Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam,

1. Evaluation of Quality and Interchangeability of Medicinal Products Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam, Tanzania Date: 10 to 14 September 2007

2. Evaluation of Quality and Interchangeability of Medicinal Products 3.0 Finished Pharmaceutical Products • 3.2 Pharmaceutical Development Presenter: Deus K. Mubangizi, pharmacist, MSc(Pharm.) deuskm@yahoo.co.uk, dmubangizi@nda.or.ug Chief Inspector of Drugs, National Drug Authority WHO expert

3. 3.2 Pharmaceutical Development Outline of presentation • Applicable Guidelines • Aim of Pharmaceutical Development • Dossier data requirements on pharmaceutical development • Pre-formulation studies • Phyisco-chemical characteristics of the API • Stress stability of the API • Choice of excipients • Choice of formulation and compatibility (Example of 4FDC FPP) • Choice of manufacturing process • Lab scale • Pilot scale • Dissolution testing • Details of batches studied • Container closure system • Microbiology attributes • Examples of ACTS • Summary of main points

4. Applicable guidelines • WHOGuideline on Submission of Documentation forPrequalification ofMulti-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)

5. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development The aim is to build a quality product by design. • DESIGN (product-specific research) • Desk research • API (specifications, stress stability testing, etc.) • FPP (pre-formulation, screening stability studies, etc.) • DEVELOPMENT[FPP andmanufacturing 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)

6. General considerations • The marketing of a new multisource FPPin the ICH region may costUSD 1 to 2 millions and may take a time of three to 5 years. • The lowest risk strategy for the development of aninterchangeablemultisource FPPis to copy the innovator FPP. • Multisource FPP manufacturers must be highly skilled in product and process development

7. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development The section should contain information on the development studies conducted to establish that • the dosage form, • the formulation, • the manufacturing process, • the container closure system, • microbiological attributes and • storage and usage instructions are appropriate for the purpose specified in the dossier.

8. 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).

9. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (pre-formulation) • Physico-chemical characteristics of the APIs • solubility (composition) • water content (stability) • hygroscopicity (stability) • particle size (solubility, bioavailability, suspension properties, stability …) • polymorphism (solubility, bioavailability, stability) • Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet …… • Experimental data (if necessary)

10. Particle size • When the solubility of an API is less than 0.1 mg/ml (>10,000ml/g, practically insoluble) 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 (>1,000ml/g, very slightly soluble).

11. Potentially critical attributes of API Key physicochemical characteristics: • Polymorphic or solid state form(amorphous,hydrate, solvate) • Solubility at 37 oC over the physiological pH range (e.g., BCS, dissolution testing, cleaning validation) • Permeability (octanol-water partition) (BCS) • Crystal habit, particle shape and size(pharmaceutical and bioequivalence, processability) • Bulk density, untapped and tapped (processability) • Flowability(processability) • Color, olor, taste, consistency (choice of dosage form) should be discussed and supported by experimental data.

12. 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. This information is partially available from the OP of the DMF

13. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of excipients) • Intended function of each excipient • Criteria • compatibility of excipients with API(s), • characteristics of the excipients (water content, particle size, flowability, density, rheological behaviour…) • Particularly : other non active constituents (lowest acceptable concentration to be chosen e.g. concentration of parabens as preservatives) • Experimental data needed.

14. EXCIPIENTS - STARCH • All starches are hygroscopic and rapidly absorbatmospheric 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.

15. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of formulation and compatibility) • Compatibility of APIs with the excipients • Compatibility of APIs between each other in case of fixed dose combinations See example of 4 FDC for TB products

16. Example: 4 FDC FPP 3.2. Pharmaceutical development (choice of formulation and compatibility) • Each tablet contains 4 APIs . Rifampicin ………………. 150 mg . Isoniazid …………………. 75 mg . Pyrazinamid …………….. 400 mg . Ethambutol 2HCl…………275 mg . Excipients ………………..

17. Example: 4 FDC FPP 3.2. Pharmaceutical development (choice of formulation and compatibility) • Rifampicin Oxidation (quinone & N-oxide) • Protect from air exposure Hydrolysis (3-formylrifamycin & 25-desacetyl) • Wet granulation/drying a potential problem ? Reaction with Isoniazid • Produces 3-(isonicotinylhydrazinomethyl) rifamycin or more commonly known as isonicotinyl hydrazone. Light sensitive • Product to be protected from light exposure

18. Example: 4 FDC FPP 3.2. Pharmaceutical development (choice of formulation and compatibility) • Isoniazid Reacts with aldehydes/reducing sugars • Sugar & lactose to be avoided in formulation !! • 3-formylrifamycin (from rifampicin) • Ethambutol hydrochloride (2HCl) Hygroscopic • Absorbs water reactions in tablets. Creates slightly acidic conditions • The acidic conditions enhance reaction between rifampicin and isoniazid (isonicotinyl hydrazone formation)

19. Example: 4 FDC FPP 3.2. Pharmaceutical development (preventive/protective measures) • Formulation – no sugar/lactose (isoniazid) • Separate granulation of rifampicin & isoniazid (limit contact) • Rifampicin as powder (not granulate) ? • Prevent oxidation & hydrolysis • Low water content of tablet • Protect product from moisture and oxygen • Film coating, • Non-permeable packaging • Light protection

20. Example: 4 FDC FPP, 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.

21. Manufacturing process development Laboratory scale

22. 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

23. 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.

24. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (choice of the manufacturing process) • Parameters : characteristics of the APIs, dosage form, composition…. . • Rational behind the choice • Justification of the overage (if any) • Identification of the critical steps • In Process Control (IPC) • Selection and optimisation of manufacturing process

25. 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.

26. Compression

27. Film-coating conditions

28. Film-coating results

29. Manufacturing process development Pilot plant scale

30. Primary (exhibit) 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.

31. 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).

32. 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.

33. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (dissolution testing) • To study dissolution operating conditions (media, pH, rotation, …) • To develop a discriminatory dissolution method • Comparative dissolution testing is a tool, mandatory in development pharmaceutics section of the dossier in PQ, See Supplement 1 • Help in selection of the formulation • compare formulation(s) with innovator product, • a basic strategy in development to maximize the chances of bioequivalence • Comparison of pivotal batches to commercial batches/ post-approval changes • Setting of dissolution specifications

34. Dissolution profiletesting • 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

35. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2. Pharmaceutical development (details of batches studied) • Provide a summary of development of the FPP from pre-formulation to production scale. • Provide a comparison of formulas (tabulated form) of : • bio-batche(s) (clinical/bioequivalence), • development batches, • stability batches, • batches for validation/production

36. 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”.

37. 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).

38. 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.

39. Example of Artemisinin Based Combinations

40. 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. Example of ACTs: Artemisinin

41. Practically insoluble in water. Slightly soluble in ethanols and dichloromethane. Both the API and the tablets are official in the Ph. Int. Example of ACTs: Artenimol

42. 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 Example of ACTs: Artesunate

43. Example of ACTs: Metabolism of Artemether and Artesunate

44. Example of ACTs: Amodiaquine Amodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck Index: pH of 1% aqeous solution is from 4.0 to 4.8.

45. Has an optically active carbon Very slightly soluble in water Has no reactive functional groups under general environmental conditions Example of ACTs: Mefloquine hydrochloride

46. Example of ACTs: Lumefantrin

47. Example of ACTs: 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 bond of artesunate is liable to hydrolysis. • The non-artemisinin APIs mentioned above are chemically stable.

48. Example of ACTs: 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.

49. Example of ACTs: References • Monographs from the Merck Index®, 13thedition (2001). • 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). • The International Pharmacopoeia, 3rd ed., Volume 5, 185-233, WHO, Geneva (2003).

50. Example of ACTs: Compatibility of APIsin FDCs • Artemether + Lumefantrine • Artesunate + Amodiaquine.2HCl* • Artesunate + Mefloquine.HCl* • Artesunate + Sulphadoxine/Pyrimethamine (SP) *Co-blistering, or bi-layered tablets