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Drs. Jan Welink

Biowaivers . Drs. Jan Welink. WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010. Guidance. WHO – Technical Report Series No. 937, May 2006

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Drs. Jan Welink

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  1. Biowaivers Drs. Jan Welink WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

  2. Guidance • WHO – Technical Report Series No. 937, May 2006 Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms • FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000) • EU-guidance: “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

  3. Bioequivalence Different approach for establishing equivalence Standard: in vivo BE studies in vitro methods clinical studies PD studies

  4. Bioequivalence Cases, where the regulatory authorities have to decide whether a bioequivalence study is mandatory or not: • inside a product: • - scale up processes • - line extensions • - variation after marketing authorisation • between different products: • - application of generics without clinical data

  5. BCS low permeability high permeability high solubility HS/HP Class I HS/LP Class III low solubility LS/LP Class IV LS/HP Class II Biowaivers based on BCS

  6. BCS 2 variables: Solubility Permeability

  7. BCS BCS VIEW of BIOEQUIVALENCE • if two products, containing the same drug, have the same • concentration-time profile at the intestinal membrane surface • then they will have the same rate and extent of absorption • same in vivo dissolution profile under all luminal conditions • - formulation components do not effect the membrane • permeability and/or intestinal transit • (Amidon et al.1995)

  8. BCS Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport drug substance in the system simplified mechanistic view of bioavailability

  9. BCS Fluid volume pH hydrodynamics surface tension other…. TIME (hours) Dissolution, solubility, and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract Stomach Small Intestine (major site for absorption)

  10. BCS Dissolution (Product) Very rapid/rapid dissolution - ensure that in vivo dissolution is not likely to be the “rate determining” step Solubility (Drug) High solubility- ensure that solubility is not likely to limit dissolution and, therefore, absorption Permeability (Drug) High permeability - ensure that drug is completely absorbed during the limited transit time through the small intestine BCS Class Boundaries: Objectives

  11. BCS Very rapid dissolution: • An IR drug product is considered VERY RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 15 minutes Rapid dissolution: • An IR drug product is considered RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 30 minutes

  12. BCS High solubility: • The highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 – 6.8 (37°C) 250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approximately 250 ml) water

  13. BCS pH in the gastro-intestinal tract

  14. BCS Highly permeable: • A drug substance is considered HIGHLY PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose, based on a mass balance determination or in comparison to an intravenous reference dose, in the absence of evidence suggesting instability in the gastrointestinal tract. Intestinal membrane permeability may be determined by in vitro or in vivo methods that can predict extent of drug absorption in humans.

  15. BCS Highly permeable: • EU guidance: linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailavility (absorption >85%). • FDA guidance: absolute bioavailability >90%.

  16. BCS 3 variables: Rapid (and similar) Dissolution High Solubility High Permeability

  17. BCS 4 variables: Rapid (and similar) Dissolution High Solubility Candidates for Biowaivers Therapeutic Window High Permeability

  18. Biowaivers BCS-based ‘Biowaiver’..... .....is defined as • in vitro instead of in vivo ‘bioequivalence’ testing • comparison of test and reference ....is not defined as no equivalence test

  19. Biowaivers acc. to the FDA guidance: ”BCS-based biowaivers are intended only for bioequivalence studies. They do not apply to food effect bioavailability studies or other pharmacokinetic studies.” (e.g., rel. bioavailability)

  20. BCS-based biowaiver Evaluation of drug substance and drug product Drug substance • pharmacodynamic / therapeutic aspects • physicochemical aspects Drug product • in vitro dissolution

  21. BCS-based biowaiver RISK assessment (see e.g. WHO guidance; sect. 9.2 and 5.1.(a)) • “critical use medicines” • “narrow therapeutic index drugs” • “documented evidence for BA or BE problems • “scientific evidence that API polymorphs, excipients or the manufacturing process affects BE”

  22. BCS-based biowaiver • meaningful literature data may be used for drug substance characteristics(and excipients) • product related data must always be actually generated for the particular product

  23. BCS-based biowaiver Class I drugs are candidates for a biowaiver: but what to be adressed? High solubility • the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C) • generate a pH-solubility profile • possible stability problems have to be considered • discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility

  24. BCS-based biowaiver High permeability • WHO guidance: at least 85 % absorption in humans • Pharmacokinetic studies in humans: • - Mass balance or absolute bioavailability • Intestinal Perfusion Methods • - Humans (In Vivo) • - Animals (In Vivo or In Situ) • In Vitro Methods Using Appropriate Membranes • - Excised intestinal tissue • - Monolayer of functional cultured human intestinal cells

  25. BCS-based biowaiver Dissolution in vitro dissolution prerequisites • reasonable, stability-indicating, validated methods • discriminative methods • reproducible methods • biorelevant methods ?

  26. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R): first option: very rapidly dissolving products • Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required • reasonable, validated experimental conditions/methods are strongly recommended!

  27. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R): Second option: rapidly dissolving products • Not less than 85 % of labeled amount are dissolved within 30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) • reasonable, validated experimental conditions/methods are strongly recommended!

  28. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R): • Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious. (see e.g. WHO guidance sect. 9.2 or app. 2 of the EU guidance; note prerequisites) • f2 = 50 x log {[ 1 + (1/n) t=1n (Rt – Tt)2]-0.5 x 100 inversely proportional to the average squared difference between the R and T profile and measures the closeness between the two profiles (similarity factor)

  29. BCS-based biowaiver f2-test: Acceptance value based on 10 % difference between profiles • „identical“ profiles: f2 =100 • „similar“ profiles: f2 between 50 and 100

  30. BCS-based biowaiver Additional issues to be addressed Pharmacokinetics Excipients Linear.. BA problems.. Well know/established.. Acceptable quantities.. No interaction PK active substance.. (surfactants, absorption enhancers, GIT transit time)..

  31. BCS-based biowaiver need for BE study risk for differences And the other classes? LS/LP LS/HP HS/LP HS/HP

  32. BCS-based biowaiver solubility (mg/ml) Verapamil HCl aqueous solubility at 25°C 100 80 60 40 20 0 pH 1 2 3 4 5 6 7 8 9 Class II (LS/HP): - critical parameter solubility - due to pH, may be acceptable

  33. BCS-based biowaiver 100 ibuprofen O O O O pH O pH 8 X X dissolution (%) X X X 6 50 4 X X X X X X X O 2 O O O O O O 30 60 time (min) Example of a dissolution profile of an ibuprofen (Class II) tablet formulation at different pH levels:

  34. BCS-based biowaiver Class III (HS/LP): critical parameter permeability; but to which extent? • less dependent on formulation • often exhibit site-dependent absorption • (transit time may be critical: • dissolution criteria!!)

  35. Experience BCS-based biowaiver Biowaivers accepted by FDA • Cefadroxil • Galantamine HBr • Labetalol • Levetiracetam • Levofloxin • Memantine HCl • Metoprolol • Ofloxacin • Pramipexole dihydrochloride • Pregabalin • Propanolol • Ramelteon • Rivastigmine HCl • Sotalol HCl • Tiagabine HCl • Timolol • Venafaxine HCl Presentation LX Yu, January 2006, SODD workshop, Lake Tahoe

  36. Experience BCS-based biowaiver Biowaivers accepted by Sweden • Phenoxymethylpenicillin • Prednisolone • Transexamic acid • Acetaminophen and codeine • IbuprofenPresentation of C. Graffner, “Practical Applications of MPA”, Lisboa, April, 2003.

  37. Experience BCS-based biowaiver Biowaivers accepted by The Netherlands • Amoxicillin • Dextromethorfan • Doxycycline • Phenoxymethylpenicillin • Flunarizine • Indomethacin • Isosorbide-5-mononitrate • Lorazepam • Salbutamol www.cbg-meb.nl • Lormetazepam • Metoprolol • Naproxen • Nitrazepam • Oxprenolol • Acetaminophen • Pindolol • Piroxicam • Temazepam www.cbg-meb.nl

  38. Current situation WHO biowaivers • Based upon this information (Programme experience and applied biowaivers by other NRAs) decision made to select drug substances. • The following drug substances have been identified as eligible for a BCS-based biowaiver application as either monocomponent or fixed-dose combination (FDC) products • Monocomponent or FDC products containing other drug substances must be supported with in vivo BE data

  39. Current situation WHO biowaivers • Medicines for HIV/AIDS and related diseases • Lamivudine (Class I) • Stavudine (Class I) • Zidovudine (Class I) • Anti-tuberculosis medicines • Ethambutol (Class III/I) • Isoniazid (Class III/I) • Levofloxacin (Class I) • Ofloxacin (Class I) • Pyrazinamide (Class III/I)

  40. Current situation WHO biowaivers • The identified comparators: HIV/AIDS: • Lamivudine: Epivir 150 and 300 mg tablet • Stavudine: Zerit 30 mg capsule • Zidovudine: Retrovir 300 mg tablet, 100 and 250 mg capsule •  combination: lamivudine/zidovudine: Combivir (150/300 mg) Anti-tuberculosis medicines • Ethambutol: Myambutol 400 mg tablet • Isoniazid: Isozid (100 mg tablet)/Isoniazid 100 and 300 mg (US RLD) • Levofloxacin: Tavanic and Levaquin (US RLD) • Ofloxacin: Tarivid and Ofloxacin (US RLD) • Pyrazinamide: Pyrazinamide Lederle

  41. Class I Drug Substances • Selection of comparator product • Biobatch reflective of proposed commercial product • Comparison of products • Should employ well known excipients in usual amounts • Beneficial to contain similar amounts of the same excipients • Critical excipients (e.g., mannitol, sorbitol, surfactants), if present, should not differ qualitatively or quantitatively

  42. Class I Drug Substances • Comparative in vitro dissolution • Comparative testing should ensure the similarity of the test and comparator product in three different pH media considered relevant for absorption from the GI tract • Comparative in vitro dissolution testing should be conducted in at least three media of pH 1.2, 4.5, and 6.8 • 12 units • Paddle apparatus at 75 rpm or basket apparatus at 100 rpm • Use of surfactants strongly discouraged

  43. Class I Drug Substances • ‘Very rapidly’ dissolving products • At least 85% of the labelled amount is released within 15 minutes or less from the test and comparator product • In this case, profile comparison is not needed • ‘Rapidly’ dissolving products • At least 85% of the labelled amount is released within 30 minutes or less from the test and comparator product • Profile comparison (e.g., f2 testing) required

  44. Class III/I Drug Substances • Drug substances are highly soluble but limitations to absorption due to various reasons • Comparison of products (test vs. comparator) • Qualitatively the same excipients • Quantitatively very similar (as per Level 1 change according to SUPAC) • Comparative in vitro dissolution • At least 85% dissolved within 15 minutes for both products • At least 85% dissolved within 30 minutes is acceptable if dissolutionprofiles are similar and product compositions are very similar

  45. Guidance: • Biowaiver application form, identifying clearly what should be submitted. • Detailed information on Test product (generic) • Detailed Information on comparator/reference product (identification). • Comparability between Test and comparator • In vitro dissolution data • Quality assurance

  46. Report Format report dissolution test: 1. Purpose of study 2. Products / batch information • Batch numbers, manufacturing and expiry dates, batch size of the test product, Certificates of Analysis (CoAs) and packaging of the batches used in the study • Batch manufacturing record(s) for the batch of the test product used in the comparative dissolution study. 3. Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study. It should be indicated how and when the samples were filtered. Any problems with pH related stability of samples should be indicated and discussed in terms of preventive handling measures, analysis and interpretation of data. 4. Analytical method including validation, or reference to the quality part of the dossier. 5. Results (% API dissolved) • Tabulated (individual results, mean and %CV) • Graphically • Similarity determination / f2 calculation if necessary and applicable 6. Conclusion/recommendation.

  47. Problems identified: • Wrong comparator • Failing comparability regarding excipients • Failing excluding/including critical excipients • Failing dissolution tests

  48. Example: 1.

  49. Example: 2.

  50. Good news: • Successful BCS-based biowaiver applications have been submitted for HIV/AIDS and anti-tuberculosis products • Successful BCS-based biowaiver applications for FDCs have been submitted • BCS-based biowaiver approach for certain drug substances introduced in 2009 • Approaches employed by regulatory authorities considered carefully • Drug substances on Expressions of Interest being reviewed • Potential additions to list of eligible drug substances

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