Conditions to apply for biowaiver for pharmaceutical Generic formulations.

1. Sonia Nagvenkar,
Scientist III,
Formulation Development
Regulatory Aspects of
BIOWAIVERS
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2. Scope
• Introduction to important terms
• Biowaiver concept
• Different Biowaiver approaches
• Steps involved in Biowaiver procedure
• How to Apply of the biowaiver procedure as
a surrogate for bioequivalence testing
SONIA NAGVENKAR
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NAGVENKAR

3. Therapeutic Equivalence = Bioequivalence + Pharmaceutical
Equivalence
Bioequivalents: "The rate and extent of absorption of the test drug product
do not show a significant difference from the rate and extent of absorption of
the reference drug product when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in either a single
dose or multiple doses;"
Pharmaceutical Equivalents : FDA considers drug products to be
pharmaceutical equivalents if they meet these three criteria:
1. they contain the same active ingredient(s)
2. they are of the same dosage form and route of administration
3. they are identical in strength or concentrationSONIA
NAGVENKAR

4. Innovator pharmaceutical product is that which was first
authorized for marketing, on the basis of documentation of
quality, safety and efficacy.
Generic pharmaceutical products are intended to be
pharmaceutically equivalent and bioequivalent to the
Innovator .
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5. Pharmacokinetics :- It is defined as the
kinetics of drug absorption, distribution
,metabolism and excretion and their relation ship
with the pharmacological ,therapeutic or
toxicological response in man and animals.
Linear pharmacokinetics :- Pharmacokinetic
parameters for a drug would not change when
different doses or multiple doses of a drug were
given.
Non-linear pharmacokinetics :-
Pharmacokinetic parameters change with the size
of administered dose.
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6. In vivo comes from the Latin term "in life." The
term refers to studies of biological properties
that are performed inside a living organism.
In vitro ("in glass") studies, which are done
inside a test tube, petriplates.
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7. Narrow therapeutic index drugs are drugs where small
differences in dose or blood concentration may lead to serious
therapeutic failures and/or adverse drug reactions that are
life-threatening or result in persistent or significant disability
or incapacity.
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8. The Biopharmaceutics Classification System (BCS)
system to differentiate the drugs on the basis of their
solubility and permeability.
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9. Bioequivalence Study
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10. Bioequivalence Study
Situations where regulatory authorities have to decide whether
bioequivalence study is mandatory or not
 Approval of generics against a Reference Listed Drug
 Scale up processes or variations after marketing
authorization
(SUPAC–USFDA & Variations- EMA)
 Approval of higher dose products
 Approval of lower doses - new indications
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11. Bioequivalence testing
Different Approaches for Demonstrating
Bioequivalence study
Pharmacokinetic
study
Pharmacodynemic
study
Clinical
End point
BIOWAIVER
in-vivo studies
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12. What is a Biowaiver?
“Biowaiver” means avoiding time consuming and costly
pharmacokinetic studies and using in vitro dissolution test as a
surrogate test to evaluate the bioequivalence of a test and reference
product
Waive = refrain from insisting on or using
Advantages
•Circumvent expensive & unethically questionable human testing
•Reducing time in bringing product to the market
•Reduce product cost
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13. Biowaivers approaches
BCS Based Biowaivers
Dose Proportionality Biowaivers
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14. BCS Based Biowaivers
If the in vivo dissolution of a highly soluble compound is rapid and
excipients used in the product do not affect absorption of the API then
bioequivalence between the two pharmaceutically equivalent IR products
need not be demonstrated using in vivo studies.
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15. Evolution of Biowaiver Guidances
1995
2000
2001
2003
2006
2010
2011
SUPAC Guidances
BCS Based Biowaiver guidance for
Immediate release dosage form
Note for Guidance on investigation
of BA & BE (Variations)
BA & BE Studies for orally administered
drug products
Biowaiver Guidance Annex 8 TRS 937
Guideline on investigation of Bioequivalence
General notes on BCS based
Biowaiver applications
2015
Waiver of In Vivo BA and BE Studies for
IR Solid Oral Dosage Forms Based on a BCS
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16. Applicable dosage forms
BCS based biowaivers are
applicable to
immediate release, solid pharmaceutical products
for oral administration and
systemic action having the same pharmaceutical
form
Not applicable to
sublingual, buccal and modified release
formulations
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17. BCS Biowaiver Procedure
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18. BCS Based Solubility
Highly soluble
Dose/Solubility ratio ≤ 250mL in
aqueous buffers pHs 1 – 6.8 at 37 ± 1°C
Dose is defined differently in
different guidances
 WHO- highest dose strength
mentioned in the EML
 US FDA – maximum dose strength that
is marketed
 EMA- highest single dose that is
administered
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19. Permeability study
APIs with a permeability of ≥ 85% of the administered dose are
defined as highly permeable
Primary data (in humans)
• Absolute bioavailability
• Mass balance studies (C-14 Studies)
Secondary data
• Perfusion studies in animals
•In vitro permeability studies using CaCo-2 or MDCK cell lines
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20. Comparison Between Guidances
Class
eligible for
Biowaiver
Biowaiver Guidances
FDA EMA WHO
Class I
Class II Weak Acids
Class III*
Class IV
* Qualitative composition should be same and quantitative
composition should be very similar
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21. be Vigilant.......
• Different derivatives of the API in test
and comparator (salts that exhibit
different solubility characteristics)
• Different polymorphs in test and
comparator
• Poorly soluble drugs (most Class II and
Class IV API)
• Reports of bioinequivalence not related
to dissolution
• APIs with Narrow therapeutic
index (NTIs) are not considered
for biowaiver approachSONIA
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22. Risk Assessment
For the purpose of biowaiver “risk” can be defined as a “false
positive” decision and the ramifications of such a product on
patient safety
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23. Effect of formulation and manufacturing
variable
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24. Effect of excipients
Excipients that might affect bioavailability through non-dissolution
mechanisms should be identified
e.g. sorbitol, mannitol, SLS and other surfactants.
Their impact on
 GI motility,
 susceptibility to interactions with the drug substance,
 drug permeability and
 interactions with membrane transporters should be discussed.
These excipients should preferably be qualitatively and
quantitatively the same as in the reference product.
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25. Risk benefit analysis
The risk associated with a „false positive“ biowaiver decision should
be considered.
Bioavailability related issues like
• Previous cases of bioinequivalence reported that are not related to
the dissolution
• Effect of supra or sub therapeutic drug levels in patients
The risk of a false biowaiver decision should not
outweigh the benefits of a biowaiver procedure
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26. Dissolution Test Conditions
Apparatus: Paddle or Basket
Number of units: 12
Volume of the medium: 900mL or less
Temperature of the medium: 37±1°C
Agitation speed: 75rpm (paddle) → WHO
50rpm (paddle) → FDA/EMA or
100rpm (basket)
Sampling times: eg. 10, 15, 20, 30,45 60 min
Media: SGFsp, pH 1.2
Acetate buffer, pH 4.5
SIFsp, pH 6.8
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27. Dissolution Criteria
 No surfactants are allowed
 The use of enzymes in gelatin based products - EMA
& FDA
 Subjecting the pure drug substance to the series of
dissolution studies as for the comparator product is a
good approach to understand the drug behavior with
respect to dissolution.
It should be noted that the standard quality control
dissolution test are usually not relevant for the biowaiver
procedure.SONIA
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28. Dissolution Criteria for Biowaiver
BCS Class II: (WHO only) should be “rapidly dissolving“ product i.e. >
85% drug dissolution in 30 min from both comparator and test product in
aqueous buffer at pH 6.8 at 37°CSONIA
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29. Issues
If the comparator cannot meet the dissolution test
criteria , biowaiver based approval is not possible
Resolve
locate an acceptable alternative
demonstrate BE by in vivo studies
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30. DOSE-PROPORTIONALITY OF
BIOWAIVERS
For Multiple DP Strengths (IR and MR)
demonstrate BE with one or two strengths & BE waiver for additional
strengths can be waived depending on certain product characteristics
Advantages:
• Avoid unnecessary exposure of subjects to drug
• Modified release dosage forms
• Reduces time
• Avoids costly In-vivo studiesSONIA
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31. Criteria for D-P Biowaivers
the drug product is present in the same dosage form but in different
strengths
same manufacturing process between different strengths
the additional strengths are proportionally similar in formulation to
that of the BE approved strength
dissolution profiles of the other strengths are shown to be similar to
that of the BE approved strength
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32. Dose Proportionality Concept
Case 1: Quantitatively proportional
All active and inactive ingredients are in exactly the same proportion
between the different strengths
Strength 100mg 50mg 25mg Ratio
Active 100mg 50mg 25mg -
InAct 1 40mg 20mg 10mg 1:2.5
InAct 2 60mg 30mg 15mg 1:1.66
Total 200mg 100mg 50mg -
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33. Dose Proportionality Concept
Case 2: For highly potent drugs
EMA - Active is <5% of the tablet core weight/total capsule content
WHO- Active should be upto 10mg/dosage unit
FDA- the amount of active ingredient in dosage form is relatively low
The change in any strength is obtained by altering the
amount of active ingredient and one or more inactive
ingredients.
Case IIa
Strength 4mg 2mg
Active 4mg 2mg
InAct 1 38mg 38mg
InAct 2 58mg 58mg
Total 100mg 98mg
Case IIb
Strength 4mg 2mg
Active 4mg 2mg
InAct 1 40mg 40mg
InAct 2 56mg 58mg
Total 100mg 100mgSONIA
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34. Special mention
The bioeuivalence study should in general be conducted at a higher
strength
 Lower strength acceptability
Linear pharmacokinetics and the Drug substance is highly soluble
Safety and tolerability issue of higher strength in healty volunteers
 Higher dose acceptability - EMA
Due to problems of sensitivity of analytical methods.
 Bracketing Approach -EMA
Bioequivalence assesement at more then two strengths e.g. because
of deviation from proportional composition.
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35. Special mention....... Contd
 In-vitro dissolution study
QC method is acceptable
Otherwise, perform dissolution tests in atleast three medias (pH 1.2,
4.5 & 6.8, 7.5)
The F2 test is used to compare the dissolution profiles of diffrent
strengths.
An F2 value of > 50 indicates a sufficiently similar dissolution profile
to support a biowaiver
Acceptable benefit–risk balance in terms of public health and
risk to the individual patientSONIA
NAGVENKAR

36. Summary
Biowaiver procedure is a surrogate method of evaluating
bioequivalence of generic products
BCS Based Biowaivers
Just by belonging to Class I/III and/or fulfilling dissolution criteria does
not entitle a product eligibility for a biowaiver approval
Biowaiver decision can be arrived upon after evaluating the
biopharmaceutical and clinical properties of the drug and the product.
NTIs are NOT biowaiverable
If critical excipients are used , then explanation regarding their choice
and amounts need to be given to the regulatory authorities
Dose -Proportionality Biowaivers
Dose - proportionality across the strengths should be maintained.
In-vitro dissolution profile should be similar across the strengths.
The risk of a false biowaiver decision should not
outweigh the benefits of a biowaiver procedure
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37. • http://www.who.int/medicines/services/expertcommitte
es/pharmprep/QAS04_093Rev4_final.pdf
• https://www.fda.gov/downloads/Drugs/Guidances/ucm0
70246.pdf
• http://www.ema.europa.eu/docs/en_GB/document_librar
y/Scientific_guideline/2010/01/WC500070039.pdf
• http://www.fip.org/bcs_monographs
• http://www.ema.europa.eu/docs/en_GB/document_librar
y/Scientific_guideline/2009/09/WC500003010.pdf
References..............
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