WHO Training Workshop on Pharmaceutical Quality, G MP and Bioequivalence with a focus on artemisinines

1. János Pogány, pharmacist, Ph.D. consultant to WHO Tanzania, 22 August 2006 E-mail: pogany.janos@chello.hu WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalencewith a focus on artemisinines PQIF – FPP Manufacturing process, QC specifications, Container/closure system,Stability studies, Labelling Pogány - Dar es Salaam

2. Abbreviations APIActive Pharmaceutical Ingredient DRADrug Regulatory Authority EoIExpression of Interest FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMP Good Manufacturing Practices ICH International Conference on Harmonization MA Marketing Authorization PQIF Pharmaceutical Quality Information Form Yellow → emphasis Green → WHO Blue → ICH region Pogány - Dar es Salaam

3. Subjects for discussion • Unit and batch formulas (compositions) • Manufacturing process definition • Manufacturing process control and validation • Excipients • FPP specifications • Container/closure systems • Stability • Labelling and product information • Main points again Pogány - Dar es Salaam

4. 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 Section 3. Finished pharmaceutical product(s) [FPP(s)]

5. 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 Manufacturing process

6. Strength (label claim) See Master Production Document Reference Number and/or Version Notes Batch Size (number of dosage units) Page Ingredients Quality standard Unit composition Batch quantities mg % kg % 3.3 Formulation Pogány - Dar es Salaam

7. 3.3 Formulation • Composition of all components that are mixtures (e.g., colourants, coatings, capsule shells, imprinting inks) should be given. • Where ranges of batch size are proposed for production–blending of batches or the use of sub-batches– the acceptability should be addressed. • Description of accompanying reconstitution diluent(s), if applicable Pogány - Dar es Salaam

8. 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. Pogány - Dar es Salaam

9. 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 Pogány - Dar es Salaam

10. Narrative of manufacturing process • Mix Amodiaquine hydrochloride, lactose monohydrate and maize starch in a high-shear, high-speed granulator for approx. 8 min. • 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. • …. Pogány - Dar es Salaam

11. 3.5Manufacturing process • Equipment should, at least, be identified by type (e.g., high-speed granulator, fluid bed drier) and working capacity, where relevant. • Steps in the process should have the appropriate process parameters identified, such as time, temperature, or pH. • Associated numeric values can be presented as an expected range. • Numeric ranges for critical steps should be justified (e.g., blending parameters, LOD of the compression blend, tablet hardness, in-process as well as final yields). Pogány - Dar es Salaam

12. 3.5Manufacturing process • In certain cases, environmental conditions (e.g., experimentally documented temperature and relative humidity for granules) should be stated. • A copy of the master formula and a copy of a manufacturing record for a real batch should be provided. • Documented evaluation of at least three (3) production batches(approved batch size)should be submitted to provide assurance that the manufacturing process will reliably meet predetermined specifications. Pogány - Dar es Salaam

13. 3.6 Manufacturing Process Controls of Critical Steps and Intermediates • Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps of the manufacturing process, to ensure that the process is controlled. • Intermediates: Information on the quality and control of intermediates (e.g., granules blend for compression, tablet cores for film-coating) isolated during the process should be provided. Pogány - Dar es Salaam

14. 3.7 Process Validation and Evaluation 3.7.1 New (for the generic manufacturer) FPPs • Data should be submitted in the application for prequalification demonstrating the validity(batch-to-batch reproducibility of FPP quality) of the manufacturing process. • Summary of the process validation and/or evaluation studies conducted (e.g., batch numbers, batch sizes, testing parameters, acceptance criteria),or • Summary of the proposed validation protocol for the critical steps or critical assays used in the manufacturing process (e.g., protocol number, parameters, results): Pogány - Dar es Salaam

15. 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 Pogány - Dar es Salaam

16. 3.7 Process Validation and Evaluation 3.7.2 Established (for the generic manufacturer) FPPs • Manufacturing as well as in-process and quality controltesting 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 butmust be reported together with the reports of failure investigations.See Notes page Pogány - Dar es Salaam

17. 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 Specifications

18. 3.8.2 Excipients described in BP, PhInt, PhEur, or USP • All excipients, which are present in the product, should be listed, even those present in small amounts, such as printing inks. • Summary of the in-house specificationsof compendial excipients and supplementary tests not included in the monograph(s): • For oils of plant origin (e.g., soy bean oil, peanut oil) demonstrate the absence of aflatoxins or biocides. • List of excipients that are of human or animal origin (including country of origin): • Summary of the information (e.g., sources, specifications, description of the testing performed, viral safety data) regarding adventitious agents for excipients of human or animal origin: Pogány - Dar es Salaam

19. 3.8.2 Excipients described in BP, PhInt, PhEur, or USP • For excipients obtained from sources that are at risk of transmitting Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) agents (e.g., ruminant origin), a letter of attestation (with supporting documentation) should be provided confirming that the material is not from a BSE/TSE affected country/area. A copy of the letter may be found in: • Certificate of analysis for one batch of each excipient from the approved supplier should be provided. Pogány - Dar es Salaam

20. 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 Pogány - Dar es Salaam

21. 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. Pogány - Dar es Salaam

22. 3.9.1 Specifications for the FPP • Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media. • Validation of analytical procedures: State if in accordance with ICH or not, and mention any deviations. (All control methods, regardless of whether they are applicable to control at release or to the shelf life should be discussed here). • Requirements for FDC FPPs Pogány - Dar es Salaam

23. Dissolution report Non-compendial generic FPP • The pH solubility profile of the API • Dissolution profiles generated at different agitation speeds. Dissolution profiles generated on all strengths in at least three dissolution media. • Select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available data Compendial generic FPPs • Appropriate pharmacopeial (PhEur, PhInt, USP) method; or the dissolution method development report described above. Pogány - Dar es Salaam

24. Dissolution data for a typical IR FPP in a dossier • Dissolution results under a variety of agitation and media conditions. • A method that provides rapid dissolution profile; Mean and range of dissolution values of 12 units from the bio batch(es) plus a few to several production batches under this condition. • Stability data. Pogány - Dar es Salaam

25. Decision on FPP specifications • Sufficient data submitted; specs finalized • Insufficient data submitted • interim specs set for a limited time frame; additional data submitted; specs finalized. • specs can’t be finalized, including interim specs; additional data required; approval decision finalized. Pogány - Dar es Salaam

26. 3.9.1 Specifications for the FPP • Results of not less than three (3) batch analyses (including the date of manufacture, place of manufacture, batch size and use of batch tested) must be presented. The batch analysis must include the results obtained for all specifications at release. • Batch analysis results (n=?); do these confirm consistency and uniformity of the product? Do they indicate that the process is under control? Pogány - Dar es Salaam

27. 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 Container/closure system and other packaging

28. 3.10 Container/closure system(s) and other packaging • Description of the container closure systems, including unit count or fill size, container size or volume: • Materials of construction of each primary packaging component: • Summary of specifications of each primary and functional secondary (e.g., foil pouches) packaging components: Pogány - Dar es Salaam

29. 3.10 Container/closure system(s) and other packaging • Identification of the material generally by infrared absorption spectrophotometry, with indication of the position of characteristic absorption bands. The infrared spectrum of the reference material should be provided: other methods of identification may be appropriate. • Identification of the main additives in particular those which are likely to migrate into the contents (such as antioxidants, plasticisers, catalysts, initiators, etc.... and, for PVC, phthalates, adipates and organic tin compounds). • Identification of dyes by using chromatographic or any other appropriate method. Pogány - Dar es Salaam

30. 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 Stability studies

31. 3.11 Stability testing • The design of the formal stability studies for the finished product should be based on knowledge of the behavior and properties of the API and the dosage form. • 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. • It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage. Pogány - Dar es Salaam

32. 3.11 Stability testing • Report and discuss the results of stability testing as described in Annex 2. Organize data for all attributes separately and evaluate each attribute in the report. • Shelf life acceptance criteria should be derived from consideration of all available stability information. • Long-term studies should cover the whole shelf life. When available long-term stability data on primary batches do not cover the proposed shelf-life period granted at the time of approval, a commitment should be made in writing to continue the stability studies post approval. The post-approval stability protocol should also be provided and should be the same as that for the primary batches, unless otherwise scientifically justified. Pogány - Dar es Salaam

33. Letter of commitment We, <name of applicant> undertaketo continue long-term stability testing of <name of FPP> (batch numbers …….., ………. and ……………………) according to the stability protocol of primary batches, for a period of time sufficient to cover the whole pre-qualified shelf life (NLT 24 months ending ………………….) and to report anysignificant change and out-of-specificationresults immediately to WHO. Pogány - Dar es Salaam

34. 3.11.3Selection of Batches • At the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing. • Stability data on three primary batches are to be provided. One of the three batches should be of production scale, the remaining two batches at least pilot scale. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. Pogány - Dar es Salaam

35. Storage Conditions (C, % RH) Batch Number Batch Size Container Closure System Completed (proposed) Test Intervals (months) 3.11.10 Evaluation • Summary of stress testing and results: • Summary of accelerated and long term testing (e.g., studies conducted, protocols used, results obtained): Summary and discussion of stability study results: Proposed storage conditions and shelf life (and in-use storage conditions and in-use period, if applicable): Pogány - Dar es Salaam

36. WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalencewith a focus on artemisinines Labeling

37. 3.12 Container labeling • 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. • 3.12.2 Blisters and strips Pogány - Dar es Salaam

38. 3.13 Product information for health professionals3.14 Patient information and package inserts • 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. • Pharmaceutical data are not counter-checked against the quality part of the submission. Typical deficiencies include: • Number(s) in the national register of FPPs. • Date of first marketing authorisation/renewal of the authorisation. Pogány - Dar es Salaam

39. Points to be communicated to the applicant A.General remark, if applicable B. Observations, information C.Overall conclusion Reviewer’s conclusion, based on the review of the data on quality. D. Post-approval commitments The reviewer lists the outstanding commitments, which the applicant had undertaken in writing before the FPPwas listed on the prequalification list. Recommendations for inspection The reviewerlist quality issues identified during the dossier assessment that require verification during a product-specific inspection. Pogány - Dar es Salaam

40. Change control • Guidance on variations to a prequalified dossier. • Conditions and requirements for 40 minor changes are detailed. Typical examples: • Change of API manufacturer • Change of manufacturing site • Change of batch size • Requalification of the prequalified FPP Pogány - Dar es Salaam

41. Current regulatory developments • Pharmaceutical manufacturing operations are inefficient and costly. • Low efficiency is predominantly due to "self-imposed" constraints in the system (e.g., static manufacturing processes, focus on testing as opposed to quality by design). • ICH guidanceQ9(draft) describes the level of risk-mitigation achieved through quality by design and process understanding. Pogány - Dar es Salaam

42. Current regulatory developments • Manufacturing processes of innovator and generic manufacturers are fundamentally the same. • Efforts are primarily directed towards reducing variability in process and product quality characteristics and are not for changing the fundamental design of a manufacturing process. • Empirical methods are probably approaching their theoretical maximum effectiveness. New scientific understanding and new technologies can provide science- and engineering-based approaches. Pogány - Dar es Salaam

43. Current regulatory developments • A process is well understood when: • all critical sources of variability are identified and explained • variability is managed by the process • product quality attributes can be accurately and reliably predicted • Process understanding inversely proportional to product quality risk. • Real time product release is on the regulatory horizon. Pogány - Dar es Salaam

44. Main points again • The manufacturing process should be clearly defined (site, composition, batch size, equipment, flow diagram, narrative) and well documented. • APIs, excipients and primary packing materials should be bought only from approved suppliers. • Batch-to-batch consistency of FPP quality should be achieved through validation and annual evaluation of product and process control results. Pogány - Dar es Salaam

45. Main points again • Release specifications have to be reviewed at the end of stability studies to establish if change of acceptance criteria is justified. • The SmPC and Patients’ leaflet should reflect the design, development and manufacturing information of the submission. • Attributes of prequalified FPPs should only be changed after approval of variation by WHO. Pogány - Dar es Salaam

46. THANK YOU Pogány - Dar es Salaam