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Hier wird Wissen Wirklichkeit
South African Regional and
International Symposium 2014
Medicines eligible for Biowaivers
Prof. Jennifer B. Dressman
Institut für Pharmazeutische Technologie
JWG Universität Frankfurt
Hier wird Wissen Wirklichkeit
Substitution requirements
Therapeutic Equivalence = Pharmaceutical Equivalence
+ Bioequivalence
1) Pharmaceutical Equivalence
2) Bioequivalence
1)PK-Studies: key elements are design, power and evaluation of data
2)BCS based Biowaiver: BCS, dissolution and further criteria
3) IVIVC: more commonly used for MR formulations
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What is a “Biowaiver”?
In a “Biowaiver”-based submission the Sponsor tests bioequvalence with in vitro dissolution instead of a pharmacokinetic study
The method can be applied to approval of Generics, approval of products at lower doses and for scale-up and post-approval changes (FDA), also known as Variations (EMA), in the manufacture.
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The approach was originated by the FDA
in 1995 and applied to approval of generics
in 2002
„Biowaiver“- based approvals are linked to the
Biopharmaceutics Classification Scheme.
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I
Highly permeable
The Biopharmaceutics
Classification System (BCS)
II
Highly
soluble
III IV
Poorly permeable
Poorly
soluble
U.S. Department of Health and Human Services Food and Drug Administration Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability
and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System
Hier wird Wissen Wirklichkeit
Solubility Permeability
BCS Criteria: European Medicines Agency (EMA)
BCS
Dose/ Solubility ratio
≤ 250 ml
in >3 aqueous Media
pH 1.2 – 6.8 (preferably
1.2, 4.5, 6.8 and if
relevant pKa)
37+1°C
Absorption ≥ 85 %
BAabs-, Mass
Balance- Study (human)
Supportive data: well-
performed in vitro
permeability studies
including reference
substances; BE of
aqueous and solid dosage
forms of the API
]/[
][][/
)(max
mlmgSolubility
mgDmlSD
EMLratio
Hier wird Wissen Wirklichkeit
I
Highly permeable
Biowaiver possibilities in the USA (FDA)
II
Highly
soluble
III
IV
Not highly permeable
Not
highly
soluble
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Biowaiver- based approval
according to BCS class (EMA)
IV III
II I
Solubility
Perm
eab
ility
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I
Highly permeable
Biowaiver possibilities at the WHO
II
Highly
soluble
III
IV
Not highly permeable
Not
highly
soluble
Hier wird Wissen Wirklichkeit
BCS specific solubility data (Shake-flask method) and calculation of
D:S ratio using highest single dose
Dissolution of the pure API and its dosage form, and additionally the
comparator product, over pH range
1.2 – 6.8 under Biowaiver conditions relevant to the permeability
Permeability of the API (BAabs, Mass Balance, e.g. Caco-2, BE
with oral solution)
Consideration of further criteria:
Site-specific absorption, risk of transport protein interactions at absorptive
site, excipient composition and therapeutic risks. NTIs are a „no-go“
Physical characteristics: pKa, aqueous solubility
Hier wird Wissen Wirklichkeit
Initial characterization: pKa, aqueous solubility, API presentation
: NTI or not-NTI?
the aqueous solubility will provide a first estimate of whether the
Biowaiver can be applied. If the D:S is well above 250 ml, a biowaiver
will not in general be possible (Class II APIs) and not at all possible for
Class IV APIs.
Note: the EMA uses the Highest Single Dose in the Prescriber’s
Information as the Dose, whereas the WHO and FDA use the Highest
Dosage Strength .
If the API is an NTI substance, a biowaiver based approval will not be
possible. Both Japan and USA have lists of NTI substances – EU??
If the API is presented in a form with different properties to that in the
Reference product (e.g. salt vs. ester, type of salt etc.), it may not fulfill
the criterion of pharmaceutical similarity -> no biowaiver
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Solubility specifications for BCS
Classification: FDA, EU and WHO
FDA Guidance for
Industry
EMA Guideline
WHO Bioequivalence
of Multisource
Products
Methods
accepted
Shake-flask method
(other methods can be
used with justification)
Shake-flask method
(other methods can be
used with justification)
Not specified
pH range
pH 1 - 7.5 (pH = pka, pH
= pka 1, pH 1, pH 7.5)
pH 1.2 - 6.8 (aqueous
media), preferably 1.2,
4.5 and 6.8, when
appropriate also at pKa
pH 1.2 - 6.8 (aqueous
media)
Temperature
[ C]
37 1
37+1
37 1
Replications
at least 3
At least 2, end pH should
be verified
at least 3
D/S ratio
≤ 250 ml at highest
dosage strength
≤ 250 ml at highest
single dose administered
≤ 250 ml*
*calculated for the highest listed oral strength on WHO EML
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If the initial analysis looks promising, the next step is to
carry out the pH/solubility profile according to the
Guideline – e.g. according to EMA…..
The highest single dose administered as immediate
release formulation must dissolve completely in 250 ml
of buffer within the range pH 1-6.8 at 37+1°C.
At least three different buffers (preferably 1.2, 4.5 and
6.8) and in addition at the pKa, if relevant.
Shake-flask or other method; replications
Verification of pH before and after addition of the API
If the API is NOT highly soluble, no biowaiver will be
possible from the EMA or FDA
BCS specific solubility data (Shake-flask method) and calculation of
D:S ratio using highest single dose
Hier wird Wissen Wirklichkeit
Permeability specifications for BCS
Classification: FDA, EU and WHO
FDA Guidance for Industry
EMA Guideline
WHO Bioequivalence
of Multisource Products
Highly permeable
≥ 90 %
≥ 85 %
≥ 85 %
Accepted methods
Mass balance, absolute BA,
intestinal perfusion (in
humans)
Mass balance, absolute BA
(in humans)
Mass balance, absolute BA
(in humans)
Acceptable
alternative methods
In vivo or in situ intestinal
perfusion in a suitable animal
model, in vitro permeability
methods using excised
intestinal tissues or
monolayers of suitable
epithelial cells
none
In vivo intestinal perfusion in
humans, in vitro permeation
using excised human or
animal intestinal tissue (only
in comparison to a
reference product)
Supportive data
Not specified
Bioequivalence of aqueous
and solid formulations; well
performed in vitro
permeability studies
including reference
standards
In vivo or in situ intestinal
perfusion using animal
models or in vitro
permeation across a
monolayer of cultured
epithelial cells
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The next step is to determine the permeability, since this will
dictate what dissolution criteria are to be applied (EMA, WHO)
or whether the biowaiver can be applied at all (FDA).
Studies that can be used to support complete (>85% or 90%)
absorption are absolute bioavailability or mass-balance
studies.
Mass-balance: only metabolites formed after absorption may
be taken into account (not those formed in the GI tract) i.e.
parent (urinary) plus Phase I oxidation and Phase 2
conjugation metabolites (urinary and fecal) must together
account for at least 85% of the dose
Additional data that may be supportive: p.o. bioequivalence of
aqueous solution to solid dosage form; well-performed in vitro
permeability including reference standards.
Permeability of the API (BAabs, Mass Balance, e.g. Caco-2, BE
with oral solution)
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Consideration of further criteria I:
Site-specific absorption, risk of transport protein interactions at absorptive
site, excipient composition and therapeutic risks.
The in vitro permeability experiments may help establish the
mechanism of absorption and thus help answer questions
such as the site-specificity of the absorption (active transport,
paracellular transport) and risk of transport protein
interactions at the absorptive site (active transport).
Such information may be useful in helping forecast excipient
interactions and risks associated with biowaiving
Hier wird Wissen Wirklichkeit
Consideration of further criteria II:
Site-specific absorption, risk of transport protein interactions at absorptive
site, excipient composition and therapeutic risks.
In general, well-established excipients in usual amounts should be
employed. A description of the function of each excipient and a
justification that the amount used is in the usual range is required.
Excipient choices are more limited for Class III APIs than for Class I
APIs (EMA)
Class I: “advisable to use similar amounts of the same excipients
used in the reference product”.
Class III: Excipients have to be qualitatively the same and
quantitatively very similar to exclude different effects on
transporters”.
Problem – usual only the qualitative composition is disclosed!
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Consideration of further criteria III:
Site-specific absorption, risk of transport protein interactions at absorptive
site, excipient composition and therapeutic risks.
Excipients that might affect bioavailability through non-
dissolution mechanisms should be identified e.g. sorbitol,
mannitol, SLS and other surfactants.
These excipients should preferably be qualitatively and
quantitatively the same as in the reference product
Their impact on
GI motility,
susceptibility to interactions with the drug substance,
drug permeability and
interactions with membrane transporters
should be discussed.
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Dissolution testing requirements for
in vitro BE testing: FDA, EU und WHO
FDA Guidance for Industry
EMA Guideline
WHO Proposal to Waive in
vivo BE Requirements
Apparatus
1 (basket) or
basket
basket or
2 (paddle)
paddle
paddle
Dissolution media:
0.1 HCl or SGF USP without
enzymes and
Three buffers: pH 1-1.2, 4.5,
6.8
- Ph. Eur. Buffers
recommended
- No surfactants
- Enzymes may be
acceptable for gelatin
capsules and tablets
pH 1.2 IP standard
dissolution buffer (HCl
solution)
pH 4.5 standard buffer and
pH 4.5 IP standard
dissolution buffer (acetate
buffer)
pH 6.8 standard buffer or SIF
USP without enzymes
pH 6.8 IP standard
dissolution buffer (phosphate
buffer)
Temperature [ C]
37 0.5
37 + 1 C
37
Volume [ml]
900 or less
900 ml or less
900 or less
Agitation [rpm]
100 (apparatus 1)
usually 100 (basket) usually
50 (paddle)
100 (basket)
50 (apparatus 2)
75 (paddle)
Release
at least 85 % within 30 min
>85 % within 15 min (VRD)
or > 85% within 30 min (RD)
at least 85 % within 30 min
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The dissolution characteristics of the pure API are
always interesting as this will indicate whether there are
any wetting problems with the API and if its particle size
needs to be reduced.
For biowaiver purposes, both the test and reference
product must be subjected to exactly the same battery of
dissolution tests. The range of test conditions that can
be used is very specific to the biowaiver and the
standard QC tests are not relevant to the biowaiver
procedure.
The tests are the same for Class I and III APIs, but the
evaluation criteria are different (EMA, WHO)
Dissolution of the pure API and its dosage form, and additionally the
reference product, over pH range
1.2 – 6.8 under biowaiver conditions relevant to the permeability I
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Test conditions
Apparatus – Paddle or Basket
Volume of medium: 900 ml or less
Temperature of Medium: 37 + 1°C
Agitation: usually 50 rpm (Paddle), usually 100 rpm
(basket).
Sampling: e.g. 10, 15, 20, 30, 45 min
Buffers: 1-1.2 (usually 0.1 N HCl or SGF sans enzymes),
pH 4.5 and pH 6.8 (or SIF sans enzymes). Ph.Eur. Buffers
preferred. NO SURFACTANTS! Enzymes OK if gelatin
capsules or tablets are involved.
Dissolution of the pure API and its dosage form, and additionally the
reference product, over pH range
1.2 – 6.8 under biowaiver conditions relevant to the permeability II
Hier wird Wissen Wirklichkeit
Data Evaluation
Different criteria apply according to BCS Class of the API
Class I: either very rapid dissolution (>85% in 15 min) of both
the test and reference product
or
Similarly rapid dissolving = both reference and test product
result in >85% dissolution in 30 minutes AND profile similarity
is demonstrated with the f2 or another suitable statistical
comparison.
Class III: very rapid dissolution (>85% in 15 min) of both the
test and reference product is required.
Problem: sometimes the Reference product cannot meet the
dissolution criteria. In this case a biowaiver-based approval is
not possible.
Dissolution of the pure API and its dosage form, and additionally the
reference product, over pH range
1.2 – 6.8 under biowaiver conditions relevant to the permeability IV
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16 Point-Text: Level Biowaiver
Criteria
16
16 Point-
Biowaiver
BCS Classification
Therapeutic
Index, interactions
Of excipients with
GI physiology and
transporters
BE Studies
Aq. Solution vs.
solid dosage form
API presentation, dosage form
similarity, interactions with
excipients in the dosage form
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BCS Class (II, IV)
NTI
slow or incomplete dissolution
Interacations with excipients
lack of bioequivalence of solid
dosage form with aqueous solution
excipients that might cause
effects in GI tract
Biowaiver
BCS Class I or III
wide therapeutic index
rapid or very rapid dissolution
no interaction with excipients
No critical excipients
BE of solid dosage form with
aqueous solution
Weighing the data
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The Essential Medicines WHO
Model List (EML)
This list comprises the most important drugs which should be available in
every health care system
There are ~ 250 drug products in the “Core List” and ~ 80 in the
“Complementary List”
The products are chosen on the basis of safety, efficacy and price
The dosage form and strength is listed for each product and there are
currently about 150 IR solid oral products in total i.e. products to which in
principle the biowaiver process could be applied
http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf
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Examples of APIs on the EML
Antituberkulotics
Rifampicin
Isoniazid
Ethambutol
Pyrazinamide
Antimalarials
Quinine
Primaquine
Proguanil
Mefloquine
Sulfadoxine/ Pyrimethamine
Artemeter/ Lumefantrin
Atovaquone
Doxycycline
Hier wird Wissen Wirklichkeit
Results for Antituberculotics
API Solubility Permeability BCS Biowaiver Justification or
limitations
Test
Rifampicin borderline High II/I No Instability, poor
wettability,
Polymorphism
In vivo
Pyrazinamide High borderline III/I Under
certain
conditions
Liver toxicity ->
adequate medical
support needed
In vitro
(in vivo)
Isoniazid High borderline III/I yes Reducing sugars
should be
excluded as
excipients
In vitro
(in vivo)
Ethambutol
• 2 HCl
High low III Under
certain
conditions
Visual toxicity->
adequate medical
support needed
In vitro
(in vivo)
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Results for Antimalarials
API Löslichkeit Permeabilität BCS Biowaiver Justification or
limitations
Test-
Verfahren
Quinine
hydrochloride
High borderline III/I No NTI, does not
dissolve fast
enough
In vivo
Primaquine
diphosphate
High High I Yes
-
In vitro
Proguanil
hydrochloride
High ? III/I Yes ≥ 85 % dissolution
in 15min: test and
reference product
In vitro
Mefloquine
hydrochloride
low
?
IV/II No Low solubility In vivo
Doxycycline
hyclate
High High I Yes - In vitro
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Doxycycline hyclate
Physicochemical Properties
• MW: 512.94 g/mol
• Melting point: 201°C
• Solubility: ~ 50mg/mL
• pKa (20°C): 3,5; 7,7 and 9,5
• log P: ~ -1,90
• Tetracycline antibiotic
Structure of Doxycyclinhyclat
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Dissolution Profiles of
German Doxycycline Tablet products
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Biowaivers for the German products?
All three of the generic products were approved in Germany via
pharmacokinetic bioequivalence testing (Antadox being the innovator
product).
Doxycyclin AL dissolves 85% in 15 minutes, as does the innovator. So
it would have passed the biowaiver criteria.
Doxy- Wolff dissolves 85% in 30 minutes, and similarly to the
innovator, so it too would likely have passed the biowaiver criteria.
Doxy- Stada dissolves too slowly to meet the biowaiver criteria, so
could not have been approved through the biowaiver procedure.
These results illustrate that the biowaiver procedure is sometimes
tougher than a pharmacokinetic proof of bioequivalence!!
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Future Directions for Biowaiving……
………some ideas
Resolve the Dose to be used for Dose:Solubility calculations
Harmonize the Permeability (Suggestion – to 85% absorption)
Use BDDCS as supporting evidence for the BCS classification
* * *
Consider solubility in more biorelevant media (simple buffers are
„worst case“) but also adopt more biorelevant media volumes
Harmonize definitions of NTI on a global basis
Investigate excipient interactions that are NOT detectable with
dissolution testing more thoroughly
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Many thanks for your attention!
The Biowaiver Monographs can be accessed
at www.fip.org/bcs
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