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Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Waivers of in-vivo.

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Presentation on theme: "Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Waivers of in-vivo."— Presentation transcript:

1 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Waivers of in-vivo BE studies Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO

2 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 2 Waivers of in-vivo BE studies ♦ ‚ If a product concerns several strengths…‘ (see e.g. 5.4 EU guidance) ♦ bioequivalence proven for one strength ♦ same manufacturer and manufacturing process ♦ linear drug input (if this is not the case…..) ♦ same qualitative composition of different strengths (WHO) ♦ same ratio between active substance and excipients, or same excipients in case of low concentration (less than 5 % API) ♦ similar in vitro dissolution (WHO)  see also guidance for MR products, 5.1 of EU guidance CPMP/EWP/280/96…

3 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 3 Waivers of in-vivo BE studies  … the ‚sensitive‘ strength in case of non-linearity ♦ increase more than proportional: bioequivalence testing with the highest strength ♦ increase less than proportional : bioequivalence testing with the highest strength cave: solubility limitations… no data available…

4 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 4 Waivers of in-vivo BE studies  … what to do in case of… ♦ solubility limitations: bioequivalence testing with the highest strength (or dose) even with linear kinetics ♦ no or inconclusive data on linearity available: bioequivalence testing with the lowest and highest strength

5 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 5 Waivers of in-vivo BE studies  … MR products acc. to 5.1 of EU guidance (e.g. CPMP/EWP/280/96) …however, there is a possibility for ♦ single-unit forms: single dose study in the fasted state for every strength, multiple dose study may be waived for lower strengths ♦ multiple-unit forms: single and multiple dose studies may be waived for lower strengths in case of identical beeds or pellets cave: in vitro dissolution studies……..

6 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 6 Basis for BCS-based Biowaiver Applications/Decisions  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)  WHO – working document on multisource (generic) pharmaceutical products (QAS/04.093)  WHO – working document on a proposal to waive in vivo bioequivalence (QAS/04.109)  EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

7 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 7 Definitions 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

8 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 8 Definitions  Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)  Bioequivalence – equivalent bioavailability within pre-set acceptance ranges  Pharmaceutical equivalence  Bioequivalence  Bioequivalence  Therapeutic equivalence

9 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 9 Definitions 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)

10 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 10 BCS-based biowaiver In vivo bioequivalence testing is generally required but ” Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.”  for oral immediate release dosage forms with systemic action!

11 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 11 BCS-based biowaiver Evaluation of drug substance and drug product Drug substance  pharmacodynamic/therapeutic aspects  physicochemical aspects Drug product  in vitro dissolution

12 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 12 BCS-based biowaiver RISK assessment (see e.g. WHO QAS/04/093/rev4) 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”

13 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 13 BCS-based biowaiver Biowaiver justification based on ”……… criteria derived from the concepts underlying the Biopharmaceutics Classification System......”

14 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 14 BCS-based biowaiver Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport  drug substance in the system simplified mechanistic view of bioavailability

15 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 15 BCS-based biowaiver

16 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 16 Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3] Melting point Charge Ionisa- tion H-bonding Lipophilicity SizeShape Charge Distribution Amphiphilicity Solubility

17 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 17 BCS-based biowaiver Solubility PermeabilityDissolution Pillars of the BCS

18 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 18 BCS-based biowaiver High solubility  the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH (37 °C)  create a pH-solubility profile cave: possible stability problems have to be considered Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility Definition of low solubility?

19 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 19 BCS-based biowaiver High permeability ♦EU guidance: ”Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability” ♦FDA guidance: absolute BA >90 % ♦WHO guidance: at least 85 % absorption in humans Human data are preferred; in vitro data may be submitted if sufficiently justified and valid Definition of low permeability?

20 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 20 BCS-based biowaiver

21 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 21 BCS-based biowaiver ♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement. [Faassen et al. Clin Pharmacokinet 43 (2004)1117]  what does the product do to the drug substance?

22 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 22 BCS-based biowaiver u When are in vitro results sufficient for bioequivalence evaluation? u When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)? u Minimizing risk by means of ‘worst case’ investigation? u Which in vitro investigations may be sufficient?

23 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 23 BCS-based biowaiver in vitro dissolution objectives  quality control  justification of minor variations  iviv-correlation (e.g. major variations; bridging)  additional to BE studies  proportionality based biowaiver  BCS based biowaiver  ….

24 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 24 BCS-based biowaiver in vitro dissolution prerequisites  reasonable, stability-indicating, validated methods  discriminative methods  reproducible methods  biorelevant methods (?)  ……one fits all?!

25 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 25 BCS-based biowaiver in vitro dissolution and BCS concept  meet prerequisites  ensure risk minimization  justify absence of difference  biorelevant?!

26 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 26 BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) first option: very rapidely 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 Freasonable, validated experimental conditions/methods are strongly recommended!

27 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 27 BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) second option: rapidely 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) Freasonable, validated experimental conditions/methods are strongly recommended!

28 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 28 BCS-based biowaiver Experimental conditions: t EU guidance – no specific information yet t US-FDA guidance – ‚USP‘-conditions  50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C  WHO –  75 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C  no surfactants!

29 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 29 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 QAS/ sect. 9.2 or app. 2 of the EU guidance; note prerequisites)

30 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 30 BCS-based biowaiver f2-test t acceptance value based on 10 % difference between profiles t „identical“ profiles: f2 =100 „similar“ profiles: f2 between 50 and 100 (?!) Fany other reasonable/justified test possible!

31 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 31 BCS-based biowaiver  Requirement: either very rapid or “similar” in vitro dissolution  how similar is ‘similar’?  discussion of differences usually not appropriate

32 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 32 BCS-based biowaiver BCS based biowaiver in vitro dissolution t no iviv correlation t no biorelevant conditions (except pH) Fconcept to justify absence of difference!

33 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 33 BCS-based biowaiver  Evaluation of excipients (e.g., large amounts, possible interactions....; e.g. Isoniazid J Pharm Sci 96 March 07 : “…permeability changes due to excipient interaction cannot be detected in vitro…”)  Evaluation of manufacturing processes in relation with critical physicochemical properties

34 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 34 BCS-based biowaiver BCS-based Biowaiver for immediate release drug products containing highly soluble, highly permeable drug substances. No BCS-based biowaiver for: u locally applied, systemically acting products u non-oral immediate release forms with systemic action umodified release products u transdermal products

35 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 35 BCS-based biowaiver Provided that u drug solubility is high, u permeability is limited, u excipients do not affect kinetics, u excipients do not interact,.....

36 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 36 BCS-based biowaiver....then very rapid dissolution (e.g.>85% in 15 min) of test and reference may ensure similar product characteristics because absorption process is probably independent from dissolution and almost not product related…  limited absorption kinetics due to poor drug permeability and/or gastric emptying  Biowaiver for BCS class III drugs

37 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 37 BCS-based biowaiver For drugs showing.... u ‘very’ high permeability u pH-dependent solubility within the physiologically relevant pH range.....an ‘intermediate solubility’ class is suggested [Polli et al. J Pharm Sci 93 (2004) 1375]

38 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 38 BCS-based biowaiver pH-dependent soluble, highly permeable, weak acidic, ionizable drug compounds may be handled like BCS class I drugs (e.g. chpt 8 in: Drug Bioavailability, van de Waterbeemd, Lennernäs, Artursson (edts) 2003 Wiley-VCH)  in vitro dissolution requirements acc. to WHO doc  at least 85% within 30 min at pH 6.8 and f2 testing for pH 1.2 and 4.5 profiles  but no biowaiver for weak basic drugs

39 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 39 BCS-based biowaiver u meaningful literature data may be used for drug substance characteristics (and excipients) u product related data must always be actually generated for the particular product

40 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 40 BCS-based biowaiver u BCS-based biowaiver are not just in-vitro dissolution, but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications

41 Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 41 BCS-based biowaiver THANK YOU FOR YOUR ATTENTION!


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