Workshop on Quality Assurance and GMP of multisource HIV /AIDS medicines

1. János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hu Workshop on Quality Assurance and GMP of multisource HIV/AIDSmedicines Pharmaceutical Research and Development Quality by design Dr. Pogány - WHO, Shanghai

2. Abbreviations and Notes API Active pharmaceutical ingredient FDC(s) fixed-dose combination(s) FPP(s) Finished pharmaceutical product(s) R+D Research and development Text in green refers to WHO documents or requirements Text in yellow indicates a quality assessment issue Text in light blue highlights key words Dr. Pogány - WHO, Shanghai

3. Subjects for Discussion • Desk research—Indinavir • Submission of pharmaceutical R+D data • Research (Laboratory scale) • API (specifications, stress stability testing, etc.) • FPP ( • Development (Pilot scale) • Manufacture(Production scale) • Conclusions Dr. Pogány - WHO, Shanghai

4. What can we learn from the European Public Assessment Report(s) [EPAR(s)]? DESK RESEARCH INDINAVIR

5. Indinavir Dr. Pogány - WHO, Shanghai

6. Indinavir - Chemistry • Indinavir is a chiral molecule with 5 stereogenic centers and is used as a single isomer, the 4-(R)-epimer. • The primary degradation pathway for indinavir sulfate for both solid state and solution isamide bond hydrolysis to form lactone and aminoindanol. The degradation is humidity and temperature dependent. • Indinavir is highly hygroscopic at relative humidities above 60%. Indinavir Sulfate monoethanolateconverts to hydratewith the loss of ethanol upon exposure to moist air. Dr. Pogány - WHO, Shanghai

7. Indinavir – Physicochemistry • It has two pKb values: 6.2 and 3.8 • Aqueous solubilityis 100mg/ml at room temperaturebut the solubility decreases at higher pH. • Partition coefficient octanol/water (log P) is 2.7 at pH 7. Dr. Pogány - WHO, Shanghai

8. Indinavir - Biology • Early clinical studies revealed a more reproducibleabsorption when indinavir was administered as the sulfate salt compared with the free base. • The bioavailabilityof indinaviris good(approximately 60 %,peak plasma concentration is 0.8 ±0.3 hours), which facilitates pre-formulation and formulation research. • Toxico-pharmacological information suggests that indinavir pharmaceutical forms may be manufactured inmultiproduct plants. Dr. Pogány - WHO, Shanghai

9. Indinavir - Preformulation • In view of indinavir sulfate’s moisture and temperature sensitivity, poor flowability and relatively loose bulk density, a dry granulation formulation with acceptable compressibility and consistent fill volume during encapsulation was developed. • Anhydrous lactose was selected as a filler and binding aid because of its low moisture content, non hygroscopicity and good compactibility. • Magnesium stearate provides the lubrication required for machinability. Dr. Pogány - WHO, Shanghai

10. Quality of inactive ingredients • Both capsule manufacturers have provided assurance that gelatin used will be obtained only from BSE-free countries (BSE = bovine (animal) spongiform encephalopathy). • The same assurance could be required for magnesium stearate, or stearic acid and its derivatives in general. Dr. Pogány - WHO, Shanghai

11. Crixivan™Capsules • Indinavir, as sulfate100mg200mg • Lactose, anhydrous37mg74mg • Magnesium stearate?? • Indinavir, as sulfate 333mg400mg • Lactose, anhydrous124mg149mg • Magnesium stearate?? Dr. Pogány - WHO, Shanghai

12. Indinavir – Packing Materials • CRIXIVAN™ 100 mg: hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil induction cap. • CRIXIVAN ™ 400 mg: hard capsules are supplied in all-aluminium blisters. Dr. Pogány - WHO, Shanghai

13. Indinavir – Labeling • HDPE bottles: keep the container tightly closed in order to protect from moisture. Do not remove the desiccant canister from the bottle. • Blister packs: store in the original package in order to protect from moisture. • Note that the storage temperature is not indicated. Dr. Pogány - WHO, Shanghai

14. Indinavir – Stability of Capsules • No degradation other than the lactone and the aminoindanol were observed in any of the stressed capsules. The aminoindanol is produced in equimolar amount to the lactone. Shelf life • 24 months for CRIXIVAN™ capsules in blisters. • 36 months for CRIXIVAN™ capsules in HDPE bottles. Dr. Pogány - WHO, Shanghai

15. Indinavir – Scale up • The formulation intended for market has remained unchanged throughout the development program.Studies showed that the quality of the finished product is not compromised by the scale-up in production. • Flowability and bulk density of granules are important/critical parameters for weight variation. Dr. Pogány - WHO, Shanghai

16. Indinavir – Scale up • The manufacturing process is carried out under GMP at controlled humidity of the air in the manufacturing areas associated with roller compaction, milling and encapsulating. • HVAC system should maintain a relative humidity of ≤33% at 25oC. • The result of the manufacturing process development is a stable product with low batch-to-batch variation with the finishedproduct specification. Dr. Pogány - WHO, Shanghai

17. Indinavir – Quality control The specifications of the FPP cover the • Appearance of the capsules, • Identity, • Assay of drug substance, • Dose uniformity, • Dissolution test, • Test on degradation product and • Moisture content. Dr. Pogány - WHO, Shanghai

18. Indinavir – Quality control At release, • an assay limit of 95-105 % • lactone impurity is not more than 0.3%. • Batch analyses data for several pilot scale lots used inclinical, safety and stability studies are submitted and demonstrate a consistent quality of the product and compliance with the stated specifications. Dr. Pogány - WHO, Shanghai

19. Indinavir – Quality control At the end of shelf life, • an assay limit of93-105 % and • lactone impurityis not more than1.5%. • The stability studies of the FPP show that the drug product is stable when stored in the original container, tightly closed and protected from humidity. • Submission offull time stability data on production batches of the finished product is part of the follow-up measures. Dr. Pogány - WHO, Shanghai

20. Indinavir – Literature CPMP/589/96 —Committee for Proprietary Medicinal Products (CPMP) European Public Assessment Report (EPAR)— The European Agency for the Evaluation of Medicinal Products, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK Additional sources of information: United States patentNo. 5,413,999 Literature search on chemistry of indinavir. Dr. Pogány - WHO, Shanghai

21. 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 RESEARCH and DEVELOPMENT

22. Objective of Pharmaceutical R+D • The Pharmaceutical R+D section presents the knowledge gained through the application of scientific approaches, and risk management, to the development of a FPP and its manufacturing process. It is first submitted in the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product. • The studies described here are distinguished from routine control tests conducted according to specifications. Dr. Pogány - WHO, Shanghai

23. PREFORMULATION Laboratory scale R + D

24. Physicochemical hygroscopicity solubility water content polymorphism permeability Physical particle size bulk density(g/100ml) flowability color, olor, taste consistency Physicochemical and physical properties of API Dr. Pogány - WHO, Shanghai

25. At relative humidities (RHs) <100%, a solid API (that does not form crystalline compounds with water) will loose some bound and all its unbound water until it is in equilibrium with the surrounding atmosphere. The sum of both these moistures is the free moisture of the API (granules) at the specified RH. Equilibrium Moisture Content Dr. Pogány - WHO, Shanghai

26. Rate of Water Absorption at Different RHs Dr. Pogány - WHO, Shanghai

27. Solubility of Zidovudine at 25oC Dr. Pogány - WHO, Shanghai

28. 1 Prednisolone ... 3 Dexamethazone ... 9 Dexamethazone-acetate ... 11 Progesterone Relationship between Permeability Coefficient and Octanol-Water Partition Dr. Pogány - WHO, Shanghai

29. NORVIR (Ritonavir) EPAR/CPMP /527/96 • No polymorphism observed at the time of first submission (only form I : hard capsules and oral solution registered) • Failure in dissolution during stability studies for hard capsules • Emergence of form II (contamination of form I) • Production of hard capsules discontinued • Development and registration of soft capsules Dr. Pogány - WHO, Shanghai

30. Particle Size When the solubility of an API is less than 0.1 mg/ml, the optimization 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. Dr. Pogány - WHO, Shanghai

31. Effect of Particle Size on Dissolution Dr. Pogány - WHO, Shanghai

32. Screening of Compositions • Compatibility of an API with the excipients and the APIs with each other in FDCs is studied in open system stress stability experiments, e.g., 60-80 oC, 100% RH. • Regulatory stability studies of the final composition are frequently initiated in the pharmaceutical R + D laboratory. Dr. Pogány - WHO, Shanghai

33. Compatibility of Acetylsalicylic Acid with Excipients Dr. Pogány - WHO, Shanghai

34. Triomune - WHOPAR Experimental„studies showed chemical incompatibility for thelamivudine with stavudine and nevirapine with stavudine combination. Lamivudine withnevirapine showed no change indicating that they are compatible. Stavudine was foundincompatible with both the drugs, indicated by the brown colouration and increase in theimpurities. Therefore it was decided to separate stavudine from the other two drugs. Hence theformulation was proposed to be bilayered tablet formulation, where stavudine is in one layerand lamivudine + nevirapine in other layer. Thus contact of stavudine with the other two drugswas minimised.” Dr. Pogány - WHO, Shanghai

35. Dissolution Test and Profile • A (discriminating) dissolution test method should be developed for the final composition of the FPP. • 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. Dr. Pogány - WHO, Shanghai

36. F2 20 73 Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market Dr. Pogány - WHO, Shanghai

37. Hypothetical Dissolution Profile of a 2-FDC FPP Dr. Pogány - WHO, Shanghai

38. 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 profilesmust be provided. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate. Dr. Pogány - WHO, Shanghai

39. Excipients – Lactose (L) Different grade, different physical properties: • Angle of repose: 32- 47o (Specs.) • Bulk density: 0.34 – 0.80 g/cm3 (Specs.) • Bulk density (tapped): 0.41 – 0.95 g/cm3 • Flowability (spray processed): 4.1 g/s (Specs.) • Hygroscopicity: L monohydrate is stable in air at room temperature. Anhydrous L may absorb humidity. • Moisture content: L monohydrate contains approx. 5% w/w water of crystallization Dr. Pogány - WHO, Shanghai

40. Excipients – Lactose (L) Solubility in water • 1 in 4.63 at 25 oC • 1 in 3.14 at 40 oC • 1 in 2.04 at 50 oC • 1 in 1.68 at 60 oC • 1 in 1.07 at 80 oC Particle size distribution: depends on grade. Stability: may develop brown colouration (≥ 80% RH) Incompatibility: APIs with a primary amine group (base catalysed), aminophylline and amphetamines. Dr. Pogány - WHO, Shanghai

41. Packaging Materials • Moisture-impermeable containers: glass ampoules, vials closed with rubber stoppers and fixed with metal caps, aluminium/aluminium blisters, high density polyethylene (HDPE) or glass bottles fitted with metal metal or HDPE closures, etc. • Moisture-permeable containers: polyvinyl chloride (PVC) blisters, low density polyethylene (LDPE) bottles, HDPE bottles fitted with polypropylene closures. • Specifications of packaging materials should include thickness and permeability coefficient. Dr. Pogány - WHO, Shanghai

42. Development of a film-tablet manufacturing process Pilot scale experiments

43. Justification of Film-coating • Mask bitter taste of the tablets • Reduce skin contact (risk of allergy) • Improve colour uniformity • Facilitate packaging Dr. Pogány - WHO, Shanghai

44. Results of API Stress Stability Testing Dr. Pogány - WHO, Shanghai

45. Preformulation • API is soluble in water, it can be easily granulated, compression results in good tablets with a rapid dissolution rate. There is no need for particle size reduction. • API is compatible with all excipients, including film-coating inactive ingredients. • Decomposition of API in UV and artificial daylight is not accelerated by the excipients. Dr. Pogány - WHO, Shanghai

46. Selection of Tablet Mass Dr. Pogány - WHO, Shanghai

47. Solvent Selection for Binder Dr. Pogány - WHO, Shanghai

48. Compression Speed Dr. Pogány - WHO, Shanghai

49. Film-coating Parameters Dr. Pogány - WHO, Shanghai

50. Film-coating Results Dr. Pogány - WHO, Shanghai