1. 2005.03.01 Dr. Pogány - WHO, Shanghai 1/56 Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hupogany@axelero.hu Pharmaceutical Research and Development Quality by design

2. 2005.03.01 Dr. Pogány - WHO, Shanghai 2/56 Abbreviations and Notes APIActive pharmaceutical ingredient FDC(s)fixed-dose combination(s) FPP(s)Finished pharmaceutical product(s) R+DResearch 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

3. 2005.03.01 Dr. Pogány - WHO, Shanghai 3/56 Subjects for Discussion 1. Desk research — Indinavir 2. Submission of pharmaceutical R+D data 3. Research ( Laboratory scale )  API (specifications, stress stability testing, etc.)  FPP ( 4. Development ( Pilot scale ) 5. Manufacture ( Production scale ) 6. Conclusions

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

5. 2005.03.01 Dr. Pogány - WHO, Shanghai 5/56 Indinavir

6. 2005.03.01 Dr. Pogány - WHO, Shanghai 6/56 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 is amide 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 monoethanolate converts to hydrate with the loss of ethanol upon exposure to moist air.

7. 2005.03.01 Dr. Pogány - WHO, Shanghai 7/56 Indinavir – Physicochemistry  It has two pK b values: 6.2 and 3.8  Aqueous solubility is 100mg/ml at room temperature but the solubility decreases at higher pH.  Partition coefficient octanol/water (log P) is 2.7 at pH 7.

8. 2005.03.01 Dr. Pogány - WHO, Shanghai 8/56 Indinavir - Biology  Early clinical studies revealed a more reproducible absorption when indinavir was administered as the sulfate salt compared with the free base.  The bioavailability of indinavir is 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 in multiproduct plants.

9. 2005.03.01 Dr. Pogány - WHO, Shanghai 9/56 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.

10. 2005.03.01 Dr. Pogány - WHO, Shanghai 10/56 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.

11. 2005.03.01 Dr. Pogány - WHO, Shanghai 11/56 Crixivan™ Capsules  Indinavir, as sulfate100mg200mg  Lactose, anhydrous 37mg 74mg  Magnesium stearate ? ?  Indinavir, as sulfate333mg400mg  Lactose, anhydrous124mg149mg  Magnesium stearate ? ?

12. 2005.03.01 Dr. Pogány - WHO, Shanghai 12/56 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.

13. 2005.03.01 Dr. Pogány - WHO, Shanghai 13/56 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.

14. 2005.03.01 Dr. Pogány - WHO, Shanghai 14/56 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.

15. 2005.03.01 Dr. Pogány - WHO, Shanghai 15/56 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.

16. 2005.03.01 Dr. Pogány - WHO, Shanghai 16/56 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 25 o C.  The result of the manufacturing process development is a stable product with low batch-to-batch variation with the finished product specification.

17. 2005.03.01 Dr. Pogány - WHO, Shanghai 17/56 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.

18. 2005.03.01 Dr. Pogány - WHO, Shanghai 18/56 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 in clinical, safety and stability studies are submitted and demonstrate a consistent quality of the product and compliance with the stated specifications.

19. 2005.03.01 Dr. Pogány - WHO, Shanghai 19/56 Indinavir – Quality control At the end of shelf life,  an assay limit of 93-105 % and  lactone impurity is not more than 1.5%.  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 of full time stability data on production batches of the finished product is part of the follow- up measures.

20. 2005.03.01 Dr. Pogány - WHO, Shanghai 20/56 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 patent No. 5,413,999 Literature search on chemistry of indinavir.

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. 2005.03.01 Dr. Pogány - WHO, Shanghai 22/56 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.

23. PREFORMULATION Laboratory scale R + D

24. 2005.03.01 Dr. Pogány - WHO, Shanghai 24/56 Physicochemical and physical properties of API Physicochemical  hygroscopicity  solubility  water content  polymorphism  permeability Physical  particle size  bulk density (g/100ml)  flowability  color, olor, taste  consistency

25. 2005.03.01 Dr. Pogány - WHO, Shanghai 25/56 Equilibrium Moisture Content 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.

26. 2005.03.01 Dr. Pogány - WHO, Shanghai 26/56 Rate of Water Absorption at Different RHs

27. 2005.03.01 Dr. Pogány - WHO, Shanghai 27/56 Solubility of Zidovudine at 25 o C pHDissolved material (mg/ml) 3.021 4.020 5.320 6.021 7.022 Distilled water20 8.021

28. 2005.03.01 Dr. Pogány - WHO, Shanghai 28/56 Relationship between Permeability Coefficient and Octanol-Water Partition 1 Prednisolone... 3 Dexamethazone... 9 Dexamethazone-acetate... 11 Progesterone

29. 2005.03.01 Dr. Pogány - WHO, Shanghai 29/56 NORVIR (Ritonavir) EPAR/CPMP /527/96 1.No polymorphism observed at the time of first submission (only form I : hard capsules and oral solution registered) 2.Failure in dissolution during stability studies for hard capsules 3.Emergence of form II (contamination of form I) 4.Production of hard capsules discontinued 5.Development and registration of soft capsules

30. 2005.03.01 Dr. Pogány - WHO, Shanghai 30/56 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.

31. 2005.03.01 Dr. Pogány - WHO, Shanghai 31/56 Effect of Particle Size on Dissolution

32. 2005.03.01 Dr. Pogány - WHO, Shanghai 32/56 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 o C, 100% RH.  Regulatory stability studies of the final composition are frequently initiated in the pharmaceutical R + D laboratory.

33. 2005.03.01 Dr. Pogány - WHO, Shanghai 33/56 Compatibility of Acetylsalicylic Acid with Excipients Time (week)Talc ATalc B Salicylic acid, % 00.10 40.325.85 80.4113.00 120.8028.50

34. 2005.03.01 Dr. Pogány - WHO, Shanghai 34/56 Triomune - WHOPAR Experimental „studies showed chemical incompatibility for the lamivudine with stavudine and nevirapine with stavudine combination. Lamivudine with nevirapine showed no change indicating that they are compatible. Stavudine was found incompatible with both the drugs, indicated by the brown colouration and increase in the impurities. Therefore it was decided to separate stavudine from the other two drugs. Hence the formulation was proposed to be bilayered tablet formulation, where stavudine is in one layer and lamivudine + nevirapine in other layer. Thus contact of stavudine with the other two drugs was minimised.”

35. 2005.03.01 Dr. Pogány - WHO, Shanghai 35/56 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.

36. 2005.03.01 Dr. Pogány - WHO, Shanghai 36/56 Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market F2F2 20 73

37. 2005.03.01 Dr. Pogány - WHO, Shanghai 37/56 Hypothetical Dissolution Profile of a 2-FDC FPP

38. 2005.03.01 Dr. Pogány - WHO, Shanghai 38/56 Pivotal Batches A tabulated summary of the compositions of the clinical, bioequivalence, stability and validation FPP 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.

39. 2005.03.01 Dr. Pogány - WHO, Shanghai 39/56 Excipients – Lactose (L) Different grade, different physical properties:  Angle of repose: 32- 47 o (Specs.)  Bulk density: 0.34 – 0.80 g/cm 3 (Specs.)  Bulk density (tapped): 0.41 – 0.95 g/cm 3  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

40. 2005.03.01 Dr. Pogány - WHO, Shanghai 40/56 Excipients – Lactose (L) Solubility in water  1 in 4.63 at 25 o C  1 in 3.14 at 40 o C  1 in 2.04 at 50 o C  1 in 1.68 at 60 o C  1 in 1.07 at 80 o C 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.

41. 2005.03.01 Dr. Pogány - WHO, Shanghai 41/56 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.

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

43. 2005.03.01 Dr. Pogány - WHO, Shanghai 43/56 Justification of Film-coating 1. Mask bitter taste of the tablets 2. Reduce skin contact (risk of allergy) 3. Improve colour uniformity 4. Facilitate packaging

44. 2005.03.01 Dr. Pogány - WHO, Shanghai 44/56 Results of API Stress Stability Testing Initial assay98.1% Storage conditionsAssay (%) 50 o C99.9 60 o C98.4 70 o C99.9 30 o C/90%RH100.2 40 o C/90%RH100.1 LIGHT93.3

45. 2005.03.01 Dr. Pogány - WHO, Shanghai 45/56 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.

46. 2005.03.01 Dr. Pogány - WHO, Shanghai 46/56 Selection of Tablet Mass CompositionABC API (mg)500 Excipients (mg)200125 56 Tablet mass (mg):700625556 Granules, LOD (%)0,90,8 Median diameter (μm)194186189 Tablets, hardness (kp)12.813.312.4 Friability (%)0.70.5 Disintegration time6’30’’7’40’’10’50’’ Dissolution (%, 15’)96.695.696.7

47. 2005.03.01 Dr. Pogány - WHO, Shanghai 47/56 Solvent Selection for Binder Povidone, water (W), ethanol (E)W-EWE Granules LOD(%)0.80.90.8 Median diameter (μm)186179184 Tablets Average weight (mg)626624628 Hardness (kp)13.311.212.9 Friability (%)0.5 0.4 Disintegration time7’4’’2’10’’6’35’’ Dissolution (%, 15’)95.696.375.7

48. 2005.03.01 Dr. Pogány - WHO, Shanghai 48/56 Compression Speed Tabletting machineBB3 β-Press Granules, (Mg-stearate %)0.250. 50 LOD (%)1.5 Median diameter (μm)341 Tablets Average weight (mg)605607599 Hardness (kp)10.99.77.3 Friability (%)0.30.50.8 Disintegration time6’48’’14’19’’8’14’’ Dissolution (%, 15’)99.576.792.0

49. 2005.03.01 Dr. Pogány - WHO, Shanghai 49/56 Film-coating Parameters Spraying conditionsPilot batch 1Pilot batch 2 Film-coaterManesty Nozzle (mm)0.8 Spraying pressure (psi)40/25 Inlet temperature ( o C)8171 Outlet temperature ( o C)4544 Spray rate (g/min)3626 Drum speed (rpm)810

50. 2005.03.01 Dr. Pogány - WHO, Shanghai 50/56 Film-coating Results Quality parameter Pilot batch 1Pilot batch 2 CoreCoatedCoreCoated Weight increase (%)2.122.04 Appearancegood Mean thickness (mm)4.254.284.344.37 Hardness (kp)9.214.78.710.8 Friability (%)0.300.440 Disintegration time3’40’’5’32’’1’44’’2’46’’ Dissolution (15’, %)-93-98

51. 2005.03.01 Dr. Pogány - WHO, Shanghai 51/56 Choice of Container 1. Amber glass bottles with LDPE snap-fitting caps, and 2. Amber PVC/aluminium foil blister packs General principle Packaging should be selected to ensure the quality of the FPP throughout its shelf life.

52. Pharmaceutical R + D Process includes Transfer of Technology to the Production Plant Production scale experiments with validation batches

53. 2005.03.01 Dr. Pogány - WHO, Shanghai 53/56 Validation protocol and report  Data should be submitted in the application for prequalification demonstrating the validity of a given process.  Formal studies of production scale batches (normally not less than three consecutive batches) are required before the product is placed on the market.  Where validation data on production scale batches are not provided with the application, the applicant should submit the validation protocol.  Following completion of the programme, a validation report should be generated for examination by WHO.

54. 2005.03.01 Dr. Pogány - WHO, Shanghai 54/56 Main points again  Pharmaceutical R + D is an essential part of applications for Marketing Authorization.  Desk research gives valuable information.  Laboratory scale studies should identify critical product quality attributes.  FDCs require particular tests.  Packing materials should also be selected through documented experiments.

55. 2005.03.01 Dr. Pogány - WHO, Shanghai 55/56 Main points again  Pilot plant experiments should provide the basis for process optimisation, process validation and process control requirements.  Validation batches at production scale should establish the critical process parameters (e.g., granulation end point, drying temperature) that should regularly be monitored or controlled to guarantee batch-to-batch consistency of quality.

56. 2005.03.01 Dr. Pogány - WHO, Shanghai 56/56 THANK YOU 谢谢 !