharmaceutical Quality Information Form „A properly filled out and signed original copy of the PQIF with all its annexes (including a copy on CD-ROM in Win-Word format ) must be submitted.”

5. Critical factors of FPP quality INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS Manufacturing authorization GMP standards FPP MANUFACTURER Pharmacopeia standards Marketing authorization NATIONAL DRA2 NATIONAL DRA1

6. High-risk APIs • FPPisnot registeredin theICH region and associated countries • APIis not official in the internationally used major pharmacopoeias andICH guidelinesshould be used for evaluation • Reference standard/comparator is not available for: • Pharmaceutical equivalence studies • Bioequivalence studies • Require particular attention bynational DRAs as regards assessment of applications for marketing authorization / prequalification

7. Low-risk APIs • Certificate of suitability (CEP) is submitted (DRA) • ActivePharmaceuticalIngredientMasterFile • Open part (APPLICANT) • Closed part(WHO orDRA) • Pharmacopoeia monograph • Literature evidence of stability • Synthesis impurities and degradants are controlled by monograph • Class1 solvents excluded; class2 / class 3 solvents controlled • FPP is registered in the ICH region(DRA)

8. Guideline onAPIMF procedure • Full details of development chemistry, scale up, manufacturing process and process controls, validation, specifications at batch release and stabilityare available for assessment • Once the APIMF is prequalified, reference may be made to it in subsequent FPP applications • Conditions for reference • Version number and date must be assigned • Information on regular updates must be provided http://mednet3.who.int/prequal/ • Availability of APIMF is critical for API inspection

9. 2.2 Properties of API(s) • 2.2.1 API not described in PhInt, PhEur or USP • Considered new, used for the first time in a FPP • Risk estimation high • Full information necessary • 2.2.2 API described in PhInt, PhEur or USP • In use for a certain period of time • Information on safety and efficacy available • Risk estimation low(er) • Control by the monograph, additional information beyond the scope of the monograph necessary

10. API not described in PhInt, PhEur or USP • Any in-house analytical procedure needs to be validatedICH Q2(R1) • Reference standards/materials should be well characterized with documented purityICH Q2(R1) • Source • Official pharmacopoeial standards • In-house standards • Characterization and evaluation of non-official standards • Method of manufacture • Elucidation of structure • Certificate of analysis • Calibration against an official standard (if available)

11. PhInt - Reference substances • International Chemical Reference Substances are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations.(The stability of the International Chemical Reference Substances kept at the Collaborating Centre is monitored by regular re-examination.) • International Infrared Reference Spectra • WHO Collaborating Centre for Chemical Reference Substances (Apoteket AB, Centrallaboratoriet, ACL, Prismavägen 2, SE-141 75 Kungens Kurva, Sweden; Fax: +46 8 740 60 40; E-mail: who.apl@apoteket.se)

12. APIdescribed in PhInt, PhEur or USP • Properties relevant/critical for the performance of the API • potential polymorphic forms • particle size distribution • User requirement for low solubility drugs (dissolution, bioequivalence) • additional characteristics (e.g. hygroscopicity) • All manufacturing steps covering aseptic processing or sterilization must be validated • Proof of TSE-safety • CEP • Letter of attestation

13. Q3A(R2) Decision tree – Impurities

14. Decision tree – Polymorphism

15. Residual solvent impurities

16. 2.5.1 API described in PhInt, PhEur or USP • Name the monograph • Name any test methods referenced in the monograph but not appearing in it • List of tests beyond the scope of the monograph:residual solvents, particle size, polymorphs, loss on drying, etc. • Whenever an API has been prepared by a method liable to leave impurities not controlled in the pharmacopoeial monograph, these impurities (based on 3 to 10 batch analysis results) including residual organic solvents, as well as their maximum tolerance limits should be declared and controlled by a suitable test procedure. 2.6 Container closure system 2.7 APIstability

17. Batch number(s) of the FPPs used in

18. 3.5Manufacturing process • A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. Stages of manufacture, at which sampling is carried out for in-process control tests, should be indicated. • A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. For sterile products, details of sterilization processes and/or aseptic procedures used must be described.

19. Flow diagramof a process Breaking the process down into unitoperations and steps(activities) Decision on sampling and IPC results Start Activity Activity Decision Action No Yes End Flow diagram

20. Narrative of manufacturing process • Mix Amodiaquine hydrochloride, lactose monohydrate and maize starch in a high-shear, high-speed granulator for approximately8 minutes • Mix maize starch and purified water in the heater until complete dissolution at approx.70°C. • Cool the mixture prepared in step 2 until the required temperature (NMT 60°C) is reached. • Granulate the mixture prepared in step 1 whilst adding the mixture prepared in step 3 andmix until granulation endpoint is reached. • Add silica colloidal anhydrous and if necessary add purified water to the mixture from step4 and mix until the granulation endpoint is reached. • ….

21. 3.7 Process validation report 3.7.1 New (for the generic manufacturer) FPPs • Tabulated batch analytical and in-process control data • Certificates of analysis • Batch production records • Unusual findings, modifications or changes found necessary • Conclusions

22. 3.7 Process Validation and Evaluation 3.7.2 Established (for the generic manufacturer) FPPs • Manufacturing as well as in-process and quality control testing data should be evaluated. All but NLT a total of 10-25 consecutive batches, manufactured over the period of the last 12 months, should be used when reviewing the results, to provide a statistically significant picture. Trend analysis should be presented. • Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations.See Notes page

23. Case summary of 20 batches

24. Standard Claimed (e.g., In-house, BP, PhEur, PhInt, USP) Specification Reference Number and/or Version Test Analytical Procedure (Type/Source/Version) Acceptance Criteria Batch release Shelf life 3.9.1 Specifications for the FPP

25. 3.9.1 Specifications for the FPP • Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria, exclusion of certain tests, differences from compendial standard): • Acceptance criteria for degradants in FDC-FPPs should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, then its acceptance limits should be calculated with reference to the worst case (API with the smallest area under the curve). Alternatively, the content of such impuritiescould be calculated in relation to their reference standards. • Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media.

26. Labeling and product information • 3.12.1 Outer packaging or, where there is no outer packaging, on the immediate packaging. Typical deficiencies: • List of excipients known to be a safety concern for some patients–e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine– are not indicated. • Storage instructionsdo not reflect stability conditions. • Summary of Product Characteristics (SmPC) is frequently not approved by the national DRA. (Particular problem with artemisinin-derivative FPPs.) • The structure of SmPC does not follow that recommended by WHO.

27. Documentation for FPPs from ICH regions • An original or certified copy of WHO-type Certificate of a Pharmaceutical Product (CPP) • Assessment report(s) issued by a DRA in the ICH regions • If the composition, strength, specifications, materials, etc. are different from the product for which the CPP was issued, then pharmaceutical equivalence and bioequivalence should be demonstrated. • If the primary packaging material of the product is different from the one approved by the DRA of the ICH regions, then stability testing data should be submitted. • A sample should be provided. • Change control: approved variations to the MA should be notified.

28. New products developed bygeneric manufacturers

29. Quality risks • Manufacture of APIsisnot regulated • Pharmaceutical exports are not regulated • Marketing Authorization (MA) is issued without evaluation by the NDRA • Clinical studies are not requiredfor generic MA • Stability studies are not requiredfor generic MA • National GMP do not comply with WHO-GMP

30. New products developed bygeneric manufacturers Artemisinine-type antimalarial FPPs • Artesunate 60mg powder for injection is a life-saving FPP • Clinical studies on efficacy and safety should be evaluated • High risk API (at the start of the PQ project) • All issues described with non-compendial APIs and FPPs apply • The FPP manufacturing process and its validation is complex • It takes time to get into compliance 4-FDC antituberculotic FPPs and 3-FDC antiretroviral FPPs: • Compatibility testing of APIs • Dissolution test development • Non-routine manufacturing process

31. Solubility of Artesunate and stability of solutions

32. Main points • Generic guideline is used for the assessment of dossiers submitted for prequalification • An electronic version of the PQIF facilitates evaluation • APIMF is the preferred form of presenting data and information on APIs • Innovator FPPs are prequalified by a simple procedures • New products developed bygeneric manufacturers deserve special attention by quality assessors

33. THANK YOU