Dossier Requirements (quality part)

1. Dossier Requirements(quality part) Workshop on GMP and Quality Assurance of Multisource Tuberculosis Medicines Kuala Lumpur – Malaysia 21-25 February 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa iiftgd@puk.ac.za

2. Some abbreviations API Active pharmaceutical ingredient BP British Pharmacopoeia CEP EU certificate of suitability CPP WHO-type Certificate of a Pharmaceutical Product EOI Expression of interest FDC Fixed dose combination FPP Finished pharmaceutical product ICH International Conference onHarmonization Int.Ph. International Pharmacopoeia JP Japanese Pharmacopoeia Ph.Eur.European Pharmacopoeia SmPC Summary of product characteristics TB Tuberculosis USP United States Pharmacopeia

3. 5th Invitation for EOI (July 2004) (1) First-line anti-TB products • Ethambutol hydrochloride (Eth) 400 mg tablets • Pyrazinamide (Py) 400 mg tablets • Isoniazid (INH) 300 mg tablets • Fixed dose combinations: • 2FDC: Rif/INH 150/75 mg tablets • 2FDC: Rif/INH 150/150 mg tablets • 2FDC: Eth/INH 400/150 mg tablets • 3FDC: Rif/INH/Eth 150/75/275 mg tablets • 4FDC: Rif/INH/Py/Eth 150/75/400/275 mg tablets • Streptomycin Sulfate 1g vial (injection)

4. 5th Invitation for EOI (July 2004) (2) Second-line anti-TB products • Water for injection 5ml vial (injection) • Amikacin 500mg/2 ml vial (injection) • Kanamycin 1g powder for injection, vial • Capreomycin 1g powder for injection, vial • Cycloserine 250mg tablets • Ethionamide 125 mg or 250mg tablets • Ofloxacin 200 mg tablets • Protionamide 125 mg or 250mg tablets • Para-Aminosalicylic Acid 100 g or 4 g granules or powder • Moxifloxacin 400 mg tablets

5. 5th Invitation for EOI (July 2004) (3) Formulations for children • Dosage forms should be • soluble tablets, • tablets with break line, and or • sachets • Rifampicin 60 mg / Isoniazid 60mg / Pyrazinamide 150 mg (R60/H30/Z150) • Rifampicin 60 mg / Isoniazid 30mg (R60/H30) • Rifampicin 60 mg / Isoniazid 60 mg (R60/H60) Total number of products on current list: 22

6. Product characteristics • When developing, evaluating and considering finished pharmaceutical products (FPPs), the following are the main characteristics: • Safety • Efficacy • Quality • These aspects are to some extent interrelated • Quality (as part of GMP) must ensure consistency of safety and efficacy of all batches produced

7. Guideline (ICH registered products) Guideline on Submission of Documentationfor 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 inter alia the European Union, Japan and USA (handout)

8. ICH registered products - requirements • Certified copy of WHO-type CPP • Assessment report(s) issued by DRA • WHO-type batch certificate • Primary packaging differs from ICH approved? • Stability data in new packaging • Formulation, strength (??), specs., etc. differ? • Justification in favour of acceptability (BE?) • Submit sample(s) of FPP

9. Guideline (Not ICH registered products) Guideline on Submission of Documentationfor Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs)used in the Treatment of HIV/AIDS, Malaria and Tuberculosis (hand-out) Based on Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority (Blue Book)

10. Quality assessment - summary The quality assessment includes the following aspects: 1 Characteristics of FPP 2/33 2 API (impurities, stability, specifications, etc) 3/33 3 Finished pharmaceutical product (FFP) 8/33 • Pharmaceutical development 8/33 • Formulation 9/33 • Manufacturing process/validation 9/33 • Excipients 12/33 • Product specifications/control 12/33 • Packaging 14/33 • Stability testing (shelf-life) 14/33 • Labelling/SmPC/PIL 19/33

11. Administrative 1/33 A: Covering letter • Statement: information is true and correct B: Application (FPPdossier) • Four main sections (with subsections) • Stick to the sections prescribed • Sections should be clearly marked (preferably with securely fixed tags) • Number all pages • Table of contents

12. Section 1. Characteristics of FPP 2/33 • Details of product • Sample for visual inspection of product and packaging • Regulatory status in other countries. List countries in which: • This product has been granted a marketing authorization • this product has been withdrawn from the market • the application for marketing has been rejected, deferred or withdrawn

13. Section 2. Active pharmaceutical ingredient (API) 3/33separate topic 2.1 Nomenclature (INN, Systematic, CAS, etc.) 2.2 Properties (structure, stereochemistry, etc) 2.3 Site of manufacture 2.4 Route of synthesis (impurities, etc) 2.5 Specifications (pharmacopoeia?) 2.6 Container closure system 2.7 Stability testing – re-test period & storage - • Open part of Drug Master File (DMF) • CEP

14. Section 2. API 3/33 The API (name) & strength per unit dose can be considered the only constants when starting to development the dosage form and to chose primary packaging materials. Thus, it is important to understand: • The physical properties, whichshould be well studied and dealt with (e.g. flowability, particle size, polymorphism, hygroscopicity, solubility) • The chemical properties, especially aspects such as- stability (mainly hydrolysis, oxidation & photolysis)- possible API-excipient interactions- API-API interactions in FDCs (API details will be dealt with in separate session)

15. Section 3. Finished pharmaceutical product (FPP) 8/33 3.1 Authorisation8/33 • Submit valid manufacturing authorisation for pharmaceutical production • Submit marketing authorisation • To demonstrate that product is registered or licensed according to national requirements

16. 3.2 Pharmaceutical development 8/33separate topic Pharmaceutical R & D provides the foundation of the activities aimed at ensuring thatthe patient receives an FPP (product) that consistently meets established standards & specifications of • Safety • Efficacy • Quality, including stability Typical aspects covered in development studies: • Choice of dosage form, excipients & packaging • Compatibilities of API with excipients, primary packaging materials, and other APIs (in FDCs) • Development/validation of analytical methods

17. Pharmaceutical development • Learn about the product through desk research: • Collect & analyse available information on e.g. APIs, formulas, excipients, compatibility, stability, dosage form, strength, packaging & analysis. • Compile a Product Profile Report • Development according toplan, including: • Preformulation studies • Formula / dosage form development & packaging • Development/validation of analytical techniques • Comparative dissolution studies • (Accelerated) stability • Final formula / manufacturing process • Provide a development report

18. 3.3 Formulation 9/33 • Formula in tabulated form for: • Administration unit (e.g. one tablet) • Typical batch • Excipients • State function (e.g. lubricant, disintegrant) • Special technical grade (e.g. micronised, purified water) • Also those removed during process (e.g. water) • Also those not always added (e.g. acid & alkali) • Capsule shells, inked imprints on dosage form

19. Formulation table example ٭Removed during process (not in total mass)

20. 3.4 Sites of manufacture 9/33 For each facility where all/part of manufacturing occurs, including production, packaging & QC: • Name of manufacturer • Street address • Phone & fax numbers • E-mail addresses • For major production sites submit • WHO type of CPP • Valid GMP certificate

21. 3.5 Manufacturing process9/33 • Flow diagram • Indicate critical steps – in-process controls • Description of manufacturing/packaging • Scale • Equipment by type (e.g. tumble dryer) & capacity • Process parameters for steps, e.g. time, temp, pH • Environmental conditions, e.g. rel. humidity for hygroscopic FPPs.

22. Manufacturing process (continued) • Proposal for reprocessing – justified with data • Copy of master formula • Batch manufacturing record – real batch • Sterile products – sterilisation steps &/or aseptic procedures • Description of in-process tests • Data for ≥ 3 full scale batches to support achievement of predetermined specifications

23. 3.6 Process controls10/33 • Critical steps • Acceptance criteria (justified) • Tests (cross reference) • Intermediates isolated during process • Acceptance criteria (justified if not compendial) • Tests (cross reference)

24. 3.7 Process validation & evaluation10/33 Differentiate between the following generics: 3.7.1 New FPPs (new for manufacturer) • FPPs that have been newly developed by the manufacturer, though it will be a generic • Full validation required 3.7.2 Established FPPs • The manufacturer has manufactured & marketed this FPP for quite some time and now wishes to prequalify the FPP • ≥ 10 recent consecutive batches – result/trend/statistical analysis & discussion

25. 3.7.1 Validation “new” product10/33 Demonstrate validity of the process • Report for 3 production batches, including • Batch analytical data • CoAs • Batch production records • Conclusions • Otherwise validation protocol – with commitment • See guidelines for protocol requirements (page 11/33) • Report will be available for inspection • Validation report to be submitted (page 11/33) Sound pharmaceutical R&D and a valid process = reproducible product of good quality

26. 3.8 Excipients - specifications12/33 • Of natural origin? • Microbial limits (skip-testing) • Of human or animal origin? Info on adventitious agents, such as: • TSE/BSE (e.g. Mg-stearate from animal origin) • Asbestos in talc (test included in current BP/Ph.Eur. – IR and XRPD) • Colours permitted by: • EU, FDA, Japan (references bottom p. 12/33)

27. 3.8.1 Excipients not in compendia12/33 • Such excipients not recommended • See guideline for requirements • Some standard mixtures comprising excipients in pharmacopoeia, e.g. Opadry colours • Table with composition of such mixture • Specifications with tests (normally from supplier) Compendia (pharmacopoeias) considered: • International Pharmacopoeia (Int.Ph.) • BP, JP, Ph.Eur, USP (ICH region)

28. 3.8.2 Excipients described in compendia12/33 • Provide a copy of monograph • Also copies of methods referred to in monograph but not appearing in monograph • Current pharmacopoeial monograph always applicable • If monograph change, new monograph valid • Details of any specifications additional to monograph • E.g. particle size, residual solvents

29. 3.9 Control of FPP12/33 Four subsections: • Specifications • Analytical procedures • Validation of analytical procedures • Batch analysis

30. 3.9.1 Specifications for the FPP12/33 Specifications are one part of a total control strategy for the FPP designed to ensure product quality and consistency (ICH: Q6A). • Others include adherence to GMP; e.g., suitable facilities, a validated manufacturing process, in-process testing, stability testing, API testing, etc. • Product specifications (as in pharmacopoeia) orsplit into: • Release specifications • Shelf-life specifications (may differ if justified)

31. 3.9.1 FPP specifications – continued Important reading for setting specifications: • ICH guideline Q6A (also good for generics): • Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Specifications based on pharmacopoeia: • Additional product related specifications, e.g. • Those standard for the dosage form (e.g. friability, tablet hardness, mass uniformity) • ID of (coating) colorants, microbial limits (skip testing?) • Related substances in USP monograph for TB 4FDC

32. 3.9.1 FPP specifications – typical • Appearance • Identification of the following in FPP • APIs • Colorants (skip testing possible) • Preservatives • Physical tests appropriate to dosage form e.g. • LOD, friability, hardness (tabs), relative density • Uniformity of dosage units (mass / content) • Pharmaceutical tests, e.g. dissolution

33. 3.9.1 FPP specifications – typical (con.) • Purity tests • Degradation products (related substances) • Residual solvents (solvents used in process) • Microbial count / sterility / bacterial endotoxins • Content of APIs in FPP (assay) • Limits 95.0% – 105.0%, unless justified • Content of preservatives • Limits 90.0% – 110.0%, generally acceptable

34. Example - FPP specs – uncoated tablets

35. Example of FPP specs – uncoated tabs (con.)

36. FPP specifications – special for FDCs • Degradants (related substances) must be stated & calculated in % with reference to the parent API, not the sum of the APIs, e.g. • Rifampicin / isoniazid tablets. Rifampicin quinone (degradant) as % of rifampicin. • If 2 APIs react with each other, then the degradant to be stated with respect to worst case, e.g. • Rifampicin / isoniazid tablets. A Hydrazone forms from the 2 APIs. Specification: % hydrazone with respect to rifampicin (worst case in mass balance). • Unknown degradants – with respect to worst case • Dissolution – include all APIs (e.g. FDCs in the USP)

37. 3.9.2 Analytical procedures13/33 • Methods to be described in detail • Copy of standard monograph tests (e.g. friability) • System suitability included in HPLC methods • Pharmacopoeial based control: • Copy of monograph (latest edition) • Methods of additional tests (e.g. ID of coating colorants)

38. 3.9.3 Validation analytical methods13/33 • Non-pharmacopoeial methods • All methods should be validated • Validation reports, including data & conclusions • Stability of sample/standard solutions • Pharmacopoeial methods • Partial validation (to show validity for this formulation – specificity important) • Validation study - ICH guidelines: • Q2A & Q2B

39. ICH (Q2A) table - validation parameters13/33

40. 3.9.4 Batch analysis14/33 Results of at least 3 batches • Testing against for full set of specifications • Test date • QA certified • Batch number • Date of batch manufacture • Place of manufacture • Batch size (kg & units) • Primary packaging materials • Purpose of batches (stability, commercial, etc.) • API batch number

41. 3.10 Packaging14/33 • Container/closure system • Suitability for storage, transport, compatibility • Detailed description, including liner/wadding • Specifications: - Description- Identification (Typical: IR - specific)- Drawings and critical dimensions • Outer packaging • Description, material

42. 3.11 Stability testing14/33 separate topic • The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light and to establish a shelf-life for the FPP (from current EMEA guidance CPMP/QWP/122/02). • Stability studies should be performed- on each individual strength- each type of commercial container and- each container size (unless bracketing/matrixing)

43. Stability parameters (attributes) Stability studies should include testing of those attributes of the FPP that are • susceptible to change during storage and are • likely to influence quality, safety, and/or efficacy. • The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system) From ICH Q1A(R2)

44. Tablets – stability parameters • Parameters specifically for tablets (often omitted) • Tablet strength, friability and moisture can change with time– if not in release specs, include in stability– these are interrelated, also with dissolution • Microbial limit at release and end-of-shelf • Dissolution specification must be same as for release

45. Stability report See Annex 2 (Guidelines) • Info on batches tested • Unit composition (or cross-reference) • Container closure system (commercial!!) • Literature and/or supporting data • Methods – stability indicating (cross-reference) • Stability plan (schedule) • Tabulated test data (including specifications) • Analysis/discussion of data (statistical if negative trend) • Shelf-life proposal (including storage condition) • Post approval commitments

46. Testing frequency & storage conditions Solid oral dosage forms (tablets, capsules): • Zone IV is real-time condition for prequalification project unless otherwise justified • Zone II only if justified (may be fall-back for zone IV) • ASEAN proposal for zone IV: 30ºC / 75% RH

47. 3.12 Container labelling 19/33 • Outer packaging (where no outer packaging, on immediate packaging – e.g.securitainer) • Blisters and strips • All the elements as listed on pages 19-20 of: • Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.

48. SmPC and PIL 20/33 3.13 Summary of product characteristics (SmPC) • To appear in WHOPAR • Changes to SmPC to be approved by WHO • See Annex 3 of guideline 3.14 Patient information leaflet (PIL) • To appear in WHOPAR • In conformance with SmPC • From quality side, include in SmPC & PIL: • Identification of dosage form in detail • Presentation in detail • Storage requirements and approved shelf-life

49. Variations Draft guidance on variations with respect tothe dossier submitted and accepted in thePrequalification Programme (Handout) • ANNEX I (p. 3) - minor changes • ANNEX II (p. 27) - major changes in general • ANNEX III (p. 29) - types of changes requiring a new application

50. Minor changes • A minor change is a change concerning an amendment to the contentsof the documents such as they existed at the time of listing as prequalified • The request, with documentation, for a minor change must be submitted for approval • The minor changes in the guideline are listed in numerical order, with the conditions to meet and documentation required • Currently 41 minor type of changes listed • A few examples to follow (follow guideline numbers)