Assessment of Interchangeable Multisource Medicines

BCS-Biowaivers

Dr. Henrike Potthast (h.potthast@bfarm.de)

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Basis for BCS-based Biowaiver Applications/Decisions
♦ 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 andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1
2 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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

3 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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)

4 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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

5 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

August 2009 .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! 6 | Assessment of Interchangeable Multisource Medicines. Kenya.

August 2009 and .BCS-based biowaiver Evaluation of drug substance drug product Drug substance ♦ pharmacodynamic/therapeutic aspects ♦ physicochemical aspects Drug product ♦ in vitro dissolution 7 | Assessment of Interchangeable Multisource Medicines. Kenya.

Kenya. WHO guidance. August 2009 .1.(a)) ♦ “critical use medicines” ♦ “narrow therapeutic index drugs” ♦ “documented evidence for BA or BE problems ♦ “scientific evidence that API polymorphs.g. sect. 9.2 and 5. excipients or the manufacturing process affects BE” 8 | Assessment of Interchangeable Multisource Medicines.BCS-based biowaiver RISK assessment (see e.

. Kenya.” 9 | Assessment of Interchangeable Multisource Medicines. August 2009 ..BCS-based biowaiver Biowaiver justification based on ”………criteria derived from the concepts underlying the Biopharmaceutics Classification System ....

August 2009 .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 10 | Assessment of Interchangeable Multisource Medicines. Kenya.

van de Waterbeemd/ Eur J Pharm Sci 7 (1998).1: Physicochemical properties that affect absorption (after oral administration) [H. August 2009 .Melting point Charge Ionisation Solubility Size H-bonding Lipophilicity Charge Distribution Shape Amphiphilicity Fig. 1-3] 11 | Assessment of Interchangeable Multisource Medicines. Kenya.

BCS-based biowaiver Pillars of the BCS Solubility Permeability Dissolution 12 | Assessment of Interchangeable Multisource Medicines. August 2009 . Kenya.

. i.8 (37 °C) ♦ generate a pH-solubility profile cave: possible stability problems have to be considered  Discussion on ‘intermediate solubility’. pH-dependent (high) solubility  Definition of low solubility? 13 | Assessment of Interchangeable Multisource Medicines.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. Kenya. August 2009 .e.

August 2009 . Kenya. in vitro data may be submitted if sufficiently justified and valid  Definition of low permeability? 14 | Assessment of Interchangeable Multisource Medicines.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.

g.BCS-based biowaiver Solubility high low high low Permeability high high low low BCS classification I (e.g. Glibenclamide) III (e. Propranolol) II (e.g. Azathioprine) 15 | Assessment of Interchangeable Multisource Medicines. Kenya.g. August 2009 . Atenolol) IV (e.

Kenya. the human body should always do the same with the absorbed compound …Even in a disease state. August 2009 . this argument is still a valid statement.BCS-based biowaiver ♦ „…. Clin Pharmacokinet 43 (2004)1117] � what does the product do to the drug substance? 16 | Assessment of Interchangeable Multisource Medicines.“ [Faassen et al.if the fraction of the dose absorbed is the same.

August 2009 . Kenya.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 | Assessment of Interchangeable Multisource Medicines.

g. bridging) ♦ additional to BE studies ♦ proportionality based biowaiver ♦ BCS based biowaiver ♦ ….BCS-based biowaiver in vitro dissolution objectives ♦ quality control ♦ justification of minor variations ♦ iviv-correlation (e. Kenya. August 2009 . major variations. 18 | Assessment of Interchangeable Multisource Medicines.

Kenya. August 2009 . stability-indicating. validated methods ♦ discriminative methods ♦ reproducible methods ♦ biorelevant methods (?) ……one fits all?! 19 | Assessment of Interchangeable Multisource Medicines.BCS-based biowaiver in vitro dissolution prerequisites ♦ reasonable.

BCS-based biowaiver in vitro dissolution and BCS concept 20 18 ♦ meet prerequisites ♦ ensure risk minimization ♦ justify absence of difference ♦ biorelevant?! % 16 14 12 10 8 6 4 2 0 0 5 10 time 15 20 20 | Assessment of Interchangeable Multisource Medicines. Kenya. August 2009 .

8 phosphate buffer) – no further profile comparison of T and R is required � reasonable.5 acetate buffer. August 2009 . validated experimental conditions/methods are strongly recommended! 21 | Assessment of Interchangeable Multisource Medicines. Kenya.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. pH 6.

validated experimental conditions/methods are strongly recommended! 22 | Assessment of Interchangeable Multisource Medicines. Kenya.8 phosphate buffer) � reasonable.2. pH 4. August 2009 . pH 6.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 1.5 acetate buffer.

900 ml. USP buffer. Kenya. USP buffer. 37 °C ♦ WHO – ♦ 75 rpm (paddle) or 100 rpm (basket). 37 °C ♦ all: no surfactants! 23 | Assessment of Interchangeable Multisource Medicines. August 2009 .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 or less.

August 2009 . WHO guidance sect. note prerequisites) 24 | Assessment of Interchangeable Multisource Medicines. Kenya. unless similarity is obvious (see e. using f2-test.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.2 or app. 2 of the current EU guidance.g. 9..

August 2009 .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! 25 | Assessment of Interchangeable Multisource Medicines. Kenya.

BCS-based biowaiver ♦ Requirement: either “very rapid” or “similar” in vitro dissolution ♦ how similar is ‘similar’? ♦ discussion of differences usually not appropriate 26 | Assessment of Interchangeable Multisource Medicines. Kenya. August 2009 .

Kenya. August 2009 .BCS-based biowaiver BCS-based biowaiver in-vitro dissolution  no iviv correlation  no biorelevant conditions (except pH) � concept to justify absence of difference! 27 | Assessment of Interchangeable Multisource Medicines.

Kenya.g.. August 2009 .. e. possible interactions... Isoniazid J Pharm Sci 96 March 2007: “…permeability changes due to excipient interaction cannot be detected in vitro…”) ♦ Evaluation of manufacturing processes in relation with critical physicochemical properties 28 | Assessment of Interchangeable Multisource Medicines..BCS-based biowaiver ♦ Evaluation of excipients (e.g. large amounts.

systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products 29 | Assessment of Interchangeable Multisource Medicines. No BCS-based biowaiver for:     locally applied. August 2009 . Kenya.BCS-based biowaiver BCS-based Biowaiver for immediate release drug products containing eligible drug substances.

30 | Assessment of Interchangeable Multisource Medicines. Kenya. drug solubility is high..BCS-based biowaiver Provided that .. excipients do not interact ..... August 2009 .    permeability is limited. excipients do not affect kinetics.....

.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 (see WHO guidance) 31 | Assessment of Interchangeable Multisource Medicines.... .then very rapid dissolution (at least >85% in 15 min) of test and reference may ensure similar product characteristics because.. Kenya.. August 2009 ...BCS-based biowaiver .

Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of Glucophage® or Glucofit® in 0.6 (□.BCS-class III?! Fig.1N HCI (○.●) pH 4. .■) and pH 6.▲) buffer solution. 1.8 (∆.

Fig. . August 2009 Glucophage (○) or Glucofit (●).BCS-class III?! Fig. Mean2in vivo plasma conentration-time profiles of metformin in 12 healthy Fig. Kenya. 2. Chinese subjects after oral administration of a 500mg immediate-release tablet of 33 | Assessment of Interchangeable Multisource Medicines.

8.01N hydrovhloric acid (HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0. pH 4. Data for the Tagamet® tablet were obtained from dissolution testing in 0. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine tablets containing methacrylate copolymer and Tagamet® tablets in different media. August 2009 . Jantratid et al 2006 34 | Assessment of Interchangeable Multisource Medicines. (b) phosphate buffer. Each value is the mean of six observations. 1. (c) SIFsp.BCS-class III?! Fig.5. Clin Pharmacokinet. pH 2.5 pancreatin. pH 6. Kenya. and (d) fasted-state simulated intestinal fluid. pH 6.01N HCI.

Each point represents the mean plasma cimetidine concentration (standard error) from 12 subjects. Kenya. Fig.BCS-class III?! 35 | Assessment of Interchangeable Multisource Medicines. Jantratid et al 2006 . August 2009 of mean plasma cimetidine concentration-time profiles obtained after administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or Tagamet® tablets. 2. Comparison Clin Pharmacokinet.

BCS-based biowaiver ♦ biopharmaceutics assessment (with necessary underlying PK background!!) ≠ pure PK assessment ♦ differentiation between solubility (API) and dissolution (product performance) ♦ volume of dissolution medium (900 vs 500 ml) not relevant (no concerns regarding hydrodynamics. August 2009 . recent findings). Kenya. sink conditions! ♦ in-vitro/in-vivo relationship rather than correlation!! ♦ slow absorption… intestinal transit about 3hs!! 36 | Assessment of Interchangeable Multisource Medicines.

..   ‘very’ high permeability pH-dependent solubility within the physiologically relevant pH range .BCS-based biowaiver For drugs showing .. J Pharm Sci 93 (2004) 1375. Kenya...an ‘intermediate solubility’ class is suggested [Polli et al. August 2009 . see WHO guidance] 37 | Assessment of Interchangeable Multisource Medicines...

g. August 2009 . highly permeable.BCS-based biowaiver “pH-dependent soluble.8 and f2 testing for pH 1. to WHO guidance ♦ at least 85% within 30 min at pH 6. Artursson (edts) 2003 Wiley-VCH) ♦ in vitro dissolution requirements acc. chpt 8 in: Drug Bioavailability. ionizable drug compounds may be handled like BCS class I drugs” (e. Kenya. Lennernäs.5 profiles ♦ but no biowaiver for weak basic drugs 38 | Assessment of Interchangeable Multisource Medicines. van de Waterbeemd. weak acidic.2 and 4.

Kenya.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 39 | Assessment of Interchangeable Multisource Medicines. August 2009 .

BCS-based biowaiver  BCS-based biowaiver are not just in-vitro dissolution. Kenya. August 2009 . but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications 40 | Assessment of Interchangeable Multisource Medicines.

int/pq/info_applicants/info_for_applicants_BE_studies. ethambutol and pyrazinamide if the same “very rapid” dissolution (T and R) is demonstrated see specific. August 2009 .htm  41 | Assessment of Interchangeable Multisource Medicines. currently published WHO guidance documents at: http://healthtech. Kenya.who.BCS-based biowaiver � Current recommendation for TB drugs    no BCS-based biowaiver for RMP ‘regular’ BCS-based biowaiver possible for levofloxacin and ofloxacin (“rapid dissolution”) currently a BCS-based biowaiver is possible for isoniazid (cave: excipients!).

. 2008.] 42 | Assessment of Interchangeable Multisource Medicines.: Pyrazinamide [Dressman et al. unpubl.BCS-based biowaiver ex. August 2009 . Kenya.

Kenya.: Pyrazinamide [Dressman et al.] 43 | Assessment of Interchangeable Multisource Medicines.. August 2009 .BCS-based biowaiver ex. unpubl. 2008.

unpubl.BCS-based biowaiver ex.. 2008. August 2009 . Kenya.] 44 | Assessment of Interchangeable Multisource Medicines.:Pyrazinamide [Dressman et al.

unpubl.BCS-based biowaiver ex. August 2009 . Kenya..] 45 | Assessment of Interchangeable Multisource Medicines. 2008.: Isoniazid [Dressman et al.

] 46 | Assessment of Interchangeable Multisource Medicines.BCS-based biowaiver ex. 2008. August 2009 . unpubl.. Kenya.: Isoniazid [Dressman et al.

] 47 | Assessment of Interchangeable Multisource Medicines. August 2009 . unpubl. Kenya. 2008..BCS-based biowaiver ex.: Isoniazid [Dressman et al.

2008. Kenya.] 48 | Assessment of Interchangeable Multisource Medicines. unpubl. August 2009 .: Ethambutol [Dressman et al.BCS-based biowaiver ex..

2008.. Kenya. August 2009 .: Ethambutol [Dressman et al.] 49 | Assessment of Interchangeable Multisource Medicines. unpubl.BCS-based biowaiver ex.

: Ethambutol [Dressman et al.BCS-based biowaiver ex. Kenya.. 2008. unpubl. August 2009 .] 50 | Assessment of Interchangeable Multisource Medicines.

Shah VP. Midha KK. Midha KK. J Pharm Sci. Kalantzi L. 2005 Oct. chloroquine sulfate. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride. Shah VP. Kenya. August 2009 . Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.96(3):522-31. Shah VP. Dressman JB.95(1):4-14. Reppas C. Kortejärvi H. and chloroquine hydrochloride. Stavchansky S. J Pharm Sci. Oeser H. Shah VP. Yliperttula M. Dressman JB. 2007 Mar. J Pharm Sci. Shah VP. Vogt M. Junginger HE. Barends DM.BCS-based biowaiver  Becker C. Midha KK. Potthast H. Junginger HE. Shah VP. 2008 Apr. Dressman JB. Junginger HE. Dressman JB. Midha KK. Kopp S. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide. Kopp S. Junginger HE. 2005 Aug.94(7):1389-95. Amidon GL. Shah VP. Dressman JB. Stavchansky S. Junginger HE. Verbeeck RK. J Pharm Sci. Midha KK. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride.96(6):1480-9. Stavchansky S. Amidon GL. Becker C.94(10):2121-31. J Pharm Sci. J Pharm Sci. 2005 Jul. J Pharm Sci. Midha KK. Midha KK. Krämer J. Midha KK. 2006 Jan. Junginger HE. [Epub ahead of print] Becker C. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol). International Pharmaceutical Federation. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: prednisone. Stavchansky SA. Junginger HE.94(8):1617-25. Kopp S. Junginger HE. Vogelpoel H. Groupe BCS: Biowaiver monographs for immediate release solid oral dosage forms: isoniazid. J Pharm Sci. Stavchansky S. 2007 Jun. 51 | Assessment of Interchangeable Multisource Medicines.        ………. Barends DM: Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate. Amidon GL.97(4):1350-60. Dressman JB. 2008 Feb 12. Dressman JB. Amidon GL. Derendorf H. Shah VP.

Kenya. August 2009 .BCS-based biowaiver THANK YOU FOR YOUR ATTENTION! 52 | Assessment of Interchangeable Multisource Medicines.