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
Solubility
Size
Ionisation
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
Solubility
high
low
high
low
Permeability
high
high
low
low
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BCS classification
I
(e.g. Propranolol)
II (e.g. Glibenclamide)
III
(e.g. Atenolol)
IV (e.g. Azathioprine)
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
20
18
 meet prerequisites
16
14
 ensure risk minimization
%
12
10
8
6
 justify absence of difference
 biorelevant?!
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4
2
0
0
5
10
time
15
20
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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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.
Fig. 2. Mean
Fig. 2in 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?!
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,
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
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, 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
THANK YOU FOR YOUR
ATTENTION!
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