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1 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical Research and Development Considerations Workshop on GMP and Quality Assurance of Multisource Tuberculosis.

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Presentation on theme: "1 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical Research and Development Considerations Workshop on GMP and Quality Assurance of Multisource Tuberculosis."— Presentation transcript:

1 1 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical Research and Development Considerations Workshop on GMP and Quality Assurance of Multisource Tuberculosis Medicines Kuala Lumpur – Malaysia February 2005 Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa

2 2 TG Dekker – WHO, Malaysia Feb 2005 Abbreviations APIActive pharmaceutical ingredient BCSBiopharmaceutics classification system BPBritish Pharmacopoeia CEPEU certificate of suitability EOIExpression of interest FDCFixed dose combination FPPFinished pharmaceutical product ICHInternational Conference on Harmonization Int.Ph.International Pharmacopoeia R&DResearch and development TBTuberculosis XRPDX-ray powder diffractogram USPUnited States Pharmacopeia

3 3 TG Dekker – WHO, Malaysia Feb 2005 The perspective  Pharmaceutical R & D provides the foundation of the activities aimed at ensuring that the patient receives an FPP (product) that consistently meets established standards & specifications of  Safety  Efficacy  Quality  The FPP should be stable - and thus retain these standards – throughout the shelf-life,  if kept in the original packaging  when correctly distributed, stored & handled

4 4 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical R&D 1.Learn about the product through desk research:  Don’t try to reinvent the wheel  Collect & analyse available information on e.g. APIs, formulas, excipients, compatibility, stability, dosage form, strength, packaging & analysis  Compile a Product Profile Report 2.Development according to plan, including:  Preformulation studies  Formula / dosage form development & packaging  Comparative dissolution against comparator FPP  Accelerated stability  Final formula / manufacturing process

5 5 TG Dekker – WHO, Malaysia Feb 2005 Topics for discussion 1.Desk research – Product Profile Report 2.The FDCs anti-tuberculosis tablets – a problem mix  API-API interactions of particular importance 3.Solid state properties of APIs  Rifampicin as example 4.Biowaiver type of comparative dissolutions  Formulation development & comparison of pivotal batches  Setting product dissolution specifications  Pre-BE control  Post-approval changes

6 6 TG Dekker – WHO, Malaysia Feb 2005 Product profile report  Objective  To compile a comprehensive summary, with conclusions, of all available information that may be important for the development of the product  To have a standard (pro-forma) style for the report, facilitating compilation/application  Assign experts in preparation of relevant parts  To use this report as base for development pharmaceutics (though considered part thereof)  Example  4FDC anti-tuberculosis tablets

7 7 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (1) PRODUCT UNDER CONSIDERATION  4FDC anti-tuberculosis solid oral dosage form Reference product(s) information 1.Category  Anti-tuberculosis agent 2.WHO model list of essential drugs (current)  Rifampicin 150 mg, Isoniazid 75 mg, Pyrazin- amide 400 mg & Ethambutol 2HCl 275 mg 3.Prequalification EOI requirement (current)  As for WHO model list – as tablets

8 8 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (2) 4.Prequalified products according to current list  Wyeth Pakistan - tablet (blister)  Lupin India – tablet (blister, HDPE bottle)  Sandoz – tablet (blister) 5.Public assessment reports available  None (FDA, EPAR, WHOPAR) 6.Comparator product (bio-section)  Sandoz (registered in Sweden)? Clarify  Combination of loose tablets? Clarify 7.Other products with “marketing authorisation”  List such products, where considered necessary

9 9 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (3) 8.Products available for inspection/testing  Wyeth Pak, Lupin, Sandoz, others  Comparator for comparing dissolution profiles 9.Description/appearance of reference products  Especially the prequalified products (i.a. for patient compliance)  Product A: Red oblong film-coated tablets, etc. 10.Packaging / pack sizes  Prequalified products important (see website)  HDPE bottles (100s?), 3 x 10 blisters (alu/alu?)?

10 10 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (4) 11.Storage requirements /shelf life  Especially the prequalified 4FDC tablets  From SmPC or PIL 12.Published product specific excipients  Tabulate for all prequalified/registered products where available (table for comparative purposes)  Public assessment reports (not available for the 4FDC tablets)  From SmPCs (also available on internet)  Document known incompatibilities with APIs

11 11 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (5) 13.Published formulas  Formulas are published for older products in standard works and journals (see next page) 14.Official product monographs  USP 28 (always current) for 4FDC  2 HPLC assay methods for all four APIs  Dissolution test for all four APIs  Related substances (degradants) not included 15.Safety & efficacy information  Requirements for BE studies  Comparator product(s)

12 12 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (6) Typical books for formulation and excipients:  S. K. Niazi. Handbook of Pharmaceutical Manufacturing Formulations. CRC Press, Boca Raton (current edition):  Volume 1. Compressed Solid Products  Volume 2. Uncompressed Solid Products  Volume 3. Liquid Products  Volume 4. Semisolid Products  Volume 6. Sterile Products  Handbook of Pharmaceutical Excipients. A.H. Kibbe, ed. 3 rd edition. American Pharmaceutical Association, Washington, 2000 (Pharmaceutical Press, London)

13 13 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (7) API information 16.Nomenclature  INN, USAN, Systematic name, CAS, etc. from e.g. Merck Index for each API (standard) 17.General physical properties  Discuss/tabulate properties of each API in terms of the guidance for dossier requirements, with special attention to unique API properties, e.g.  Rifampicin (pseudo) polymorphism and dissolution  Hygroscopicity of ethambutol 2HCl  Comparison of solubilities (analytically important)

14 14 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (8) 18.Compedial monograph(s)  BP/Ph.Eur., Int.Ph. and USP for all 4 APIs 19.Stability & degradation routes  Compile expert report for each of the 4 APIs  Stress data and mild conditions from literature in: - solution and solid state  API/API and API/excipient interactions  Storage conditions and optimal analytical stability  Conclusions and precautions with respect to intended product

15 15 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (9) 20.Possible BCS classification  Biowaivers (in vitro dissolution instead of bioequivalence studies) for immediate release solid orals (tablets, capsules) are not in current prequalification guidelines. Biowaivers used for demonstration of equivalence of lower vs higher strength in proportional similar formulations.  FDA and EMEA guidelines exist for classification “rules”, dissolution requirements and similarity of profiles

16 16 TG Dekker – WHO, Malaysia Feb 2005 Typical product profile report (10) Recommendations  File hard copies of all sources in support of the Product Profile Report  The data in the Product Profile Report can be used inter alia:  To form the basis of development pharmaceutics & to identify further experimental investigations  To alert the development team of possible problems  To identify monograph & analytical shortcomings

17 17 TG Dekker – WHO, Malaysia Feb FDC tablets – a problem mix (1) Composition in current Essential Drug List  Rifampicin150 mg  Isoniazid75 mg  Pyrazinamide400 mg  Ethambutol 2HCl275 mg  Total API weight900 mg  Typical tablet weight~ 1.3 g

18 18 TG Dekker – WHO, Malaysia Feb FDC tablets – a problem mix (2) Rifampicin  Oxidation (quinone & N-oxide)  Protect from air exposure  Hydrolysis (3-formylrifamycin & 25-desacetyl)  Wet granulation / drying a potential problem?  Reaction with Isoniazid  3-(isonicotinylhydrazinomethyl)rifamycin or more commonly known as isonicotinyl hydrazone  isonicotinyl hydrazone major decomposition product  Light sensitive  Product to be protected from light exposure

19 19 TG Dekker – WHO, Malaysia Feb FDC tablets – a problem mix (3) hydrolysis Rifampicin oxidation hydrolysis

20 20 TG Dekker – WHO, Malaysia Feb FDC tablets – a problem mix (4) Isoniazid  Reacts with aldehydes/reducing sugars  Sugar & lactose to be avoided in formulation !!  3-Formylrifamycin (from rifampicin) Ethambutol hydrochloride (2HCl)  Hygroscopic  Absorbs water for reaction in tablets  Creates slightly acidic conditions  pH of 2% w/v solution: (BP)  The acidic conditions enhance rifampicin/isoniazid reaction (isonicotinyl hydrazone formation)

21 21 TG Dekker – WHO, Malaysia Feb FDC tablets – a problem mix (5) Isonicotinyl hydrazone (3-(isonicotinylhydrazinomethyl)rifamycin)  This is major decomposition product in tablets containing rifampicin and isoniazid  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, (2000)  The reactions shown on next slide are from the above publication

22 22 TG Dekker – WHO, Malaysia Feb FDC tablets – hydrazone formation

23 23 TG Dekker – WHO, Malaysia Feb FDC-TB tablets exposed to 40°C/75%RH for one week Two products. “Bleeding” may start after more exposure (in-house)Control on left

24 24 TG Dekker – WHO, Malaysia Feb FDC-TB tablets preventative/protective measures  Formulation - no sugar/lactose (isoniazid)  Separate granulation of rifampicin & isoniazid  Rifampicin as powder (not granulate)?  Prevent oxidation & hydrolysis  Low water content of tablet (USP ≤ 3.0%)  Protect product from moisture and oxygen  Non-permeable packaging  Do not remove from primary packaging  Avoid repackaging  Light protection  Differential formulation, e.g. delayed release & immediate release in one tablet ??

25 25 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin solid state properties  Rifampicin exist is 3 solid state forms:  Polymorph I  Polymorph II  Amorphous form  Commercial material contains:  Polymorph II (predominantly)  Mixture of polymorph II and amorphous form  Five commercial samples (A to E) in examples: Sample A: Form II Sample B: Form II Sample C: Form II + amorph Sample D: Form II + amorph Sample E: Form II

26 26 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin - SEM photos Sample ASample D Form IIForm II + amorph

27 27 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin -XRPDs Top: Sample A (Form II – sharp signals) Middle: Sample C (Form II + amorph – intensity drop) Bottom:Amorphous form (no pattern)

28 28 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin – powder dissolution (1) Medium: 0.1 M hydrochloric acid  Profiles of all samples are similar  Dissolves immediately in 0.1 M hydrochloric acid

29 29 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin – powder dissolution (2) Medium: Phosphate buffer pH 7.4  Profiles A, B & E are similar (f2 ≥ 50)  Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete  Profiles A, B, E dissimilar from profiles C,D (f2 < 50) A, B, E (form II) C, D Form II + Amorph

30 30 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin – powder dissolution (3) Medium: Water  Profiles A, B & E are similar (f2 ≥ 50)  Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete  Profiles A, B, E dissimilar from profiles C,D (f2 < 50) A, B, E (form II) C, D (form II + amorph)

31 31 TG Dekker – WHO, Malaysia Feb 2005 Rifampicin - solid state conclusions 1.Solid state forms identifiable by means of XRPD 2.Dissolution rate is not different in 0.1 M HCl 3.Presence of amorphous form slows down dissolution at higher pH (f 2 test)  Incomplete dissolution after 65 minutes !!  May fail USP tolerance at pH 6.8 (75% in 45 min.) ??  Agglomeration / wettability? 4.Comparative powder dissolution powerful tool for supplier selection Reference:  S. Q. Henwood, M. M. de Villiers, W. Liebenberg, A.P. Lötter. Solubility and dissolution properties of generic rifampicin raw materials. Drug Dev. & Ind. Pharm. 26, (2000) (Research Institute for Industrial Pharm.)

32 32 TG Dekker – WHO, Malaysia Feb 2005 Polymorphism – important situations  When it has a significant effect on the rate of dissolution of the API in water and biological fluid, that may affect the absorption of the API  Of special importance for practically insoluble APIs  When it can affect the manufacturing process, e.g. in the case of flow properties  Where the properties differs to such extent that different forms can be used in different dosage forms (nevirapine: anhydrate in tablets and the hemihydrate in suspensions)

33 33 TG Dekker – WHO, Malaysia Feb 2005 BCS classification (1)  High solubility: Highest dose strength of API should be soluble in ≤ 250 ml water at 37ºC over the pH range  High permeability: Absolute bioavailability ≥ 90 % (presently) - apart from specific permeability studies  Limiting factors for biowaivers (see FDA & EMEA) ClassSolubilityPermeability 1High 2LowHigh 3 Low 4

34 34 TG Dekker – WHO, Malaysia Feb 2005 BCS classification (2) Data from:  M Lindenberg, S. Kopp, J. B. Dressman. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm., 58, (2004)  None of other TBs (mainly for injection, thus not classified) in 5 th inv. for EOI in publication – a number of ARVs are API (INN)Class Rifampicin2 (tentative) Isoniazid1 (tentative) Pyrazinamide1 Ethambutol 2HCl3 (tentative)

35 35 TG Dekker – WHO, Malaysia Feb 2005 Biowaiver dissolution studies (1) Conditions 1.Three media ml or less - all at 37°C  1. Buffer pH 1.2, SGF without enzymes or 0.1M HCl  2. Buffer pH 4.5  3: 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

36 36 TG Dekker – WHO, Malaysia Feb 2005 Biowaiver dissolution studies (2) Evaluation of dissolution data 1.The profiles of the test and reference products must be similar in all three media for considering a biowaiver (for not doing BE) 2.The profiles of the two products in a particular medium is considered similar:  If the similarity factor f 2 ≥ 50 (see FDA/EMEA for calc) Not all values can be considered for calculation of f 2 (see EMEA guideline) – only one point beyond 85% dissolution, for both APIs (point zero also excluded)  If both products show ≥ 85% dissolution in 15 minutes

37 37 TG Dekker – WHO, Malaysia Feb 2005 Biowaiver type dissolution application 1.Important during development studies  Formulation selection. Comparison of different lab / development batches with innovator product.  Important for comparison of pivotal batches to demonstrate in vitro similarity  Aids in selecting FPP dissolution conditions/specification 2.Bioequivalence support  Ideal pre-bioequivalence control - profile similarity with comparator product good indication of BE  Biowaiver studies not in current prequalification guidelines. 3.Post-approval changes

38 38 TG Dekker – WHO, Malaysia Feb 2005 Comparative dissolution example Example  Ethambutol hydrochloride/Isoniazid 400/150 mg Tablets  Four manufacturers (A, B, C & D)  Dissolution conditions:  Paddle, 50 rpm  Phosphate buffer pH 6.8, 500 ml, undegassed, 37ºC  Pull times: 10, 15, 20, 30, 45 & 60 minutes  Source: T.G. Dekker, E.Swanepoel, A-M Redelinghuys & E.C. van Tonder - unpublished

39 39 TG Dekker – WHO, Malaysia Feb 2005 Ethambutol 2HCl & Isoniazid Tabs (1)

40 40 TG Dekker – WHO, Malaysia Feb 2005 Ethambutol 2HCl & Isoniazid Tabs (2)

41 41 TG Dekker – WHO, Malaysia Feb 2005 Ethambutol 2HCl & Isoniazid Tabs (3) A B,C D

42 42 TG Dekker – WHO, Malaysia Feb 2005 Ethambutol 2HCl & Isoniazid Tabs (4) Evaluation of dissolution data  The dissolution profiles of the APIs in a particular product are similar (this holds for all 4 products)  Both APIs are highly soluble (BCS definition)  The products show different dissolution rates  Dissolution rateA >B ≈C >> D  Disintegration (min)  Dissolution rate related to disintegration time  f 2 values show that B & C have similar profiles  Dissolution method discriminating  Typical type of results during pharmaceutical R&D

43 43 TG Dekker – WHO, Malaysia Feb 2005 Some conclusions 1.Get to know you product through systematic desk research, e.g. Product Profile Report 2.Physical properties of APIs may be important for low soluble APIs, e.g. polymorphism & particle size  Powder dissolution testing may be useful for sourcing 3.Consider important API properties and API-API interactions, especially in FDCs in formulation  Packaging to be non-permeable and light protective 4.Biowaiver type dissolutions are important in:  Choice of formulation vs comparator  Comparison of pivotal batches  Setting product dissolution specifications  Pre-BE control  Post-approval changes


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