regulatory requirements

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Transcript regulatory requirements

WHO Workshop on Assessment of
Bioequivalence Data
Addis Ababa, 31. August – 3. September 2010
BCS-based Biowaivers
Dr. Henrike Potthast ([email protected])
WHO Workshop on Assessment Bioequivalence Data, Addis Ababa, 31. August-3.September, 2010
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 Rev1, Appendix 3
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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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Definitions
 Bioequivalence study
– in vivo comparison using humans as dissolution
models
– ‚biological quality control‘
– comparative evaluation of the formulation effect
 Bioequivalence  therapeutic equivalence
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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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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
 therapeutic aspects
 physicochemical aspects
Drug product
 in vitro dissolution
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and
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
Absorption
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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 solubility acc. to WHO
♦ highest dose recommended by WHO (as recommended in the
WHO Model List of Essential Medicines)
or
♦ highest dose strength (if not listed s.o.)
 please note the differences between guidelines!
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BCS-based biowaiver
High permeability
♦ Revised EMA guidance: extent of absorption ≥ 85 % (absolute BA or
mass balance data) or ‘known absorption’
♦ FDA guidance: absolute BA >90 %
♦ WHO guidance: extent of absorption at least 85 % 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
Supportive data to investigate permeability:
♦ In vivo or in situ perfusion using animal models and
♦ In vitro permeation across a monolayer of cultured epithelial cells like e.g.
Caco 2 or other suitable, validated cell lines
are not acceptable on a stand-alone basis
(in-situ or in-vitro models for passively transported APIs only;
negative as well as positive controls needed)
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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
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 and
revised EMA 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 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,
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
According to the WHO guideline drug substances
that belong to

BCS-class 1 and 3

and some of BCS class 2 (weak acids with high permeability)
..... are in principle eligible for the BCS-based biowaiver
approach
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BCS-based biowaiver
BCS-based biowaiver approach applicable…..
 pro-drugs?
 effective metabolites?
 instability?
 polymorphic forms?
 stereochemistry (enantiomer/racemate)?
 wide therapeutic dose range?
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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
♦ „….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 to detect
possible formulation related differences?
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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
‘usual’ 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
 use of representative batches
20
 meet prerequisites
18
16
14
 justify absence of difference
12
%
 ensure risk minimization
10
8
6
4
 biorelevant?!
2
0
0
5
10
time
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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 –
 usually 50 rpm (paddle) or 100 rpm (basket); 900 ml; PhEur buffer; 37 °C;
sampling schedule
 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. 1 of the revised 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
finally EXCIPIENTS
 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
Risk assessment on EXCIPIENTS acc. to WHO
 i) the excipient is present in the comparator product, or the excipient is
present in a number of other products which contain the same API as
the multisource drug product and which have marketing authorizations
in countries participating in the International Committee on
Harmonisation (ICH) or associated countries;
and
 ii) the excipient is present in the multisource product in an amount
similar to that in the comparator, or the excipient is present in the
multisource drug product in an amount typically used for that type of
dosage form.
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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 (e.g. surfactants, mannitol, sorbitol…)
should be qualitatively and quantitatively the same
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BCS-based biowaiver
Summary Requirements - BCS class 1
 „Dosage forms of APIs which are highly soluble, highly permeable (BCS
Class 1), and are rapidly dissolving are eligible for a biowaiver based on the
BCS provided:
 (i) the dosage form is rapidly dissolving (as defined in section 9.1.2.2) and
the dissolution profile of the multisource product is similar to that of the
comparator product at pH 1.2, pH 4.5 and pH 6.8 buffer using the paddle
method at 75 rpm or the basket method at 100 rpm (as described in section
9.2) and meets the criteria of dissolution profile similarity, f2 > 50 (or
equivalent statistical criterion);
 (ii) if both the comparator and the multisource dosage forms are very rapidly
dissolving (as defined in section 9.1.2.1) the two products are deemed
equivalent and a profile comparison is not necessary.“
(see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)
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BCS-based biowaiver
Summary Requirements - BCS class 3
 „Dosage forms of APIs which are highly soluble and have low
permeability (BCS Class 3) are eligible for biowaivers provided
all the criteria (a–d) listed in section 9.2 are met and the risk–
benefit is additionally addressed in terms of extent, site and
mechanism of absorption.“
 Very rapidly dissolving (release of >85 % within 15 min) in standard
media pH 1.2, 4.5, and 6.8; 75 rpm (paddle) or 100 rpm (basket)
applies to IR products containing class III APIs.
(see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)
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BCS-based biowaiver
Summary Requirements - BCS class 3 ctd.
- criteria (a–d) listed in section 9.2:
 A biowaiver based on the BCS considers:
(a) the solubility and permeability of the API (see section 9.1);
(b) the similarity of the dissolution profiles of the multisource and comparator
products in pH 1.2, 4.5 and 6.8 media (see below);
(c) the excipients used in the formulation (see below); and
(d) the risks of an incorrect biowaiver decision in terms of the therapeutic index of,
and clinical indications for, the API (see section 5.1 for cases where an in vivo
study would be required to demonstrate bioequivalence).
(see WHO technical Report Series, No. 937, 2006 Annex 7)
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31. August – 3. September 2010, Addis Ababa
BCS-based biowaiver
Summary Requirements - BCS class 2
 „Dosage forms of APIs with high solubility at pH 6.8 but not at
pH 1.2 or 4.5 and with high permeability (by definition, some
but not all BCS Class 2 compounds with weak acidic
properties) are eligible for a biowaiver based on BCS provided
that criteria (b), (c) and (d) described in section 9.2. are met,
that the API has high permeability (i.e. the fraction absorbed is
85% or greater) and a dose:solubility ratio of 250 ml or less at
pH 6.8, and that the multisource product:….
(see WHO technical Report Series, No. 937, 2006 Annex 7)
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31. August – 3. September 2010, Addis Ababa
BCS-based biowaiver
Summary Requirements - BCS class 2 ctd…..
 „is rapidly dissolving (85% in 30 minutes or less) in pH 6.8
buffer using the test procedure conforming to section 9.2;
and
 (ii) the multisource product exhibits similar dissolution profiles,
as determined with the f2 value or equivalent statistical
evaluation, to those of the comparator product at the three pH
values (pH 1.2, 4.5 and 6.8).“
(see WHO technical Report Series, No. 937, 2006 Annex 7)
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BCS-based biowaiver
Summary Requirements - BCS class 2 ctd….
 „For multisource products containing Class 2 APIs with
dose:solubility ratios of 250 ml or less at pH 6.8, the
excipients should additionally be critically evaluated in terms
of type and amounts, e.g. of surfactants, in the formulation.
Further, if the Cmax is critical to the therapeutic efficacy of the
API, the risk of reaching an inappropriate biowaiver decision
and its associated risks to public health and for individual
patients may be deemed unacceptable.“
(see WHO technical Report Series, No. 937, 2006 Annex 7)
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31. August – 3. September 2010, Addis Ababa
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
 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
 Current recommendation for TB drugs

however – a BCS-based biowaiver is not possible due to the
comparator(!) in the case of…

Ofloxacine (since rapid dissolution is not achieved)

Ethambutol (since very rapid dissolution is not achieved)
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31. August – 3. September 2010, Addis Ababa
BCS-based biowaiver
Current recommendation for antiretroviral drugs
a BCS-based biowaiver is possible for
♦ lamivudine
♦ stavudine
♦ zidovudine
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31. August – 3. September 2010, Addis Ababa
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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31. August – 3. September 2010, Addis Ababa
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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31. August – 3. September 2010, Addis Ababa
BCS-based biowaiver
Minimize the risk by thorough and correct …

drug substance classification

In-vitro dissolution (incl. profile comparison)

demonstration that excipients are
 well-established
(?!?)
 will not differ in terms of their effect on absorption
 will not lead to interactions that alter pharmacokinetics
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31. August – 3. September 2010, Addis Ababa
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.
……….
58 | WHO Workshop on Assessment of Bioequivalence Data
31. August – 3. September 2010, Addis Ababa
BCS-based biowaiver
THANK YOU FOR YOUR
ATTENTION!
59 | WHO Workshop on Assessment of Bioequivalence Data
31. August – 3. September 2010, Addis Ababa