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

1. János Pogány, pharmacist, Ph.D. consultant to WHO Guilin, China, 10 January 2006 E-mail: pogany@t-online.hu WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalencewith a focus on artemisinines Pharmaceutical quality by design and development Pogány - Guilin

2. Abbreviations APIActive Pharmaceutical Ingredient BP British Pharmacopoeia FDCFixed-Dose Combination FPPFinished Pharmaceutical Product ICH International Conference on Harmonization PhEur European Pharmacopoeia PhInt International Pharmacopoeia USP United States Pharmacopeia Pogány - Guilin

3. Subjects for discussion • DESIGN (product-specific research) • Desk research • API (specifications, stress stability testing, etc.) • FPP (pre-formulation, stability studies, etc.) • DEVELOPMENT (manufacturing process) • Laboratory • Pilot plant • Production plant • Main points again Pogány - Guilin

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 3.2.2 Information from literature(Desk research)

5. EOI – Oral Preparations • Artesunate*+ Amodiaquine • Artemether*+Lumefantrine* • Artesunate*+ Mefloquine • Artesunate*+ SP (sulphadoxine / pyrimethamine) *No comparator at the beginning*High-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 - Guilin

6. EOI – Other dosage forms • Artemether Injection and rectal FPPs • Artemotil (arteether) Injection • Artesunate Injection and rectal FPPs Only FPPs listed in the EOI are discussed. Pogány - Guilin

7. 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 - Guilin

8. Practically insoluble in water Artemether injection is an oily soulution The API, the capsules, the tablets and the injection are official in the Ph. Int. Artemether Pogány - Guilin

9. 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 - Guilin

10. 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 - Guilin

11. Metabolism of Artemether and Artesunate Pogány - Guilin

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

13. Has an optically active carbon Very slightly soluble in water Has no reactive functional groups under general environmental conditions Mefloquine hydrochloride Pogány - Guilin

14. Lumefantrin Pogány - Guilin

15. 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 - Guilin

16. 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 - Guilin

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 3.2 Pharmaceutical development

18. 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 - Guilin

19. Pogány - Guilin

20. Product-specific physical API properties Product-specific physical properties depend on crystallization and subsequent physical processing. Pogány - Guilin

21. Potentially critical attributes of API Key physicochemical characteristics: • Solubility over the physiological pH range (e.g., BCS, dissolution testing, cleaning validation) • Octanol-water partition (BCS) • Particle size(pharmaceutical and bioequivalence, processability) • Polymorphic or solid state form (if relevant) • 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 - Guilin

22. Solubility of artesunate Pogány - Guilin

23. Degradation of artesunate in aqueous solution Pogány - Guilin

24. 1 Prednisolone ... 3 Dexamethazone ... 9 Dexamethazone-acetate ... 11 Progesterone Relationship between permeability coefficient and octanol-water partition Pogány - Guilin

25. 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 - Guilin

26. 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. Pogány - Guilin

27. Rate of water absorption as a function of RH Pogány - Guilin

28. 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 - Guilin

29. Compatibility of APIsin FDCs • Artemether + Lumefantrine • Artesunate + Amodiaquine.2HCl • Artesunate + Mefloquine.HCl • Artesunate + Sulphadoxine/Pyrimethamine (SP) Pogány - Guilin

30. Compatibility of the API with excipients and diluents • 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 of the drug product with reconstitution diluentsshould be addressed, e.g. in Artesunate injection. Pogány - Guilin

31. Selection of excipients - Talc Pogány - Guilin

32. Selection of tablet mass Pogány - Guilin

33. Selection of binder and solvent Pogány - Guilin

34. 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 - Guilin

35. 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 - Guilin

36. Dissolution testing • 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 - Guilin

37. Hypothetical dissolution profile of a 2-FDC FPP Pogány - Guilin

38. 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 - Guilin

39. 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 - Guilin

40. 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 - Guilin

41. 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 - Guilin

42. 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 - Guilin

43. 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 - Guilin

44. Special attention in assessment • Specifications and sampling of the primary packing materials. • Heavy-duty compression machine. • Validation batches and annual product review reports. • Stability testing of the FPP to include visual inspection, assay, impurities and degradants (in particular isonicotinyl hydrazone), water, hardness, and other attributes. Pogány - Guilin

45. Container closure system • The choice and rationale for selection of the container closure system for the commercial product [described in 3.10Container/closure system(s) and other packaging] should be discussed. • The data should include details on: • tightness of closure. • protection of the contents against external factors. • container/contents interaction (e.g. sorption, leaching). • influence of the manufacturing process on the container (e.g. sterilisation conditions). Pogány - Guilin

46. Microbiological attributes • The microbiological attributes of the FPP should be discussed in this section. The discussion should include, for example: • The rationale for performing or not performing microbial limits testing for non-sterile FPPs (e.g., Decision Tree #8 in ICHQ6A Specifications). • Antimicrobial preservative effectiveness should be demonstrated during development. Pogány - Guilin

47. Pivotal batches A tabulated summary of the compositions of the clinical, bioequivalence, stability and validationFPP batches together with documentation(batch number, batch size, manufacturing date and certificate of analysis at batch release) and a presentation of dissolution profiles must be provided. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate. Pogány - Guilin

48. Manufacturing Process Development The progress from pre-formulation (size:1x) → formulation (10x) → pilot manufacture (100x but not less than 100,000 capsules or tablets) → production scale(approved batch size) manufacture should be shown in the dossier submitted for prequalification to be logical, reasoned and continuous. A pilot batchis manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. Pogány - Guilin

49. Manufacturing Process Development • Significant differences between the manufacturing processes used to produce batches for pivotal clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary stability studies and the process described in 3.5 Manufacturing processshould be discussed. • The information should include, for example, • the identity (e.g., batch number) and use of the batches produced (e.g., bioequivalence study batch number), • the manufacturing site, • the batch size, and • significant equipment differences (e.g., different design, operating principle, size). Pogány - Guilin

50. Manufacturing Process Development • The selection, the control, and any improvementof the manufacturing process described in 3.5 Manufacturing processshould be explained. • Appropriateness of the equipment used for the intended product(s) should be discussed. • Process development studies should provide the basis for process improvement, process validation, continuous process verification (where applicable), and any process control requirements. Pogány - Guilin