Supplementary T raining Workshop on Good Manufacturing Practices (GMP)

1. Supplementary TrainingWorkshop on GoodManufacturing Practices (GMP) MANUFACTURING PROCESS VALIDATION Solid Dosage Forms János Pogány, pharmacist, PhD, consultant to WHO Pretoria, South Africa, 28 June 2005 E-mail: pogany@t-online.hu Dr. Pogány - WHO, Pretoria

2. WHO GMP and related guides • WHO good manufacturing practices (GMP): main principles for pharmaceutical products • Section 4.Qualificationand validation • Supplementary guidelines ongood manufacturing practices(GMP):Validation (2003) – Draft. Dr. Pogány - WHO, Pretoria

3. WHO GMP and related guides • WHO good manufacturing practices: main principles for pharmaceutical products–Validation of manufacturing processes • Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:14–79 (WHO Technical Report Series, No. 823). Dr. Pogány - WHO, Pretoria

4. ICH guidelines • PHARMACEUTICAL DEVELOPMENT, Q8, Draft ICH Consensus Guideline, Released for Consultationon 18 November 2004, at Step 2 of the ICH Process • QUALITY RISK MANAGEMENT, Q9, Draft ICH Consensus Guideline, Released for Consultationon 22 March 2005, at Step 2 of the ICH Process Dr. Pogány - WHO, Pretoria

5. PROSPECTIVE VALIDATION Pharmaceutical Development Laboratory scale R + D

6. 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, Pretoria

7. 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, Pretoria

8. Rate of Water Absorption at Different RHs Dr. Pogány - WHO, Pretoria

9. Solubility of Zidovudine at 25oC Dr. Pogány - WHO, Pretoria

10. Solubility of Artesunate Dr. Pogány - WHO, Pretoria

11. Decomposition of Artesunatein aqueous solution Dr. Pogány - WHO, Pretoria

12. 1 Prednisolone ... 3 Dexamethazone ... 9 Dexamethazone-acetate ... 11 Progesterone Relationship between Permeability Coefficient and Octanol-Water Partition Dr. Pogány - WHO, Pretoria

13. 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, Pretoria

14. 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, Pretoria

15. Effect of Particle Size on Dissolution of Nevirapine tablets Dr. Pogány - WHO, Pretoria

16. 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, Pretoria

17. Compatibility of Acetylsalicylic Acid with Excipients Dr. Pogány - WHO, Pretoria

18. 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, Pretoria

19. 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, Pretoria

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

21. Hypothetical Dissolution Profile of a 2-FDC FPP Dr. Pogány - WHO, Pretoria

22. 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. Dr. Pogány - WHO, Pretoria

23. 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, Pretoria

24. 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, Pretoria

25. Surface of a film-coated tablets containing a high level of a superdisintegrant Dr. Pogány - WHO, Pretoria

26. 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, Pretoria

27. CONCURRENT VALIDATION Commitment Batches

28. Technical pharmacy • Pharmaceutical production system (from purchasing API to packaging FP) • Utility support system (HVAC, water, HPLC, etc. equipment containing many items) • Process (tablet making) • (Unit) operation(granulation, compression) • Step(sifting, sizing) • Procedure, method, technique(SOP) Dr. Pogány - WHO, Pretoria

29. Causes of variation • Man (different operators - lack of proper training) • Machine / equipment (variation of tablet weight) • Measurement (lack of calibration) • Method (validated manufacturing methods) • Material (batch-to-batch variation of the same crystal form – different crystal forms (ASA)] • Environment (OoS T and RH in capsule filling) Dr. Pogány - WHO, Pretoria

30. 4.10 Scientific approach • „Processes and procedures should be established on the basis of the results of the validation performed.” Objectives • To prove that the tests, measurements, results and interpretation of formal studies on (manufacturing) processes and procedures/methods are appropriate and accurate. • To stabilize new processes (to reduce variability, to increase batch to batch consistency of quality attributes of products). • To reduce defect levels (standardize yields). • To reduce production costs. Dr. Pogány - WHO, Pretoria

31. Process approach CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM CUSTOMER SATISFACTION CUSTOMER Management responsibility REQUIREMENTS Resource management Monitoring, improvement Manufacture Product Inputs Dr. Pogány - WHO, Pretoria

32. Measure of variation (spread of data) 68.26% 95.46% Dr. Pogány - WHO, Pretoria

33. Mean (average) chart Abnormal variation of process – special causes UCL Upper control limit Normal variation due to common causes average = mean LCL Lower control limit Abnormal variation of process – special causes Dr. Pogány - WHO, Pretoria

34. Process capability index, Cp acceptance limits UCL - LCL Cp = = process capability 6σ* 6σ* Three sigma: Cp = = 1 6σ* 12σ* Six sigma: Cp = = 2 6σ* σ* ... is the measured standard deviation of the process Dr. Pogány - WHO, Pretoria

35. Process capability index, Cpk UCL - x Cpk = 3σn UCL ... upper control limit x ... mean of the acceptance criteria, target value σn ...is 50% of the measured standard deviation of the process Cpk shows the closeness of the process mean to the target value. Dr. Pogány - WHO, Pretoria

36. Output of processes for differentCpk indices Dr. Pogány - WHO, Pretoria

37. The process reveals serious risks and it is not controlled The process is not yet controlled but acceptance criteria are met The process is under control and the product has a consistently high quality Objective and result of process control UCL N LCL UCL N LCL UCL N LCL Dr. Pogány - WHO, Pretoria

38. Process under control • Mostpoints fall near the central line (68% within one σ) • A few points fall near the control limits (5% in the third σ) • Points shold balance on both sides of the mean • Points should cross the mean line often. • Points should show a random pattern (no trends, cycles, clustering) Dr. Pogány - WHO, Pretoria

39. 4.8-4.9 Protocols and reports • Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols. • A written report summarizing the results recorded and the conclusions reached should be prepared and stored. Dr. Pogány - WHO, Pretoria

40. Process validation protocol/report • Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation. • Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate). • Sampling plan — where, when, how and how many samples are taken. • Details of methods for recording and evaluation of results. Dr. Pogány - WHO, Pretoria

41. Illustrative variables of wet granulation Dr. Pogány - WHO, Pretoria

42. Illustrative variables of wet granulation Dr. Pogány - WHO, Pretoria

43. Flat Shallow convex Standard convex Deep convex Ball-shaped Indentation hardness profiles for tablets of different shape Dr. Pogány - WHO, Pretoria

44. Areas most prone to surface erosion for flat, shallow convex, caplet-shaped and deep convex tablets Dr. Pogány - WHO, Pretoria

45. Erosion on the surface of the tablet with a logo Dr. Pogány - WHO, Pretoria

46. Twinning during the coating process for flat-faced and caplet shaped tablets Dr. Pogány - WHO, Pretoria

47. Measurement points of film thickness across the tablet surfaces FACE EDGE SIDE Dr. Pogány - WHO, Pretoria

48. Illustrative variables of compression and film-coating Dr. Pogány - WHO, Pretoria

49. Illustrative variables of tablet packaging Dr. Pogány - WHO, Pretoria

50. 4.10 Scientific approach • Processes and procedures should be established on the basis of the results of the validation performed. Dr. Pogány - WHO, Pretoria