Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Pharmaceutical Development Developing formulation and manufacturing process Presenter: János Pogány, pharmacist, PhD pogany.janos@chello.hu WHO expert

3. Abbreviations APIActive Pharmaceutical Ingredient EoIExpression of Interest FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization MA Marketing Authorization PQPPreQualification Project TRSTechnical Report Series of WHO Red → emphasisGreen → WHOViolet → ICH region

4. Pharmaceutical Development Outline and Objectives of presentation • Objective, guidelines • Literature and patent survey • Generic pharmaceutical product and process development –assessors view of a science- and risk-based approach • Laboratory scale • Pilot plant • Production plant • Presentation of dossier for prequalification • Continuous improvement • Main points again

5. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Objective, guidelines

6. Interchangeability (IC) INTERCHANGEABILITY (IC) OF MULTISOURCE FPPs = THERAPEUTICAL EQUIVALENCE WITH A COMPARATOR (REFERENCE) FPP = PHARMACEUTICAL EQUIVALENCE (PE) + BIOEQUIVALENCE (BE) IC=PE+ BE

7. Pharmaceutical equivalence • Products are pharmaceutical equivalents1 if they contain the • same molaramount of the same active pharmaceutical ingredient(s) • in the same dosageform • if they meetcomparable standards, and • if they are intended to be administeredby the same route 1Pharmaceutical equivalence does not necessarilyimply therapeutic equivalence, as differences in the excipients and/orthe manufacturing process and some other variables can lead to differencesin product performance. • Pharmaceutical development equivalence, including stability equivalence (and packaging equivalence) • WHO-GMP(manufacturing process equivalence)

8. Focus on paediatric dosage forms • Epivir (lamivudine) 10 mg/ml oral solution • Retrovir (zidovudine) 100 mg/10 ml oral solution • Sustiva(efavirenz) 30 mg/ml oral solution • Viramune (nevirapine) 50 mg/5 ml oral suspension • Zerit (stavudine) 200 mg powder for oral solution • Powder for oral suspension, capsules, film-coated tablets and chocolate pastilles can also be considered Once safe and effective doses are established, generic FPPs can be developed and bioequivalence demonstrated

9. Pharmaceutical development C O N T I N U O U S I M P R O V E M E N T

10. Guidelines used in PQP • Annex 6. Validation of manufacturing processes, in WHOTRS No. 863 (1996). • WHO „Guideline 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) • 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.)

11. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Desk research Nevirapine 50mg/5 ml oral suspension

12. Information on Nevirapine • Thesynthesis of the two crystal forms is similar until the final drying step • Impurity profile iswell characterised. Impurities arising from synthesis have beentoxicologically qualified • The API is milled in order to obtain an acceptableparticle size distribution • The API is non-hygroscopic • No polymorphic changes were observedunder stressedconditions • No degradation products have been detected during stability testing • Batch analysis data confirm that nevirapine hemihydrate complies with thespecifications http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf http://www.fda.gov/cder/ogd/rld/20933s3.PDF • Nevirapine is official in the PhInt

13. Nevirapine is lipophilic (partition coefficient 83) and is essentially nonionized at physiologic pH. As a weak base (pKa 2.8), Nevirapine is showing increased solubility at acidic pH values. Source: Meck Index Aqueous solubility(anhydrate) (90μg/ml at 25°C). Nevirapine ishighly stable Information on Nevirapine

14. Viramune 50 mg/5 ml oral suspension • Oral suspension containing 10 mg/ml of nevirapine as 10.35mg/ml Nevirapine Hemihydrate as the API. • Excipients: Carbomer, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbitol, sucrose, polysorbate80, sodium hydroxide and purified water. (FDA excipient list: Carbomer 934P). • Shelf life: 3 years The product should be used within 2 months of opening. • No special precautions for storage • Nature and contents of containerWhite HDPE bottle with two piece child-resistant closure (outer shellwhite HDPE, inner shell natural polypropylene) with LDPE foam liner. Each bottle contains 240 ml of oral suspension. Clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber piston seal. Clear low density polyethylene bottle-syringe adapter. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf http://www.fda.gov/cder/ogd/rld/20933s3.PDF • Nevirapine oral suspension monograph (PhInt) is being developed

15. Viramune 50 mg/5 ml oral suspension • The HDPE bottle material is inert and was shown to becompatiblewith the active substance and other ingredients of the formulation. • The levels of preservatives have been correlated with antimicrobial effectiveness tested accordingto PhEur • Acceptable data demonstrating theprecision and accuracy of the dosing syringe were provided. • Synthesis impurities are not degradants and not part of FPP specifications • The method of preparation of the oral suspension is standard for this form and has been adequatelydescribed. Validation data presented on three production batches manufactured using three differentlots of nevirapine anhydrous (?) were adequate to demonstrate that the process is under control andensures both batch-to-batch reproducibility and compliance with standard specifications. Tests atrelease are standard and ensure reproducible clinical performance of the product.

16. Viramune 50 mg/5 ml oral suspension • Stability data up to 18 months for the newlyrecapped oral suspension and 24 months with the old pulpboard liner confirmed the physical andchemical stability of the oral suspension and the antimicrobial efficacy of the preservative. Theseresults support a shelf life of 24 months. Long-term stability data will be submitted on ongoing basis. • An in-use stability study designed to mimic the delivery of 2 ml dose, which represents one of thelowest projected doses, twice a day, using the delivery device intended for marketing has beenperformed. • An additional study is presented on the stability of the product exposed to freeze-thawconditions. On the basis of results from both studies, the claimed in-use shelf life of 60 days with nospecial storage precautions is supported.

17. Clinical information • Nevirapine was readily absorbed (> 90 %) after oral administration in healthy volunteers and in adultswith HIV-1 infection. • A 3-way crossover study compared the bioavailability from three production/commercialscale batches with varying dissolution profiles. All three batches were bioequivalent with respect tosystemic exposure (AUC). The significantly different values for Cmax and tmax were considered not tobe clinically relevant. • In studies 1100.1231 and 1100.896 in which the suspension was administered directly using a syringe,it was demonstrated that the suspension and tablet formulations were comparably bioavailable withrespect to extent of absorption. In study 1100.1213 the suspension was administered in a dosing cupwithout rinsing. The suspension intended for marketing was bioequivalent to the suspension usedduring clinical trials but was not bioequivalent to the marketed tablets. This could be attributed toincomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.

18. Clinical information • It has been later determined in a single dose study in 9 patients agedbetween 9 months and 14 yearsadministered after an overnight fast (3 patients per dose levelequivalent to 7.5 mg/m², 30.0 mg/m² and 120.0 mg/m²). • Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatricpopulation. A 4 mg/kg dose is proposed for all children regardless the age. Although no particularstudy has been performed to find the optimal lead-in dose, this dose was considered acceptableconsidering the enzyme induction to achieve initial antiretroviral activity. The final recommended doses for the different ages are therefore the following: • Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7 mg/kg bid • Patients from 8 years to 16 years are 4 mg/kg once daily followed by 4-mg/kg bids.

19. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Generic pharmaceutical product and process development

20. Pharmaceutical development for generics • Product target profile (PTF) is different: • Innovator PTP is based on clinical studies • Generic FPP targets the innovator FPP • Multisource FPP manufacturers must be highly skilled in product development • The chances of developing a bioequivalent generic product can be significantly increased by using the formulation of the innovator. The lowest risk strategy for the development of aninterchangeablemultisource FPPis to copy the innovator FPP. • Manufacturing processes are the same for innovators and generic manufacturers.

21. Innovator suspension – bench marking (1) • Sample confirmation • Batch numbers • Shelf life: 3 years and within 2 months of opening. • Storage instructions: No special precautions for storage • Container and closure system: as per EPAR • QC analysis(hypothetical figures) • Assay: 99.9% of labelled amount (LA) • Methylparaben (HPLC): 0.18% w/v • Propylparaben (HPLC): 0.02% w/v • Total related substances: 0.03% • Specific gravity (at 25oC): 1.150 • Viscosity (at 25oC): 1,150 cPs • pH: 5.80

22. The composition suggests that: Sucrose and sorbitol are used to adjust the density of the medium Carbomer 934P is used to adjust viscosity Polysorbate is a wetting agent Sodium hydroxide is used to adjust the pH to 5.8 Innovator suspension – bench marking (2)

23. Innovator product – bench marking (3) • Dissolution profile (% LA) • Apparatus: USP II (paddle, 25rpm) • Medium: 0.1N HCl • Volume: 900ml • http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March 2007

24. Innovator product – bench marking (4) Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated

25. Pharmaceutical development protocol • API experiments • Solubility at 37 oC • Particle size distribution • Density • Formulation experiments • Screening laboratory batches with different proportions of excipients to match innovator dissolution • Stress testing of the selected composition • Compatibility with excipients • Antimicrobial effectiveness test accordingto PhEur • Packing materials • Dimensions and tolerances of packing components • Precision and accuracy of the dosing syringe

26. Product-specific physical API properties PhInt specifications + residual solvents from APIMF. Product-specific physical properties depend on crystallization and subsequent physical processing. Density and particle size distribution of Nevirapine Hemihydrateare critical quality attributes of the API. Acceptance criteria are established by measurement of particle size of innovator’s API in suspension and through the similarity of dissolution profiles of innovator and generic products.

27. Stress stability testing - Nevirapine

28. Solubility of nevirapine hemihydrate at 37oC Nevirapine Hemihydrate belongs to BCS Class 2 (low solubility, high permeability). Solubility data are also important for cleaning validation

29. Dissolution profiles of innovator and generic FPPs M e a n % A P I d i s s o l v e d ▀innovator ▀generic Similarity factor, f2=73 Time (minutes)

30. Selected generic composition (hypothetical figures) Ingredientsmg/5ml • Nevirapine hemihydrate 51.7 • Excipients • Carbomer 934P 8.0 • Methyl parahydroxybenzoate 10.0 • Propyl parahydroxybenzoate 1.0 • Sorbitol 800.0 • Sucrose 700.0 • Polysorbate80 3.0 • Sodium hydroxide q.s. • Purified water to make 5.0 ml

31. Compatibility with excipients Nevirapine Hemihydrate in solid state – illustrative example: heat To do: stress testing the dose-proportional mixture of the APIs in aqueous medium.

32. Risk assessment matrix – illustrative Potentially critical to Q Monitoring strategy Critical to Q Control strategy Not critical to Q

33. Process development • Selection of process: standard for oral aqueous suspensions • The progress from pre-formulation → formulation → pilot manufacture(not less than 1/10th of production batch) → 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. • Manufacture of primary batches in the proposed container and closure systems for: • Bioequivalence and dissolution studies • Regulatory stability studies ( including in-use stability study and an additional study under freeze-thawconditions.) • Prospective validation of bioequivalence, dissolution and stability batches

34. Proposed FPP specifications • Description • Identification (HPLC) • Dissolution (UV): Q = 70% in 45 minutes • pH = 4.8 – 6.2 • Deliverable volume • Average fill volume: NLT 240 ml • Fill volume variation: should meet PhInt requirements • Related substances: not tested • Preservative content (HPLC) • Methylparaben: 98 to 102% of LA [End of shelf life: 80 to 102% of LA] • Propylparaben: 98 to 102% of LA [End of shelf life: 80 to 102% of LA] • Assay: 95.0 to 105.0% of LA End-of shelf-life acceptance limits for assay should not be proposed at this stage.

35. Scale up activities • Stability protocol is prepared • A large number of samples is tested from pilot scale batches to establish provisional acceptance limits for the control of critical process parameters (prospective validation, IPC limits) in order to define design space (process knowledge)and control strategy(risk mitigation)that encompasses aspects of scale, environmental aspects of site, packaging, as well as final product stability. The process will be well understood when: • all critical sources of variabilityhave beenidentified and explained • variability is managed by the process • product quality attributes can be accurately and reliably predicted • Validation protocol is written • Dossier is submitted for prequalification

36. High-shear batch mixer and in-line mixer

37. Dissolution (and bioequivalence) batch Generic FPP Innovator FPP Dissolution test 3 batches Production batch, or NLT 1/10 of final size Select a batch showing intermediate dissolution Test product Reference product Dissolution profile

38. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Special features of FDCs

39. 4-FDC antituberculosis FPP Originator FPP in ICH region • None FPP in current (14th) List Essential Medicines • Rifampicin 150 mg • Isoniazid 75 mg • Pyrazinamide 400 mg • Ethambutol 275 mg

40. 4FDC-TB tablets exposed to40°C/75%RH for one week Two different products. “Bleeding” may start after more exposure to stress testing without packing material. (Source: North-West University, South Africa) Control on left Control on left

41. A typical incompatibility • Magnesium stearate is incompatiblewith salts of weak bases and strong acids, such as: • Amodiaquine hydrochloride • Ethambutol hydrochloride • Mefloquine hydrochloride • because the formed MgCl2 is highly hygroscopic (the hexahydrate is also deliquescent) and, as a result, the lubricant properties of magnesium stearate also change.

42. Critical quality variables • The formulation is hygroscopic, sensitive to lightand unstable (reaction between rifampicin and isoniazid). • Moisture content of FPP and intermediates (granules and uncoated tablets). • Ethambutol.2HCl provides acidic conditions to accelerate reaction between rifampicin and isoniazid. • Packing materials are critical for stability. • Compatibility of APIs with each other and with excipients • Stress stability testing of the final formulation • Control of temperature and RH during the manufacturing process • 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), LOD, hardness, and other attributes.

43. Main points again • Pharmaceutical development is an essential part of applications for prequalification. • Desk research gives valuable information for generic pharmaceutical product and process development for paediatric formulations. • FPP-specific quality and processability requirements are integrated into the API specifications during pharmaceutical development studies. • A science- and risk-based pharmaceutical development of generic FPPs provides a high level of assurance for interchangeability with the innovator product. • Manufacturing process design and optimization identifies the critical attributes whose control leads to the batch-to-batch consistency of quality.

44. Science- and risk-based approach means: There will be no weak eye in the pharmaceutical development chain

45. THANK YOU