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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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… The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 : cave: solubility limitations… no data available… The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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…….. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

BCS-based biowaiver RISK assessment “critical use medicines” (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” The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

simplified mechanistic view of bioavailability 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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

BCS-based biowaiver The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

BCS-based biowaiver Pillars of the BCS Solubility Permeability Dissolution The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

BCS-based biowaiver 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) 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? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

BCS-based biowaiver The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

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 …. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

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

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 reasonable, validated experimental conditions/methods are strongly recommended! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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) reasonable, validated experimental conditions/methods are strongly recommended! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

Experimental conditions: BCS-based biowaiver Experimental conditions: EU guidance – no specific information yet 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! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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/04.093 sect. 9.2 or app. 2 of the EU guidance; note prerequisites) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

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

BCS-based biowaiver BCS based biowaiver in vitro dissolution no iviv correlation no biorelevant conditions (except pH) concept to justify absence of difference! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

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

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

BCS-based biowaiver 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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

THANK YOU FOR YOUR ATTENTION! BCS-based biowaiver THANK YOU FOR YOUR ATTENTION! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health