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 Pharmaceutical quality by design and development 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 • DESIGN (product-specific research) • Desk research • API (specifications, stress stability testing, etc.) • FPP (pre-formulation, screening stability studies, etc.) • DEVELOPMENT[FPP andmanufacturing process (same for innovator and generic FPPs)] • Laboratory • Pilot plant (dissolution equivalence, stability and bioequivalence studies, tentative FPP specifications, prospective validation) • Production plant (concurrent validation) • Main points again Pogány - Dar es Salaam

4. Applicable guidelines • Annex 6. Validation of manufacturing processes, in WHO TRS No. 863 (1996). • WHO „Guideline on Submission of Documentation forPrequalification ofMulti-source (Generic) Finished Pharmaceutical Products (FPPs)Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.3.2 Pharmaceutical Development • ICH Q8 Pharmaceutical Development (Nov. 2005) • ICH Q9 Quality risk management (E.g.,FMEA … might be used to analyze a manufacturing operation and its effect on product or process. It identifies elements/operations within the system that render it vulnerable.) Pogány - Dar es Salaam

5. WHO guidelines • Annex 7 - Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, in WHO TRS, No. 937, 2006 • Annex 8 - Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (ibid) • Annex 11 - Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products, in WHO Technical Report Series, No. 902, 2002 • Annex 5 - Guidelines for registration of fixed-dose combination medicinal products, in WHO TRS, No. 929, 2005 Pogány - Dar es Salaam

6. Related WHO guidelines • Guideline on Submission of Documentation for Prequalification ofMulti-source (Generic) Finished Pharmaceutical Products (FPPs)Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis • Guidance on Variations to a Prequalified Dossier Pogány - Dar es Salaam

7. EOI – Scope of presentation • Artesunate*+ Amodiaquine • Artemether*+Lumefantrine* • Artesunate*+ Mefloquine • Artesunate*+ SP (sulphadoxine / pyrimethamine) *No comparator at the beginning*High quality-risk API + ... FDC or co-blistered (co-packaged) FPPs All oral FPPs include paediatric formulations. (EOI is included in the Notes Page of this and the subsequent slides) Pogány - Dar es Salaam

8. EOI – Scope of presentation • Artemether Injection and rectal FPPs • Artemotil (arteether) Injection • Artesunate Injection and rectal FPPs Only FPPs listed in the EOI are discussed. Pogány - Dar es Salaam

9. Pogány - Dar es Salaam

10. 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 3.2.1 Information from literature(Desk research)

11. General considerations • The marketing of a new multisource FPPin the ICH region may costUSD 1 to 2 millions and may take a time of three to 5 years. • The lowest risk strategy for the development of aninterchangeablemultisource FPPis to copy the innovator FPP. • Multisource FPP manufacturers must be highly skilled in product and process development Pogány - Dar es Salaam

12. Active antimalarial constituent of the traditional Chinese medicinal herb 青蒿素Artemisia annua L., Compositae Artemisinin has seven (7) centers of assymetry but Artemisia annua makes only one configuration (Identification) Practically insoluble in water The bond energy of the O-O bond is ~30 kcal/mol When the peroxide comes into contact with high iron concentrations, the molecule becomes unstable and "explodes" into free radicals. The API, the capsules and the tablets are official in the Ph. Int. Not included in the current EOI. Artemisinin Pogány - Dar es Salaam

13. Practically insoluble in water. Slightly soluble in ethanols and dichloromethane. Both the API and the tablets are official in the Ph. Int. Not included in the current EOI Artenimol Pogány - Dar es Salaam

14. Very slightly soluble in water The ester linkage is inalpha configuration. Both the API and the tablets are official in the Ph. Int. Two functional groups are liable to decomposition Artesunate Pogány - Dar es Salaam

15. Metabolism of Artemether and Artesunate Pogány - Dar es Salaam

16. Amodiaquine Amodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck Index: pH of 1% aqeous solution is from 4.0 to 4.8. Pogány - Dar es Salaam

17. Has an optically active carbon Very slightly soluble in water Has no reactive functional groups under general environmental conditions Mefloquine hydrochloride Pogány - Dar es Salaam

18. Lumefantrin Pogány - Dar es Salaam

19. Pharmaceutical information • Artemisinin derivatives may have α- or β-configurationand each of them can exist in two conformations. The literature does not reveal any impact of the geometric isomerism on efficacy, safety or quality of artemisinins. • The internal peroxide bound is the most reactive part of the molecule. When the peroxide comes into contact with high iron concentrations, the molecule becomes unstable and "explodes" into free radicals. • The ester bound of artesunate is liable to hydrolysis. • The non-artemisinin APIs in the EoI are chemically stable. Pogány - Dar es Salaam

20. Biopharmaceutical information • The internal peroxide bound is fundamental for antimalarial activity. • Artemisinin has a • poor solubility in both water and oil, • short pharmacological half life, • high first-pass metabolism, and • poor oral bioavailability. • Its lactol ethers –artemether and arteether– are soluble in oils. • The lactol hemiester –artesunate– is slightly soluble in water and soluble at a basic pH. Pogány - Dar es Salaam

21. References • Monographs from the Merck Index®, 13thedition (2001). • Xuan-De Luo and Chia-Chiang Shen: The Chemistry, Pharmacology and Clinical Applications of Qinghaosu (Artemisinin) and its Derivatives (Med. Research Reviews, Vol. 7, No.1, 29-52 (1987). • The International Pharmacopoeia, 3rd ed., Volume 5, 185-233, WHO, Geneva (2003). Pogány - Dar es Salaam

22. 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 3.2.2Company R & D Laboratory scale

23. 3.2.1Company research and development The Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are distinguished from routine control tests conducted according to specifications. The summary should highlight the evolution of the formulation design from initial concept up to the final design and it should also take into consideration the choice of drug product components (e.g., the properties of the drug substance,excipients, container closure system, the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s). Pogány - Dar es Salaam

24. 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 API properties

25. Potentially critical attributes of API Cross reference to stress testing (forced degradation): • Sensitivity to temperature (wet granulation, sterilization) • Sensitivity to moisture (wet granulation, hygroscopicity) • Sensitivity to light (packing materials) • Sensitivity to oxidation (inert gas atmosphere in ampoules) • Sensitivity to pH (FDC with HCL salts of weak bases) • Sensitivity to metal ions (internal peroxide bond) Expected degradants, manufacturing conditions, etc. This information is partially available from the OP of the DMF Pogány - Dar es Salaam

26. Product-specific physical API properties Product-specific physical properties depend on crystallization and subsequent physical processing. Pogány - Dar es Salaam

27. Potentially critical attributes of API Key physicochemical characteristics: • Polymorphic or solid state form(amorphous,hydrate, solvate) • Solubility at 37 oC over the physiological pH range (e.g., BCS, dissolution testing, cleaning validation) • Permeability (octanol-water partition) (BCS) • Crystal habit, particle shape and size(pharmaceutical and bioequivalence, processability) • Bulk density, untapped and tapped (processability) • Flowability(processability) • Color, olor, taste, consistency (choice of dosage form) should be discussed and supported by experimental data. Pogány - Dar es Salaam

28. Solubility of artesunate Pogány - Dar es Salaam

29. Stress-testing of artesunate in aqueous solution Pogány - Dar es Salaam

30. Particle size When the solubility of an API is less than 0.1 mg/ml and does not change with pH in the physiological range, then the optimisation of the particle size during preformulation may be critical to efficacy or pharmaceutical equivalence. Other researchers believe that particle size may be critical at a solubility of 1 mg/ml or less. Pogány - Dar es Salaam

31. Effect of Particle Size on Dissolution Dissolution profiles in USP apparatus 2 at 50 rpm and pH 4.5 for product produced with different particle size of the API Pogány - Dar es Salaam

32. F2 20 73 Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market xxxxxxx Pogány - Dar es Salaam

33. Dissolution profiletesting • Three media - 900 ml or less - all at 37°C • Buffer pH 1.2, SGF without enzymes or 0.1M HCl • Buffer pH 4.5 • Buffer pH 6.8 or SIF without enzymes • 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 Pogány - Dar es Salaam

34. Rate of water absorption as a function of RH Pogány - Dar es Salaam

35. Overages in the formulation Information should be provided on the • amount of overage, • reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and • justification for the amount of overage (API but not EXCIPIENT). The overage should be included in the amount of drugsubstance listed in the batch formula. Pogány - Dar es Salaam

36. EXCIPIENTS - STARCH • All starches are hygroscopic and rapidly absorbatmospheric moisture. Approximate equilibrium moisture content values at 50% relative humidity are: • 11% FOR MAIZE (CORN) STARCH, • 18% FOR POTATO STARCH, • 14% FOR RICE STARCH, AND • 13% FOR WHEAT STARCH. • Between 30-80% relative humidity, corn starch is the least hygroscopic starch and potato starch is the most hygroscopic starch. Pogány - Dar es Salaam

37. Compatibility of APIsin FDCs • Artemether + Lumefantrine • Artesunate + Amodiaquine.2HCl* • Artesunate + Mefloquine.HCl* • Artesunate + Sulphadoxine/Pyrimethamine (SP) *Co-blistering, or bi-layered tablets Pogány - Dar es Salaam

38. Compatibility of the API with excipients and diluents • Select innovator excipients (WHOPAR, EPAR, Section 6.1) • Magnesium stearate is incompatible with salts of weak bases and strong acids (e.g. Amodiaquine.2HCl) because the formed MgCl2 is highly hygroscopic and, as a result, its lubricant properties also change. • The compatibility and in-use stabilityof the FP with reconstitution diluentsshould be addressed, e.g. in Artesunate injection. Pogány - Dar es Salaam

39. Selection of excipients - Talc Pogány - Dar es Salaam

40. 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 Pre-formulation

41. Dissolution testing* • Dissolution testing is used for the selection of the formulation andcomparison of the dissolution profiles with that of the innovator productand clinical batches. This should be a basic strategy in pharmaceutical development to maximize the chances of bioequivalence. • Limits should be set for each API in fixed-dose FPPs. • The dissolution method should be incorporated into the stability and quality control programs. • Multipoint dissolution profiles of both the test and the reference FPPs should be compared. *Supplement 1 to the Generic Guideline. Pogány - Dar es Salaam

42. Selection of tablet mass Pogány - Dar es Salaam

43. Selection of binder and solvent Pogány - Dar es Salaam

44. Special requirements In case of tablets designed with a score line, information should be given whether or not reproducible dividing of the tablets has been shown. e.g. „the scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses”, „the tablet can be divided into equal halves”. Pogány - Dar es Salaam

45. Artemether injection Possible design and development issues: • Selection of oil. • Heat stability of the oil and the oily solution of artemether (standard conditions for dry heat sterilization: NLT 160oC, two hours) • Alternatively, sterile filtration under aseptic conditions. Pogány - Dar es Salaam

46. Artesunate injection • Inthe treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. • „Every 60mg vial contained anhydrous artesunic acid, which we dissolved in 1mL 5% sodium bicarbonate and then mixed with 5mL of 5% dextrose before injecting as abolus into an indwelling intravenous cannula”. www.thelancet.com Vol366 August 27, 2005 Pogány - Dar es Salaam

47. 4-FDC antituberculosis FPP Originator FPP in ICH region • None FPP in current Essential Drug List • Rifampicin 150 mg • Isoniazid 75 mg • Pyrazinamide 400 mg • Ethambutol 275 mg Pogány - Dar es Salaam

48. 4FDC-TB tablets exposed to40°C/75%RH for one week Two different products. “Bleeding” may start after more exposure to stress testing without packing material. (North-West University, South Africa) Control on left Control on left Pogány - Dar es Salaam

49. Critical quality variables • The formulation is hygroscopic, sensitive to light and unstable. • Moisture content of FPP and intermediates. • Ethambutol.2HCl provides acidic conditions to accelerate decomposition between rifampicin and isoniazid. • Packing materials are critical for stability. Pogány - Dar es Salaam

50. Special attention in assessment • Compatibility of APIs with each other and with excipients. • Stress stability of the final formulation. • Equilibrium moisture content of granules and uncoated tablets. • Control of temperature and RH during the manufacturing process. Pogány - Dar es Salaam