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WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China

WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007. Finished Pharmaceutical Products (FPPs). Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy

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WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China

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  1. WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007 Finished Pharmaceutical Products (FPPs) Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa

  2. What is an FPP? Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient Finished Pharmaceutical Product (FPP) A product that has undergone all stages of production, including packaging in its final container and labelling Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority(WHO, Blue Book)

  3. Section 3. Dossier requirements for a Finished Pharmaceutical Product (FPP) Guideline Guideline on Submission of Documentationfor Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs)used in the Treatment of HIV/AIDS, Malaria and Tuberculosis (Generic guideline – under revision)

  4. Section 3. FPPs: content of dossier 3.1Manufacturing and marketing authorization ** 3.2 Pharmaceutical development 3.3 Formulation 3.4 Sites of manufacturing ** 3.5 Manufacturing process 3.6 Process controls, critical steps & intermediates 3.7 Process validation and evaluation 3.8 Specifications for excipients ** 3.9 Control of the FPP (specifications) 3.10 Container closure system & other packaging 3.11 Stability testing (shelf-life) 3.12, 3.13, 3.14 Labelling/SmPC/PIL **Not discussed in session

  5. 3.2 Pharmaceutical development • The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. • Information from pharmaceutical development studies can be a basis for quality risk management Quality is built in by design, not tested in ICH Q8

  6. 3.2 Pharmaceutical developmentWhat if not? • Poor or no development can lead to a bad product • Very high risk • Example: TB 4-FDC tablets • one year from expiry Photo from: S. Singh & B. Mohan, Int. J. Tuberc. Lung. Dis., 7, 298 (2003)

  7. 3.2.1 Company R&DAspects important for development • Properties of the API, such as • Stability for instance against • heat, oxidation by air and hydrolysis • Solubility • Hygroscopicity • Crystal form and particle size • especially for practically insoluble APIs

  8. 3.2.1 Company R&D (2)Aspects important for development • Choice of excipients, e.g. • Compatibility with API(s) • Intended functions and concentrations in product • Characteristics (flowability, density, water content, etc) • Safety aspects, e.g. TSE risk, to be addressed • For fixed-dose combination (FDC) products • Compatibility of APIs with each other • WHO Guidelines for registration of fixed-dose combination medicinal products • WHO TRS 929 (on WHO Prequalification website)

  9. 3.2.1 Company R&D (4)Aspects important for development • Comparative dissolution testing(separate topic) • Assist in selection of the formulation • Retention of dissolution properties • from pivotal batch to production batch • Setting of dissolution specifications • Selection, optimisation and validation of manufacturing process • Critical aspects • Method of sterilisation, with justification (where appropriate) • Overages (justification) • Unsatisfactory processes to be rectified

  10. 3.2.1 Company R&D (5)Aspects important for development • Packaging • should ensure stability of the product • Summary of development of the FPP from pre-formulation to production scale • Comparison of formulas (tabulated form) of • bio-batch(es) (clinical / bioequivalence) • development batches • stability batches • batches for validation / production

  11. 3.2.2 Information from literature (Desk research)TB 4FDC tablets Supportive data from literature can be included • Strongly recommended • Scientifically sound & do not reinvent the wheel • Examples • Indinavir sulfate • Excellent analysis of published data(EPAR): Dr. J. Pogány: Research & Development, WHO workshop, 28 February 2005, Shanghai (PQ website) • TB 4FDC tablets • A problem mix … 4FDC = Fixed-Dose combination, containing 4 APIs

  12. 3.2.2 Pharmaceutical developmentDesk research: TB 4FDC tablets (1) Composition in current Essential Medicines List and on current EoI for TB products • Rifampicin 150 mg • Isoniazid 75 mg • Pyrazinamide 400 mg • Ethambutol 2HCl 275 mg • Total API weight 900 mg • Typical tablet weight ~ 1.2 to 1.3 g

  13. 3.2.2 Pharmaceutical developmentTB 4FDC tablets (2) Rifampicin (see API presentation) • Oxidation (quinone & N-oxide) • Protect from air exposure • Hydrolysis (3-formylrifamycin & 25-desacetyl) • 3-formylrifamycin - an aldehyde - reacts with isoniazid • Wet granulation / drying a potential problem? • Reaction with Isoniazid • producesisonicotinyl hydrazone (see API presentation) • isonicotinyl hydrazone major decomposition product • Light sensitive • Product to be protected from light exposure

  14. 3.2.2 Pharmaceutical developmentTB 4FDC tablets (3) Isoniazid • Reacts with aldehydes/reducing sugars • Sugar & lactose to be avoided in formulation !! • 3-Formylrifamycin (from rifampicin) • Isonicotinyl hydrazone • Series of articles by dr. S. Singh et al. (NIPER), e.g. • S. Singh, T. T. Mariappan, N. Sharda, S. Kumar & A. K. Chakraborti. The reason for an increase in decomposition of rifampicin in the presence of isoniazid under acid conditions. Pharm. Pharmacol. Commun., 6, 405-410 (2000) • The pathway for the formulation of the hydrazone is discussed in the above publication

  15. 3.2.2 Pharmaceutical developmentTB 4FDC tablets (4) Ethambutol hydrochloride (2HCl) • Hygroscopic • TB FDC tablets containing ethambutol 2HCl show tendency to absorb water at 40°C/75%RH • The water can act as solvent for • “bleeding” and degradation reactions in tablets • Creates slightly acidic conditions • pH of a 2% m/v solution, 3.0 - 4.5 (PhInt) • The acidic conditions enhance reaction between rifampicin and isoniazid reaction (isonicotinyl hydrazone formation) • Reacts with Mg-stearate • Forms Mg-chloride (highly hygroscopic)

  16. 3.2.2 Pharmaceutical developmentTB 4FDC tablets (5) Ethambutol hydrochloride powder - water absorption: ▲ at 45°C/75%RH + light ● at 45°C/75%RH • 73% in 32 hours • Dissolves in water absorbed S. Singh et al., Int. J. Pham., 245, 37 (2002)

  17. 2.2.2 Parma. developmentTB 4FDC tablets (6) ProductsB A FPPs (packed products) Unpacked tablets (control) After 5 days at 40°C/75% RH After 5 days at 40°C/75% RH + Light S. Singh, Int. J. Tuberc. Lung. Dis., 7, 298 (2003) Quality of the products not known “bleeding”

  18. 3.2.2 Pharmaceutical developmentTB 4FDC tablets (7) Two TB 4FDC tablets were exposed to accelerated conditions (dark) • 7 days at 40°C/70% RH • unpacked (data generated at RIIP, North-West University, RSA) Observations: • darkening, but no bleeding of product on left (proven quality) Control Control

  19. 4FDC-TB tablets (8)preventative/protective measures • Formulation -no sugar/lactose (isoniazid) • Separate granulation of rifampicin & isoniazid (limit contact) • Rifampicin as powder(not granulate)? • Prevent oxidation & hydrolysis • Differential formulation, e.g. delayed release/immediate release tablet (combined technology) • Low water content of tablet (PhInt ≤ 3.0%) • Protect product from moisture and oxygen • Film coating • Non-permeable primary packaging – do not remove until use • Avoid magnesium stearate as lubricant (ethambutol hydrochloride) • Light protection !!

  20. 3.3 Formulation • Formula in tabulated form for: • Administration unit (e.g. one tablet) • Typical batch • Justify any overages • Precise quantity adjustment of API • Excipients • State function (e.g. lubricant, disintegrant) • Technical grade (e.g. micronised, purified water) • Also those removed during process (e.g. water) • Also those not always added (e.g. acid & alkali) • Also gas (inert atmosphere) • Capsule shells, inked imprints on dosage form

  21. 3.3 FormulationExample * Removed during process (not in total mass)

  22. 3.5 Manufacturing process • Flow chart • Indicate each step, show where materials enter • Indicate critical steps – in-process controls • Description of manufacturing/packaging, including • Scale • Equipment by type (e.g. tumble blender) & working capacity • Process parameters for steps, e.g. time, temp, pH • Environmental conditions, e.g. rel. humidity for hygroscopic FPPs and area class for sterile FPPs

  23. 3.5 Manufacturing process (cont.) • Proposal for reprocessing – justified with data • Copy of master formula • Batch manufacturing record – real batch • Sterile products – sterilisation steps and / or aseptic procedures • Description of in-process tests, including sampling plans and acceptance limits • Data for ≥ 3 full scale batches to support achievement of predetermined specifications

  24. 3.6 Manufacturing process controls ofcritical steps and intermediates • Critical steps • Acceptance criteria (justified) • Test methods (cross reference acceptable) • Intermediates isolated during process, • for instance tablets cores in film-coated tablet production • Acceptance criteria (justified if not compendial) • Test methods (cross reference acceptable)

  25. 3.7 Process validation & evaluation Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired qualityi.e. that the process is suitable and under control

  26. 3.7 Process validation & evaluation Distinguish between the following generics: 3.7.1 New FPPs(new for manufacturer, not market) • FPPs that have been newly developed by the manufacturer, though it will be a generic • Full validation required 3.7.2 Established FPPs • The manufacturer has manufactured & marketed this FPP for quite some time and now wishes to prequalify the FPP • ≥ 10 recent consecutive batches • result/trend/statistical analysis & discussion • Rejected batches excluded - submit failure investigation separatepresentation

  27. 3.9 Control of FPP Four subsections 3.9.1 Specifications 3.9.2 Analytical procedures 3.9.3 Validation of analytical procedures 3.9.4 Batch analysis (against full set of specifications) • Three or more batches • Full information on the batches, e.g. • Batch number and size • Date/place of manufacture and QC testing • Purpose of batches • Batch number of API • QA certified

  28. 3.9.1 Specifications for the FPP Specifications are one part of a total control strategy for the FPP designed to ensure product quality and consistency (ICH: Q6A). • Others include sound development studies and adherence to GMP; e.g., suitable facilities, a validated manufacturing process, in-process testing, stability testing, API testing, etc. • Quality is built in by design, not tested in • Product specifications • Release specifications and • Shelf-life specifications (may differ from release if justified)

  29. 3.9.1 FPP specifications (cont.) Important reading for setting specifications: • ICH guideline Q6A (also good for generics): • Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Specifications based on pharmacopoeial monographs: • Additional product related specifications, e.g. • Those standard for the type of dosage form (e.g. friability, tablet hardness, uniformity of dosage units, viscosity) • ID of colorants (skip testing?) • microbial limits (skip testing?) • ID and assay of preservatives • Limits may be tighter than in monograph

  30. 3.9.1 FPP specificationsTypical parameters (2) • Appearance • Identification of the following in FPP • APIs • Colorants (skip testing possible) • Preservatives • Physical tests appropriate to dosage form e.g. • LOD, friability, hardness (tabs), relative density • Uniformity of dosage units (mass / content) • Pharmaceutical tests, e.g. • dissolution • Each API in FDC products (see presentation on comparative dissolution)

  31. 3.9.1 FPP specificationsTypical parameters (2) • Purity tests • Degradation products (related substances) • Special attention to API-API degradation products • Residual solvents (solvents used in process) • Microbial count / sterility / bacterial endotoxins • Content of APIs in FPP (assay) • Limits 95.0% – 105.0%, unless justified • Content of preservatives • Limits 90.0% – 110.0%, generally acceptable

  32. 3.9.3 Validation analytical methods • Non-pharmacopoeial methods • All methods should be validated • Validation reports, including data & conclusions • Stability of sample/standard solutions • Pharmacopoeial methods • Full or partial validation/ verification of suitability • show validity for this formulation – specificity important • Validation study - ICH guidelines: • Q2(R1) • See: Analytical Method Development, Training Workshop, Cape Town, April 2007 (WHO Prequalification website)

  33. 3.9.3 Validation analytical methodsICH Q2(R1) table - validation parameters

  34. 3.10 Packaging • Container/closure system (immediate container) • Suitability for storage, transport, compatibility • protection against moisture, air, light as required by stability testing • Detailed description, including liner/wadding • Specifications of parts in contact with product • Description • Identification (Typical: IR - specific) • Drawings and critical dimensions, where required • Outer packaging • Description, type of material • Also protective

  35. 3.11 Stability testingThe objective • The purpose of stability testing is to provide evidence on how the quality of an API or FPP • varies with time • under the influence of a variety of environmental factors such as temperature, humidity, and light and • to establish a re-test period for the API or a shelf life for the FPP and • to recommend storage conditions ICH QA1(R2)

  36. 3.11 Stability testingGlossary(WHO) Re-test period (API) • The period of time during which the API is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the API has been stored under the defined conditions • After this period, re-testing should be performed … Re-test date (API) • The date when a active pharmaceutical ingredient should be re-examined to ensure that the material is still in compliance with the specification and thus that it is still suitable for use in the manufacture of a pharmaceutical product.

  37. 3.11 Stability testingGlossary(WHO -2) Shelf-life (FPP) • The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. • The shelf-life is used to establish the expiry date of each batch. Expiry (expiration) date (FPP) • The date given on the individual container (usually on the label)of a product up to and including which the product is expected to remain within specifications, if stored correctly. • It is established for each batch by adding the shelf-life to the date of manufacture.

  38. 3.11 Stability testingStability batches (FPPs) • Stability data for three primary batches by time of submission • One batch should at least be of production scale, the remaining 2 batches at least pilot scale • The formulation and manufacturing process should be the same as proposed for marketing • In container-closure system as proposed for marketing • Preferably manufactured from different API batches • Full info on batches tested (tabulated format) • Next slide

  39. 3.11 Stability testingInformation required on batches

  40. 3.11 Stability testingStability specifications Stability studies should include testing of those attributes (parameters) of the FPP that are • susceptible to change during storage and thus • are likely to influence quality, safety, and/or efficacy • The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system) From ICH Q1A(R2)

  41. 3.11 Stability testingExample - FPP specs – uncoated tablets

  42. 3.11 Stability testingExample - FPP specs – uncoated tablets (2)

  43. 3.11 Stability testingSignificant changes during stability • A 5% change in assay from its initial value (or failure to meet acceptance criteria when using biological methods) • Any degradation product exceeding its acceptance criterion • Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, phase separation, resuspendibility, hardness, dose delivery per actuation); • and, as appropriate for the dosage form: • Failure to meet the acceptance criterion for pH; or • Failure to meet the acceptance criteria for dissolution for 12 dosage units

  44. 3.11 Stability testingStorage conditions & frequency Example: Tablets and capsules • Zone IVb is recommended as long term storage condition to cover all climate conditions as defined by WHO (TRS 937) • Long-term data to cover minimum of 12 months by submission • However, see Supplement 2 of guideline • 6 month data for certain FPPs containing stable APIs

  45. 3.11 Stability testingStability indicating analytical methods • Analytical methods must be suitable and valid for the purpose of stability testing (stability indicating), particularly in the case of • Assay of the API(s) in the FPP • Determination of the degradation product • Determination of preservatives • Specificity

  46. 3.11 Stability testingRifampicin containing FDC products • Particular degradants to consider: • Isonicotinyl hydrazone • Rifampicin quinone • Rifampicin N-oxide • 3-Formyl rifamycin (present in FDCs?) • 25-Desacetyl rifampicin • All to be determined & expressed with respect to rifampicin • PhInt monograph test: assay and related substances • Specific for both tests – suitable for the purpose • Chromatogram on next slide • Sample preparation under revision

  47. 3.11 Stability testingRifampicin HPLC (spiked) - PhInt method C-18 column: methanol/phosphate buffer pH 7.0 : 6/4 Signals well separated, resolution test included rifampicin 3-Formyl rifamycin Hydrazone Quinone N-Oxide

  48. 3.12 Container labelling • Outer packaging • where no outer packaging, on immediate packaging, e.g. HDPE bottle • Blisters and strips • All the elements as listed on page 23/50 of the Generic guideline

  49. 3.13 SmPC & 3.14 PIL 3.13 Summary of product characteristics (SmPC) • To appear in WHOPAR • Changes to SmPC to be approved by WHO • See Annex 5 of guideline 3.14 Patient information leaflet (PIL) • To appear in WHOPAR • In conformance with SmPC • See Annex 6 of guideline • From quality side, include for example (where appropriate) • Identification of dosage form in detail (important for counterfeit) • Container description • Storage requirements and approved shelf-life

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