1. 2006.08.22. Pogány - Dar es Salaam 1/66 WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus on artemisinines János Pogány, pharmacist, Ph.D. consultant to WHO Tanzania, 22 August 2006 E-mail: pogany.janos@chello.hupogany.janos@chello.hu Pharmaceutical quality by design and development

2. 2006.08.22. Pogány - Dar es Salaam 2/66 Abbreviations APIActive Pharmaceutical Ingredient DRADrug Regulatory Authority EoI Expression of Interest FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization MAMarketing Authorization PQIFPharmaceutical Quality Information Form Yellow → emphasis Green → WHO Blue → ICH region

3. 2006.08.22. Pogány - Dar es Salaam 3/66 Subjects for discussion 1. DESIGN ( product-specific research )  Desk research  API (specifications, stress stability testing, etc.)  FPP (pre-formulation, screening stability studies, etc.) 2. DEVELOPMENT [FPP and manufacturing 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) 3. Main points again

4. 2006.08.22. Pogány - Dar es Salaam 4/66 Applicable guidelines  Annex 6. Validation of manufacturing processes, in WHO TRS No. 863 (1996).  WHO „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  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.)

5. 2006.08.22. Pogány - Dar es Salaam 5/66 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

6. 2006.08.22. Pogány - Dar es Salaam 6/66 Related WHO guidelines  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  Guidance on Variations to a Prequalified Dossier

7. 2006.08.22. Pogány - Dar es Salaam 7/66 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)

8. 2006.08.22. Pogány - Dar es Salaam 8/66 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.

9. 2006.08.22. Pogány - Dar es Salaam 9/66

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. 2006.08.22. Pogány - Dar es Salaam 11/66 General considerations  The marketing of a new multisource FPP in the ICH region may cost USD 1 to 2 millions and may take a time of three to 5 years.  The lowest risk strategy for the development of an interchangeable multisource FPP is to copy the innovator FPP.  Multisource FPP manufacturers must be highly skilled in product and process development

12. 2006.08.22. Pogány - Dar es Salaam 12/66 Artemisinin  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.

13. 2006.08.22. Pogány - Dar es Salaam 13/66 Artenimol  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

14. 2006.08.22. Pogány - Dar es Salaam 14/66 Artesunate  Very slightly soluble in water  The ester linkage is in alpha configuration.  Both the API and the tablets are official in the Ph. Int.  Two functional groups are liable to decomposition

15. 2006.08.22. Pogány - Dar es Salaam 15/66 Metabolism of Artemether and Artesunate

16. 2006.08.22. Pogány - Dar es Salaam 16/66 Amodiaquine Amodiaquine Hydrochloride USP, C 20 H 22 ClN 3 O.2HCl.2H 2 O. Merck Index: pH of 1% aqeous solution is from 4.0 to 4.8.

17. 2006.08.22. Pogány - Dar es Salaam 17/66 Mefloquine hydrochloride  Has an optically active carbon  Very slightly soluble in water  Has no reactive functional groups under general environmental conditions

18. 2006.08.22. Pogány - Dar es Salaam 18/66 Lumefantrin

19. 2006.08.22. Pogány - Dar es Salaam 19/66 Pharmaceutical information  Artemisinin derivatives may have α- or β-configuration and 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.

20. 2006.08.22. Pogány - Dar es Salaam 20/66 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.

21. 2006.08.22. Pogány - Dar es Salaam 21/66 References 1. Monographs from the Merck Index ®, 13 th edition (2001). 2. 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). 3. The International Pharmacopoeia, 3rd ed., Volume 5, 185-233, WHO, Geneva (2003).

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 3.2.2 Company R & D Laboratory scale

23. 2006.08.22. Pogány - Dar es Salaam 23/66 3.2.1 Company 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).

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. 2006.08.22. Pogány - Dar es Salaam 25/66 Potentially critical attributes of API Cross reference to stress testing ( forced degradation ): 1. Sensitivity to temperature ( wet granulation, sterilization ) 2. Sensitivity to moisture ( wet granulation, hygroscopicity ) 3. Sensitivity to light ( packing materials ) 4. Sensitivity to oxidation ( inert gas atmosphere in ampoules ) 5. Sensitivity to pH ( FDC with HCL salts of weak bases ) 6. Sensitivity to metal ions ( internal peroxide bond ) Expected degradants, manufacturing conditions, etc. This information is partially available from the OP of the DMF

26. 2006.08.22. Pogány - Dar es Salaam 26/66 Product-specific physical API properties Introduction of the API starting material(s) into process Production of intermediate(s) Isolation and purification Physical processing and packaging Product-specific physical properties depend on crystallization and subsequent physical processing.

27. 2006.08.22. Pogány - Dar es Salaam 27/66 Potentially critical attributes of API Key physicochemical characteristics: 1. Polymorphic or solid state form (amorphous, hydrate, solvate) 2. Solubility at 37 o C over the physiological pH range (e.g., BCS, dissolution testing, cleaning validation ) 3. Permeability (octanol-water partition) ( BCS ) 4. Crystal habit, particle shape and size ( pharmaceutical and bioequivalence, processability ) 5. Bulk density, untapped and tapped (processability) 6. Flowability (processability) 7. Color, olor, taste, consistency ( choice of dosage form ) should be discussed and supported by experimental data.

28. 2006.08.22. Pogány - Dar es Salaam 28/66 Solubility of artesunate pHDissolved material (mg/ml) 11,9 51,5 63,5 710,2 812,2

29. 2006.08.22. Pogány - Dar es Salaam 29/66 Stress-testing of artesunate in aqueous solution ConditionsTime (h)Degradation (%) Water20 0.1N HCl274 0.1N NaOH2100

30. 2006.08.22. Pogány - Dar es Salaam 30/66 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.

31. 2006.08.22. Pogány - Dar es Salaam 31/66 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

32. 2006.08.22. Pogány - Dar es Salaam 32/66 Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market F2F2 20 73 xxxxxxx

33. 2006.08.22. Pogány - Dar es Salaam 33/66 Dissolution profile 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 used additionally (not instead of) 2. Paddle at 50 or basket at 100 rpm 3. Twelve units of each product in all 3 media 4. Dissolution samples collected at short intervals, e.g.  10, 15, 20, 30, 45 and 60 minutes  Analyse samples for all APIs, when applicable

34. 2006.08.22. Pogány - Dar es Salaam 34/66 Rate of water absorption as a function of RH

35. 2006.08.22. Pogány - Dar es Salaam 35/66 Overages in the formulation Information should be provided on the 1. amount of overage, 2. reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3. justification for the amount of overage (API but not EXCIPIENT). The overage should be included in the amount of drug substance listed in the batch formula.

36. 2006.08.22. Pogány - Dar es Salaam 36/66 EXCIPIENTS - STARCH  All starches are hygroscopic and rapidly absorb atmospheric 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.

37. 2006.08.22. Pogány - Dar es Salaam 37/66 Compatibility of APIs in FDCs  Artemether + Lumefantrine  Artesunate + Amodiaquine.2HCl*  Artesunate + Mefloquine.HCl*  Artesunate + Sulphadoxine/Pyrimethamine (SP) *Co-blistering, or bi-layered tablets

38. 2006.08.22. Pogány - Dar es Salaam 38/66 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 MgCl 2 is highly hygroscopic and, as a result, its lubricant properties also change.  The compatibility and in-use stability of the FP with reconstitution diluents should be addressed, e.g. in Artesunate injection.

39. 2006.08.22. Pogány - Dar es Salaam 39/66 Selection of excipients - Talc Time (week)Talc ATalc B Salicylic acid, % 00.10 40.325.85 80.4113.00 120.8028.50

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. 2006.08.22. Pogány - Dar es Salaam 41/66 Dissolution testing*  Dissolution testing is used for the selection of the formulation and comparison of the dissolution profiles with that of the innovator product and 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.

42. 2006.08.22. Pogány - Dar es Salaam 42/66 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

43. 2006.08.22. Pogány - Dar es Salaam 43/66 Selection of binder and solvent 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

44. 2006.08.22. Pogány - Dar es Salaam 44/66 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”.

45. 2006.08.22. Pogány - Dar es Salaam 45/66 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 160 o C, two hours)  Alternatively, sterile filtration under aseptic conditions.

46. 2006.08.22. Pogány - Dar es Salaam 46/66 Artesunate injection  In the 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 a bolus into an indwelling intravenous cannula”. www.thelancet.comwww.thelancet.comVol366August 27, 2005

47. 2006.08.22. Pogány - Dar es Salaam 47/66 4-FDC antituberculosis FPP Originator FPP in ICH region  None FPP in current Essential Drug List  Rifampicin150 mg  Isoniazid 75 mg  Pyrazinamide400 mg  Ethambutol275 mg

48. 2006.08.22. Pogány - Dar es Salaam 48/66 4FDC-TB tablets exposed to 40°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

49. 2006.08.22. Pogány - Dar es Salaam 49/66 Critical quality variables 1. The formulation is hygroscopic, sensitive to light and unstable. 2. Moisture content of FPP and intermediates. 3. Ethambutol.2HCl provides acidic conditions to accelerate decomposition between rifampicin and isoniazid. 4. Packing materials are critical for stability.

50. 2006.08.22. Pogány - Dar es Salaam 50/66 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.

51. 2006.08.22. Pogány - Dar es Salaam 51/66 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.

52. 2006.08.22. Pogány - Dar es Salaam 52/66 Container closure system  The choice and rationale for selection of the container closure system for the commercial product [described in 3.10 Container/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).

53. 2006.08.22. Pogány - Dar es Salaam 53/66 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 ICH Q6A Specifications).  Antimicrobial preservative effectiveness should be demonstrated during development.

54. Manufacturing process development Laboratory scale

55. 2006.08.22. Pogány - Dar es Salaam 55/66 Selection of FPP and manufacturing process Qualitative information  Composition (innovator)  Experimental methods Tablets, hard capsules and powders  Wet granulation  Dry granulation, or  Direct compression  Film coating Primary packing Different strengths with the same composition

56. 2006.08.22. Pogány - Dar es Salaam 56/66 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 batch is manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch.

57. 2006.08.22. Pogány - Dar es Salaam 57/66 Compression Tabletting machine BB3 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

58. 2006.08.22. Pogány - Dar es Salaam 58/66 Film-coating conditions 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

59. 2006.08.22. Pogány - Dar es Salaam 59/66 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

60. Manufacturing process development Pilot plant scale

61. 2006.08.22. Pogány - Dar es Salaam 61/66 Primary (exhibit) 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.

62. 2006.08.22. Pogány - Dar es Salaam 62/66 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 process should 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).

63. 2006.08.22. Pogány - Dar es Salaam 63/66 Manufacturing Process Development  An assessment of the ability of the process to reliably produce a product of the intended quality e.g., the performance of the manufacturing process under  different operating conditions,  at different scales, or  with different equipment can be provided.  Unsatisfactory processes must be modified and improved until a validation exercise proves them to be satisfactory.  An understanding of process robustness can be useful in risk assessment and risk reduction.

64. 2006.08.22. Pogány - Dar es Salaam 64/66 The remaining steps  Pharmaceutical equivalence and bioequivalence with innovator product has been demonstrated  Production batches validated  Compilation of the dossier for prequalification  Prequalification procedure  GMP inspection  Listing the FPP on the PQ website

65. 2006.08.22. Pogány - Dar es Salaam 65/66 Main points again  Development pharmaceutics is an essential part of applications for prequalification.  Desk research gives valuable design and development information.  The specifications of an API are finalized during pharmaceutical development studies.  FPP design, characterization and selection should follow a scientific methodology.  Manufacturing process design and optimization identifies the critical attributes whose control leads to the batch-to-batch consistency of quality.

66. 2006.08.22. Pogány - Dar es Salaam 66/66 THANK YOU