:Training Workshop

Training of BE Assessors
Kiev, October 2009

BCS-based Biowaivers
Dr. Henrike Potthast (h.potthast@bfarm.de)

Training workshop: Training of BE Assessors, Kiev, October 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

and

drug product
Drug substance
pharmacodynamic/therapeutic aspects
physicochemical aspects
Drug product
in vitro dissolution

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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

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
High solubility
the highest single 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
Methods to investigate permeability
PK-studies (e.g. absolute BA or mass-balance studies)
Human intestinal perfusion studies
Animal models
Caco 2 cell lines or other suitable, validated cell lines
(in-situ or in-vitro models for passively transported APIs only)

To be noted:

the stated methods assess the fraction dose absorbed BA, which can
be reduced substantially by first-pass metabolism (see e.g. Propranolol)

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BCS-based biowaiver

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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
.Risk assessment: only if the risk of an incorrect

biowaiver decision and an evaluation of the consequences

(of an incorrect, biowaiver-based equivalence decision) in
terms of public health and risks to individual patients is
outweighed by the potential benefits acrued from the
biowaiver approach may the biowaiver procedure be
applied

[WHO Technical Report Series, No. 937, 2006; Annex 8]

is the concept scientifically sound?

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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?!

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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
Excipients generally
-

Should be well-known

Used in usual amounts

Without relevant impact on the absorption process

Preferred for class I drugs and requested for class III:

same excipients in

similar amounts as the reference

Critical excipients should be qualitatively and

quantitatively the same
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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 Fig.

conentration-time profiles of metformin in 12 healthy

Fig. 2

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

Glucophage () or Glucofit ().
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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?!

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.

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Clin Pharmacokinet.
Jantratid et al 2006

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
Some remarks:
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!!
note differences regarding the evaluation of excipients!!

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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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