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
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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

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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)

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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

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

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

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BCS-based biowaiver
Biowaiver justification based on

criteria derived from the concepts underlying the Biopharmaceutics Classification System ......

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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

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Melting point Charge Ionisation Solubility Size H-bonding Lipophilicity Charge Distribution Shape

Amphiphilicity
Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]
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BCS-based biowaiver
Pillars of the BCS

Solubility

Permeability

Dissolution

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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)
generate 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?

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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?

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BCS-based biowaiver

Solubility high low high low

Permeability high high low low

BCS classification I (e.g. Propranolol) II (e.g. Glibenclamide) III (e.g. Atenolol) IV (e.g. Azathioprine)

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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?

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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?

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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 .
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BCS-based biowaiver
in vitro dissolution prerequisites

reasonable, stability-indicating, validated methods discriminative methods reproducible methods biorelevant methods (?) one fits all?!

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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

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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!
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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!

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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 or less; USP buffer; 37 C

all: no surfactants!
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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 current EU guidance; note prerequisites)
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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!

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BCS-based biowaiver

Requirement: either very rapid or similar in vitro dissolution

how similar is similar? discussion of differences usually not appropriate

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BCS-based biowaiver
BCS-based biowaiver in-vitro dissolution
no iviv correlation no biorelevant conditions (except pH)

concept to justify absence of difference!

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BCS-based biowaiver

Evaluation of excipients (e.g., large amounts,

possible interactions....; e.g. 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

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BCS-based biowaiver
BCS-based Biowaiver for immediate release drug products
containing eligible 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

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BCS-based biowaiver
Provided that ...... drug solubility is high,

permeability is limited, excipients do not affect kinetics, excipients do not interact ,.....

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BCS-based biowaiver
....then very rapid dissolution (at least >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 (see WHO guidance)

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BCS-class III?!

Fig. 1. Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of

Glucophage or Glucofit in 0.1N HCI (,) pH 4.6 (,) and pH 6.8 (,) buffer solution.

BCS-class III?!

Fig. Fig. 2. Mean2in vivo plasma conentration-time profiles of metformin in 12 healthy Fig.

Chinese subjects after oral administration of a 500mg immediate-release tablet of

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Glucophage () or Glucofit ().

BCS-class III?!

Fig. 1. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine tablets containing methacrylate copolymer and Tagamet tablets in different media. Each value is the mean of six observations. Data for the Tagamet tablet were obtained from dissolution testing in 0.01N hydrovhloric acid (HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0.01N HCI, pH 2; (b) phosphate buffer, pH 4.5; (c) SIFsp, pH 6.8; and (d) fasted-state simulated intestinal fluid, pH 6.5 pancreatin.

Clin Pharmacokinet. Jantratid et al 2006

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BCS-class III?!

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of mean plasma cimetidine concentration-time profiles obtained after administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or Tagamet tablets. Each point represents the mean plasma cimetidine concentration (standard error) from 12 subjects.

Fig. 2. Comparison

Clin Pharmacokinet. Jantratid et al 2006

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; recent findings); sink conditions! in-vitro/in-vivo relationship rather than correlation!! slow absorption intestinal transit about 3hs!!

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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; see WHO guidance]

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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,
Lennerns, Artursson (edts) 2003 Wiley-VCH)

in vitro dissolution requirements acc. to WHO guidance

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

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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

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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

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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!), ethambutol and pyrazinamide if the same very rapid dissolution (T and R) is demonstrated
see specific, currently published WHO guidance documents at: http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htm

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BCS-based biowaiver
ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.:Pyrazinamide [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Isoniazid [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Isoniazid [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Isoniazid [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Ethambutol [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Ethambutol [Dressman et al., 2008, unpubl.]

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BCS-based biowaiver
ex.: Ethambutol [Dressman et al., 2008, unpubl.]

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

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BCS-based biowaiver

THANK YOU FOR YOUR ATTENTION!

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