Requirements on documentation of API and FPP quality and evaluation process Presenter: Hua YIN Prequalification of Medi

1. Requirements on documentation of API and FPP quality and evaluation process Presenter: Hua YIN Prequalification of Medicines ProgrammeQSM / EMP / HSS

2. Glossary • API Active Pharmaceutical Ingredient • APIMF Active Pharmaceutical Ingredient Master File • ARV Antiretroviral • CoS Certificate of Suitability • EDQM European Directorate for Quality of Medicines and HealthCare • EoI Expression of Interest • FPP Finished Pharmaceutical Product • GMP Good Manufacturing Practices • ICH International Conference on Harmonization • Int. Ph. International Pharmacopoeia • PIL Patient Information Leaflet • PQ Prequalification • PQIF Pharmaceutical Quality Information form • RH Reproductive Health • SPC Summary of Product Characteristics • TB Tuberculosis

3. WHO Reference text for Multisource (Generic) products / Definitions Active Pharmaceutical Ingredient (API) A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient) Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. Finished Pharmaceutical Product (FPP) A product that has undergone all stages of production, including packaging in its final container and labelling.

4. Guidelines for Product dossier /Quality Main Generic guide • Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis[under revision] Annex 1 - Model Certificate of a Pharmaceutical Product  Annex 2 - Model Batch Certificate of Pharmaceutical Product Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API) Annex 4 - Model Stability Report of Capsules/Tablets Annex 5 - Suggested Structure of the Summary of Product Characteristics (SmPC) Annex 6 - Suggested Structure of the Package Information Leaflet (PIL) Annex 7 - Presentation of Bioequivalence Trial Information (BTIF)  Annex 8 - Presentation of Pharmaceutical Quality Information(PQIF) • Supplement 1 : Dissolution testing • Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable)

5. Guidelines for Product dossier /Quality • Guidelines for registration of fixed-dose combination medicinal products • Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure • Guidance on variations to a prequalified dossier • Guide on Submission of Documentation for Prequalification of innovator Finished Pharmaceutical Products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory Authorities (DRAs) in the International Conference on Harmonization (ICH) region and associated countries, including among others the EU, Japan and USA • Prequalification of Generic products approved by Stringent Regulatory Authorities (SRAs) NEW • Requalification NEW • Alternative procedure for accepting 2nd line TB Product dossiers New http://www.who.int/prequal Chinese version available

6. Guidelines for Product dossier /Quality • ICH notes for guidance (When WHO or PQ guidelines silent) for instance: • Q2(R1):Validation of Analytical Procedures • Q3A(R2). Impurities in new drug substances • Q3B(R2). Impurities in new drug products • Q3C(R3). Impurities: Guideline for residual solvents • Q6A. Specifications: • Other agencies' requirements can be referenced. such as EU limits of genotoxic impurities, permitted colorants, EDQM limit of TEA 320ppm.

7. Assessment Process - Quality Submission of application PQIF, Dossier Screening (Internal) Acceptance for evaluationPQ reference No. Pre – Assessment Assessment Additional data Prequalification Requalification

8. Documentation to be submitted to the WHO PQ team • Covering letter Clearly indicate the information submitted is true and correct - Product dossier . Section 1: Characteristics of the FPP. Section 2: Active Pharmaceutical Ingredients (APIs) When more than one API used, use separate Section 2 . Section 3: Finished Pharmaceutical Products (FPPs). Section 4: Interchangeability • PQIF: =Quality overall summary. filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/under training material and workshops, Hanoi, Vietnam, January 2006 • Sample

9. Quality dossier/ Section 1 Information on the FPP 1.1. Details of the Product- Name, dosage form and strength of the product- Approved generic name (INN)- Visual description of the FPP- Visual description of the packaging 1.2. Samples to be provided (for visual examination of assessors and comparison with the SPC and PIL) 1.3. Regulatory situation in Member States / list countries- Countries where a MA has been issued- Countries where a MA has been withdrawn- Countries where a Marketing Application has been rejected, deferred

10. Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

11. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) Scientific data on the API can be submitted using following ways and order of preference • A valid Certificate of Suitability(CoS) or CEP, latest version, with all its annexes issued by EDQM, www.edqm.eu • AnAPIMF(Active Pharmaceutical Ingredient Master File)， submitted by the API manufacturer, containing the whole information requested in section 2 and presented in CTD format (see APIMF guideline) • Completesubmission of data requested in Section 2

12. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.1. Nomenclature 2.2. Properties of the API 2.3. Site(s) of manufacture 2.4. Route(s) of synthesis 2.5. Specifications 2.6. Container- closure system 2.7. Stability testing

13. Quality dossier / Section 2Active Pharmaceutical Ingredient (API)

14. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) • Generic Guideline is under revision. • The PQIF format to be consistent with the CTD format • Focus on CTD format S.1 General Information S.2 Manufacture S.3 Characterisation S.4 Control of Drug Substance S.5 Reference Standards or Materials S.6 Container Closure System S.7 Stability testing

15. S.1 General Information S.1.1 Nomenclature International non-proprietary name (INN), chemical name, Chemical abstarct service (CAS) No., other names such as BAN, USAN… S.1.2 Structure • Chemical structure, sterochemistry , molecular formula and relatively molecular mass

16. S.1 General Information S.1.3 General properties • Physical description • Solubility in water (effect of pH), and organic solvents • Solid state/crystallography (eg polymorphism, including solvation/hydration, amorphous character) • Hygroscopicity • Particle size, etc Such information which relevant to formulating, processing and performance of the FPP

17. S.2 Manufacture • Information on the manufacturer • A flow diagram of the process • A description of the manufacturing process (including, for example, starting materials, reagents, solvents, catalysts，critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API. • A description of the Source and Starting Material and raw materials used in the manufacture of the API; When the synthetic route consists limited number of steps (e.g. One to three), information of starting material should be provided (e.g route of synthesis/specification)

18. S.2 Manufacture • A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Discuss critical process intermediates; • A description of process validation and/or evaluation. • A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency. The QOS should cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes.

19. 2.3.S.3Characterisation • A summary of the interpretation of evidence of structure and isomerism. • For API described in a pharmacopoeia Confirm the structure by comparison with an official Reference Standard using a specific method e.g. IR

20. S.3 Characterisation 3.2 Impurities • Identification of potential and actual impurities arising from synthesis, manufacture and/or degradation, with an indication of their origin: • Impruities contained in the starting material • Starting material unreacted • Intermediates unreacted • By-products (unwanted reaction products) • Degradants • Reagents,Catalysts,Residual solvents • Summary of the levels of the actual impurities detected in the batch samples (e.g. non clinical, clinical, toxicological studies, stability) • Justification for selecting the limits, based on safety and toxicity data when applicable. ICH Q3A

21. S.4 Control of Drug Substance • A summary of the specification, analytical procedures and validation of the methods should be included. For Pharmacopoeial API • The current monographalways applicable • Additional critical specifications not included in monograph e.g. • particlesize & polymorphic form • impurities, resulting from specific synthesis process • residual solvents (specific to process) • Analytical procedures should be verified under actual condition of use, such as specificity, precision, and stability of the sample solution

22. S.5 Reference Standards or Materials • For pharmacopoeial APIs: use an official Reference Standard (USP, Ph. Eur., Int. Ph.) as primary standard • For non-pharmacopoeial APIs Description of how primary and/or a working standard has been established • Provide Certificate of Analyses, including storage instuctions and duration of use

23. S.6 Container closure system • Description of the packaging • Identification of materials and components of the packaging • Specifications of these materials • Justification for choice of these materials, e.g. - protection against light, humidity - compatibility of the used materials with the API, interactions between the API and the closure such as sorption, leaching (mainly in case of a liquid API)

24. S.7 Stability • Stress study • to know different degradation pathways of an API and degradation products formed • to demonstrate the intrinsic stability of the API • To demonstrate the stability indicating power of the analytical procedure used Reference can be done to the literature, if the above information is there available

25. S.7 Stability • Formal stability study • To establish a re-test period • To determine the storage / labelling statement Definition of the re-test period Period of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined storage conditions

26. S.7 Stability • A summary of the studies undertaken • conditions, • batches, • packaging • Stability-indicating quality parameters • analytical procedures) • A brief discussion of the results and conclusions • The proposed storage conditions, retest date or shelf life. • The post-approval stability protocol should be included

27. Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

28. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

29. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12. Container labelling 3.13. Product information for health professionals (SmPC) 3.14. Patient information and package leaflet 3.15. Justification for any differences to the product in the country ORcountries issuing the submitted WHO-type certificate(s) Same as CTD, only different in numbering. Product information listed at the end which are included in CTD module 1.

30. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and Marketing Authorization • Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for • Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements

31. 3.2. Pharmaceutical development The aim is to build a quality product by design. • Empirical (minimal)- essential product development for all products • Enhanced- Quality by Design Critical understanding of product and process Regulatory relief

32. 3.2. Pharmaceutical development Empirical product development • Select the product profile (FPP) based on S&E and quality • Investigate quality attributes of the formulation components such as API, excipients etc. • Establish critical quality attributes • Determine an appropriate manufacturing process and scale up (process optimization) • the container closure system • microbiological attributes • Documentation Develop a formulation similar to the innovator product. Reduce risk pertaining to compatibility, manufacturability, stability and bioavailability

33. 3.2. Pharmaceutical development • Physico-chemical characteristics of the APIs • solubility (composition) • water content (stability) • hygroscopicity (stability) • particle size (solubility, bioavailability, suspension properties, stability …) • polymorphism (solubility, bioavailability, stability) • Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet …… • Experimental data (if necessary)

34. 3.2. Pharmaceutical development • For fixed-dose combination (FDC) products • Compatibility of APIs with each other • WHO Guidelines for registration of fixed-dose combination medicinal products • WHO TRS 929 (on WHO Prequalification website) • Choice of excipients, e.g. • Compatibility with API(s) • Intended functions and concentrations in product • Characteristics (flowability, density, water content, etc) • Safety aspects, e.g. TSE risk, to be addressed

35. 3.2. Pharmaceutical development • Selection, optimisation of manufacturing process • Rational behind the choice (e.g. why a non over kill process as a sterilisation process instead of terminal sterilisation in final container) • Critical steps & In process controls • Overages (justification) • Unsatisfactory processes to be rectified

36. 3.2. Pharmaceutical development • Comparative dissolution testing • See Supplement 1 • A tool in selection of the formulation and optimisation of the process • compare formulation(s) with innovator product • a basic strategy in development to maximize the chances of bioequivalence • Comparison of pivotal batches to commercial batches • post-approval changes • Setting of dissolution specifications- a discriminatory dissolution method

37. 3.2. Pharmaceutical development comparative dissolution testing (cont’d) • Three media - 900 ml or less - all at 37°C • Buffer pH 1.2 or 0.1M HCl • Buffer pH 4.5 • Buffer pH 6.8 • Water may be usedadditionally (not instead of) • Paddle at 50 or basket at 100 rpm • Twelve units of each product in all 3 media • Dissolution samples collected at short intervals, e.g. • 10, 15, 20, 30, 45 and 60 minutes • Analyse samples for all APIs, when applicable • Calculate similarity factor f2

38. 3.2. Pharmaceutical development 6. Details of batches studied • Provide a summary of development of the FPP from pre-formulation to production scale. • Provide a comparison of formulas (tabulated form) of: • bio-batche(s) (clinical / bioequivalence), • development batches, • stability batches, • batches for validation/production

39. 3.3. Formulation • Formula in tabulated form for : • Administration unit (e.g. one tablet), • Typical batch - Precise any overage, - Precise quantity adjustment of the API, - Precise q.s. for excipient. • Excipients : • State function (e.g. lubricant, disintegrant), • Precise technical grade (e.g. micronised, purified water), • describe also those removed during process (e.g. water), • Describe also those not always added (e.g. acid & alkali for pH adjustment, • Capsule shells, inked imprints on dosage form, • Also gas (inert atmosphere).

40. 3.4. Manufacturing sites • Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control. Indicate the Unit, block if any. • Include any alternative manufacturers • Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed • Submit a valid GMP certificate

41. 3.5. Manufacturing process • A flow diagram giving the steps of the process and 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. • Description of manufacturing/packaging including • Steps of the process • Scale of production • Equipment by type (e.g. tumble blender) & working capacity • Process parameters for steps, (e.g. time, temperature, pH) • Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs • Alternative methods

42. 3.5. Manufacturing process • Proposal for reprocessing – justified with data. • Copy of master formula. • Batch manufacturing record – real batch (Biobatch) • Sterile products – sterilisation steps and/or aseptic procedures.

43. 3.6. Manufacturing Process Controls of Critical steps and Intermediates • Identification of critical steps with test methods and justified acceptance criteria • Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them

44. 3.7. Process Validation and Evaluation • Each critical step of the manufacturing process must be validated • Other steps in the process must be under control to maximize the probability that the finished product meets all quality and design specifications

45. 3.7. Process Validation and Evaluation • To understand the sources of variation • To detect the presence and degree of variation • To understand the impact of variation on the process and ultimately on product attributes • To control the variation in a manner commensurate with the risk it represents to the process and product

46. 3.7. Process Validation and Evaluation The following unit operations are generally accepted as critical for most pharmaceutical processes: • Blending operations • Encapsulation • Tablet compression • Sterilization procedures • Lyophilization

47. 3.7. Process Validation and Evaluation Validate the performance of manufacturing processes that may be responsible for causing variability in the product: • Mixing homogeneity • Tablet/capsule weight variation • Disintegration time • Dissolution rate and time • pH of aqueous solutions

48. 3.7. Process Validation and EvaluationNew Generic FPPs • Information form product development studies and primary batches should be used in designing the validation protocol • Differences in design, operating principles, size, etc. between pilot and production batches should be highlighted • Protocol should be linked to the lot of FPP used in bioequivalency studies • Comparative dissolution profiles of process validation batches against dissolution profile of the bio lot should be provided • Commitment to undertake validation of three consecutive batches should be provided

49. 3.7. Process Validation and Evaluation Validation protocol should include • brief description of the process with summary of critical steps and parameters to be followed during validation, • specifications of the FPP at release, details of analytical methods. • In-process controls with acceptance criteria(cross reference) • Additional testing intended to be carried out • sampling plan, • unifromity of dosage units is essential for FDCs, • proposed timeframe Validation report when submitted should includeresults for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions

50. 3.7. Process Validation and EvaluationEstablished FPPs • Details of the batches manufactured in the last several years, 10- 25 consecutive batches • Formulation and description of method of manufacture, including in-process control test • Specification and test methods • Changes to formulation or process, if any, or compliance problems • Comprehensive report using retrospective validation