Bundesinstitut für Arzneimittel und Medizinprodukte. Dissolution Testing. Analytik,Methodenentwicklung, Bioäquivalenz SAQ. Olten, 25.

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1 Dissolution Testing Analytik,Methodenentwicklung, Bioäquivalenz SAQ Olten, 25. Januar 2006 Dr. H. Potthast 1

2 2 Basis for Biowaiver Applications/Decisions Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98; paragraph 5.1 also considered: 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) Current scientific discussion on biowaiver extensions

3 3 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 ( biological quality control ) Pharmaceutical equivalence Bioequivalence Bioequivalence Therapeutic equivalence

4 4 Definitions Biowaiver......is defined as in vitro instead of in vivo bioequivalence testing comparison of test and reference...is not defined as no bioequivalence test

5 5 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)

6 6 EU Note for Guidance... In vivo bioequivalence testing is generally required but acc. to paragr. 4.2 and 5.1: 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!

7 7 EU Note for Guidance... Biowaiver justification paragr : This section...takes into consideration criteria derived from the concepts underlying the Biopharmaceutics Classification System...

8 8 EU Note for Guidance... Evaluation of drug substance drug product and Drug substance pharmacodynamic/therapeutic aspects physicochemical aspects Drug product in vitro dissolution

9 9 EU Note for Guidance... EU NfG paragr a)i Risk of therapeutic failure or adverse drug reactions (e.g., narrow therapeutic index drugs) examples: Theophylline, Carbamazepine, Lithium b)ii Risk of bioinequivalence (i.e., bioavailability problems are evident) examples: Ciclosporine, Glibenclamide

10 10 BCS Concept Biopharmaceutics Classification System (BCS) dissolution drug product drug substance in solution membrane transport drug substance in the system - simplified mechanistic view of bioavailability -

11 11 BCS Assumption Pillars of the BCS Solubility Permeability Dissolution

12 12 Drug Substance Characteristics Solubility Permeability BCS classification high high I (e.g. Propranolol) low high II (e.g. Glibenclamide) high low III (e.g. Atenolol) low low IV(e.g. Acetazolamide)

13 13 BCS Assumption?.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? rate aspects?

14 14 Dissolution in vitro dissolution objectives quality control justification of minor variations iviv-correlation (e.g. major variations; bridging) additiv to BE studies proportionality based biowaiver BCS based biowaiver.

15 15 Dissolution in vitro dissolution prerequisites reasonable, validated methods discriminative methods reproducible methods biorelevant methods (?) one fits all?!

16 16 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?

17 17 Dissolution and Biowaiver in vitro dissolution and BCS concept prerequisites risk minimization justification of absence of difference biorelevant?!

18 18 Dissolution and Biowaiver In vitro comparison of immediate release oral drug products (T and R) Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (ph 1 8) no further comparison of T and R is required Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious (see app. 2 of the EU guidance; note prerequisites) reasonable, validated experimental conditions/methods are strongly recommended!

19 19 Dissolution and Biowaiver Experimental conditions: EU guidance no specific information US-FDA guidance USP -conditions 50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 C no surfactants! recommendations?!

20 20 Dissolution and Biowaiver Experimental conditions: agitation: 75 rpm?! volume: less than 900/500 ml?! rapid dissolution: 15 or 30 min?! very rapid: 15 min or less?! rapid: 30 min or less?! recommendations?!

21 21 Dissolution and Biowaiver Requirement: either very rapid or similar in vitro dissolution how similar is similar? discussion of differences usually not appropriate

22 22 Dissolution and Biowaiver f2-test (see app. 2 of the EU guidance) at least 3 sampling points (excl. zero) n=12 not more than one mean result > 85% mean SD < 10 % must be carefully used!

23 23 Dissolution and Biowaiver f2-test (see app. 2 of the EU guidance) 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!

24 24 Dissolution and Biowaiver BCS based biowaiver in vitro dissolution no iviv correlation no biorelevant conditions (except ph) concept to justify absence of difference?!

25 25 Dissolution and Biowaiver Evaluation of excipients (e.g., large amounts, possible interactions...) Evaluation of manufacturing processes in relation with critical physicochemical properties

26 26 EU (FDA) Guidance Biowaiver for immediate release drug products containing highly soluble, highly permeable drug substances only. No BCS-based biowaiver for: locally applied, systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products

27 27 Biowaiver Extensions?! Provided that... drug solubility is high, permeability is limited, excipients do not affect kinetics, excipients do not interact,...

28 28 Biowaiver Extensions?!...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 not product related limited absorption kinetics due to poor drug permeability and/or gastric emptying Biowaiver for BCS class III drugs?!

29 29 Biowaiver Extensions?! 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]

30 30 Biowaiver Extensions?! ph-dependant soluble, highly permeable, weak acidic, ionizable drug compounds may be handled like BCS class I drugs (quotation) current discussions on in vitro dissolution requirements?! at least 85% within 30 min at ph 6.8 and f2 testing for ph 1.2 and 4.5 profiles probably no biowaiver for weak basic drugs (personal communication)

31 31 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

32 32 BCS Based Biowaiver THANK YOU FOR YOUR ATTENTION!