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)

EUguidance:“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 and drug product
Drug substance
 pharmacodynamic/therapeutic aspects
 physicochemical aspects
Drug product
 in vitro dissolution
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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
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BCS-based biowaiver
(BCS) dissolution drug product
 drug substance in solution membrane transport
 drug substance in the system simplified mechanistic view of bioavailability
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Charge
Ionisation
Melting point
Solubility
Size Shape
H-bonding
Lipophilicity
Charge
Distribution
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
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Dissolution

BCS-based biowaiver
 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
♦ 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
high high I (e.g. Propranolol) low high low high low low
II
IV
(e.g. Glibenclamide)
III (e.g. Atenolol)
(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
 meet prerequisites
 ensure risk minimization
 justify absence of difference
 biorelevant?!
10
8
6
4
2
0
0
20
18
16
14
12
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
 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

 how similar is ‘similar’?
 discussion of differences usually not appropriate
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BCS-based biowaiver
 no iviv correlation
 no biorelevant conditions (except pH)
 concept to justify absence of difference!
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BCS-based biowaiver

(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. 2.
Mean in vivo plasma conentration-time profiles of metformin in 12 healthy
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.
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Clin Pharmacokinet.
Jantratid et al 2006

BCS-class III?!
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Fig. 2.
Comparison 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.
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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,
Lennernäs, 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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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, Krämer 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.
 Kortejärvi 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
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