South African Regional and International Symposium 2014

South African Regional and
International Symposium 2014
Medicines eligible for Biowaivers
Prof. Jennifer B. Dressman
Institut für Pharmazeutische Technologie
JWG Universität Frankfurt
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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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The Biopharmaceutics
Classification System (BCS)
Highly permeable
I
II
Highly
soluble
Poorly
soluble
III
IV
Poorly permeable
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
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BCS Criteria: European Medicines Agency (EMA)
Solubility
Permeability
 Absorption ≥ 85 %
 Dose/ Solubility ratio
≤ 250 ml
D / Sratio [ml ]
D max ( EML) [mg ]
Solubility [mg / ml ]
 in >3 aqueous Media
pH 1.2 – 6.8 (preferably
1.2, 4.5, 6.8 and if
relevant pKa)
 37+1°C
 BAabs-, Mass
Balance- Study (human)
BCS
Supportive data: wellperformed in vitro
permeability studies
including reference
substances; BE of
aqueous and solid dosage
forms of the API
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Biowaiver possibilities in the USA (FDA)
Highly permeable
I
II
Not
highly
soluble
Highly
soluble
III
IV
Not highly permeable
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Biowaiver- based approval
according to BCS class (EMA)
Permeability
I
II
III
IV
Solubility
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Biowaiver possibilities at the WHO
Highly permeable
I
II
Not
highly
soluble
Highly
soluble
III
IV
Not highly permeable
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Physical characteristics: pKa, aqueous solubility
BCS specific solubility data (Shake-flask method) and calculation of
D:S ratio using highest single dose
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“
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
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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
EMA Guideline
FDA Guidance for
Industry
WHO Bioequivalence
of Multisource
Products
Methods
accepted
Shake-flask method
(other methods can be
used with justification)
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
Temperature
[ C]
37
37+1
37
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*
1
Shake-flask method
(other methods can be
used with justification)
Not specified
pH 1.2 - 6.8 (aqueous
media)
1
*calculated for the highest listed oral strength on WHO EML
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BCS specific solubility data (Shake-flask method) and calculation of
D:S ratio using highest single dose
 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
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Permeability specifications for BCS
Classification: FDA, EU and WHO
FDA Guidance for Industry
Highly permeable
≥ 90 %
Accepted methods
Mass balance, absolute BA,
intestinal perfusion (in
humans)
Acceptable
alternative methods
EMA Guideline
≥ 85 %
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
Supportive data
Not specified
Mass balance, absolute BA
(in humans)
none
Bioequivalence of aqueous
and solid formulations; well
performed in vitro
permeability studies
including reference
standards
WHO Bioequivalence
of Multisource Products
≥ 85 %
Mass balance, absolute BA
(in humans)
In vivo intestinal perfusion in
humans, in vitro permeation
using excised human or
animal intestinal tissue (only
in comparison to a
reference product)
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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Permeability of the API (BAabs, Mass Balance, e.g. Caco-2, BE
with oral solution)
 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.
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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
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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 nondissolution 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
Apparatus
EMA Guideline
1 (basket) or
basket
2 (paddle)
Dissolution media:
0.1 HCl or SGF USP without
enzymes and
pH 4.5 standard buffer and
pH 6.8 standard buffer or SIF
USP without enzymes
Temperature [ C]
37
0.5
Volume [ml]
900 or less
Agitation [rpm]
100 (apparatus 1)
paddle
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
37 + 1 C
900 ml or less
usually 100 (basket) usually
50 (paddle)
50 (apparatus 2)
Release
at least 85 % within 30 min
WHO Proposal to Waive in
vivo BE Requirements
basket or
paddle
pH 1.2 IP standard
dissolution buffer (HCl
solution)
pH 4.5 IP standard
dissolution buffer (acetate
buffer)
pH 6.8 IP standard
dissolution buffer (phosphate
buffer)
37
900 or less
100 (basket)
75 (paddle)
>85 % within 15 min (VRD)
at least 85 % within 30 min
or > 85% within 30 min (RD)
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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
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)
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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
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.
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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
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.
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Biowaiver
Criteria
16 Point-Text: Level
BCS Classification
16 Point-
16
Therapeutic
Index, interactions
BE Studies
Aq. Solution vs.
solid dosage form
Of excipients with
Biowaiver
GI physiology and
transporters
API presentation, dosage form
similarity, interactions with
excipients in the dosage form
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Weighing the data
 BCS Class (II, IV)
 NTI
 BCS Class I or III
 slow or incomplete dissolution
 wide therapeutic index
 Interacations with excipients
 lack of bioequivalence of solid
dosage form with aqueous solution
 excipients that might cause
effects in GI tract
 rapid or very rapid dissolution
Biowaiver
 no interaction with excipients
No critical excipients
 BE of solid dosage form with
aqueous solution
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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
Antimalarials
 Rifampicin
 Quinine
 Isoniazid
 Primaquine
 Ethambutol
 Proguanil
 Pyrazinamide
 Mefloquine
 Sulfadoxine/ Pyrimethamine
 Artemeter/ Lumefantrin
 Atovaquone
 Doxycycline
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Results for Antituberculotics
API
Solubility
Permeability
BCS
Biowaiver
Justification or
Test
limitations
Rifampicin
borderline
High
II/I
No
Instability, poor
In vivo
wettability,
Polymorphism
Pyrazinamide
High
borderline
III/I
Under
Liver toxicity ->
certain
adequate medical
conditions
Isoniazid
High
borderline
III/I
yes
In vitro
support needed
(in vivo)
Reducing sugars
In vitro
should be
excluded as
(in vivo)
excipients
Ethambutol
• 2 HCl
High
low
III
Under
Visual toxicity->
certain
adequate medical
conditions
support needed
In vitro
(in vivo)
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Results for Antimalarials
API
Löslichkeit
Permeabilität
BCS
Biowaiver
Justification or
limitations
Quinine
High
borderline
III/I
No
NTI, does not
TestVerfahren
In vivo
dissolve fast
hydrochloride
Primaquine
enough
High
High
I
Yes
-
diphosphate
Proguanil
In vitro
High
?
III/I
Yes
≥ 85 % dissolution
In vitro
in 15min: test and
hydrochloride
reference product
Mefloquine
low
?
IV/II
No
High
High
I
Yes
Low solubility
In vivo
hydrochloride
Doxycycline
-
In vitro
hyclate
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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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