Biowaivers, BCS Class 2 and 3 · –Class 4: Low Solubility / Low Permeability (LS/LP) •It is a...
Transcript of Biowaivers, BCS Class 2 and 3 · –Class 4: Low Solubility / Low Permeability (LS/LP) •It is a...
New Knowledge with Regard to
BCS and its Impact in the
Determination and Evaluation Criteria
for BA and BE Testing (Biowaivers)
Vinod P. Shah, Ph. D. Pharmaceutial Consultant
II Symposium: New Frontiers in Manufacturing
Technology, Regulatory Sciences and
Pharmaceutical Quality System Brasilia, Brazil, June 24-25, 2013
Bioavailability and Bioequivalence
• 1977: BA/BE Regulations – 21 CFR 320.
• Bioavailability: “ … the rate and extent to which the active ingredient
or active moiety is absorbed from a drug product and
becomes available at the site of action … “
• Bioequivalence: “ … as the absence of a significant difference in the
rate and extent to which the active ingredient or active
moiety in the pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the
site of drug action when administered at the same
molar dose under similar conditions …”
Drug Regulations
• Pharmaceutical Sciences - Provided the scientific basis for the 1984 Drug
Price Competition Act, providing statutory
authority for FDA BE based approval of new
generic drugs, - provided scientific basis for
accepting BE studies as a surrogate for clinical
studies.
• Using the principles of BCS, provided
justification for drug approval based on in vitro
information.
Thank You for
Your Attention
Generic Drug Products
• FDA ensures that the generic drug products are
safe and effective, are pharmaceutically
equivalent and bioequivalent to the brand-name
counterparts.
• Generic drugs have to meet the same rigid
standards as the innovator drug. Be manufactured
under the same strict standards of FDA’s good
manufacturing practice regulations required for
innovator products.
• This provides the drug product AB rating –
product to be TE = TI.
Immediate Release Products
• A single dose fasted study comparing the
highest strength of test and reference
product
• Food effect study, if required (labeling)
• Must meet BE requirements - criteria
• In vitro drug release
Modified Release Drug Products
• Single dose study is considered more
sensitive in assessing the drug product
quality - release of the drug substance from
the drug product into circulation
• A multiple-dose BE study for MR dosage
forms is not generally recommended
Extended Release Products
ANDA: BE Studies
• A single dose fasted study comparing the
highest strength of test and reference
product
• A food-effect study comparing highest
strength of Test and Reference Product
• Must meet BE requirements (criteria)
• In vitro drug release
Bioavailability and Bioequivalence
• 1977: BA/BE Regulations – 21 CFR 320.
• Bioavailability:
“ … the rate and extent to which the active
ingredient or active moiety is absorbed from a
drug product and becomes available at the site of
action … “
• Bioequivalence:
“ … as the absence of a significant difference in
the rate and extent to which the active ingredient
or active moiety in the pharmaceutical equivalents
or pharmaceutical alternatives becomes available
at the site of drug action when administered at the
same molar dose under similar conditions …”
Challenges for BE
• Highly Variable Drugs
• Narrow Therapeutic Index Drugs
• Multiphasic Extended Release Drug
Products
Highly Variable Drugs
• HVD: Drugs for which within-subject variability in
AUC and/or Cmax is >30%
• Safe drugs but have difficult BE criteria
----------------
• Characteristics of Highly Variable Drug Substances
– Poor and variable absorption
– Extensive pre-systemic metabolism
– Food effects
– Low oral BA
– Instability in GI tract
– Poor aqueous solubility
Highly Variable Drugs Recommended Approach for BE
• Reference-scaled average BE (ABE) for CV > 30%
– Three period, reference replicated, crossover study
design with sequences of TRR, RTR, RRT. Four
period design is acceptable.
– Minimum number of subjects 24
– PK measures - include Cmax, AUC0-t and A0-∞
– Widening of BE limits as a function of within subject
variability of the reference product. Point estimate
constraint, mean ratio between T and R should be
80-120. • Ref: SH Haidar et.al., Pharm Res. 25, 237-241, 2008
NTI Drugs
• What are NTI Drugs?
– Where a small difference in dose or blood
concentration may lead to serious therapeutic failures
and/or adverse drug reactions.
• NTI drugs generally have the following
characteristics
– Steep dose-response curves for both safety and
efficacy
– Subject to therapeutic monitoring based on PK or PD
measures
– Small within subject variability
NTI Drugs
• Drug product quality requirements
- identity, purity, assay and other quality
attributes and rigid standards of GMP;
- assay potency limits: proposed 95-105%
instead of 90-110% and USP <905> content
uniformity
• BE Criteria
- 90% CI of geometric mean ratio of AUC and
Cmax between T and R proposed to change to
90-111% instead of 80-125%.
NTI Drugs (Proposed) ACPS: July 26, 2011
BE Studies:
• Two treatment, four period replicated crossover design to
quantify the variability of both T and R products and use
reference scaled average BE approach for determination of
BE.
• The BE limits would change as a function of within subject
variability of the reference product. FDA proposes for NTI
drugs that the default BE limits be 90-111% and that they be
scaled using a regulatory constant of sigma 0 = 0.1 (which
corresponds to a CV of 10.03%).
• Point estimate limits for Cmax and AUC and a requirement
that 90% CI of T/R Cmax and AUC ratios include 100%.
Multiphasic MR Dosage Forms
• Multiphasic MR dosage form comprised of IR and
DR and/or ER portions, e.g., Zolpidem ER tablet
– Exhibits biphasic absorption characteristics
– Treatment of insomnia, difficulties with sleep onset
and/or maintenance
– IR portion is needed for rapid onset of activity
– DR or ER portion is needed to sustain the activity
• BE requirements include
– Additional measure of pAUC in BE studies
(For Zolpidem ER AUC0-1.5)
– Four BE metrics (BE limits of 80-125) are needed:
Cmax, AUC0-T, AUCT-t and AUC0-∞
Biowaiver
The term biowaiver is applied to a regulatory
drug approval process when the dossier
(application) is approved based on evidence
of equivalence other than in vivo
bioequivalence test.
For solid oral dosage forms, Biowaiver(s) is
generally based on a dissolution test.
Guidance for Industry
Waiver of In Vivo Bioavailability and
Bioequivalence Studies for
Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics
Classification System http://www.fda.gov/cder/guidance/index.htm
August 2000
Biopharmaceutics Classification System
• It is a framework for classifying drug substance
based on its solubility and permeability
• Drug Substance (API) classified into 4 classes:
– Class 1: Highly Soluble / Highly Permeable (HS/HP)
– Class 2: Low Solubility / Highly Permeable (LS/HP)
– Class 3: Highly Soluble / Low Permeability (HS/LP)
– Class 4: Low Solubility / Low Permeability (LS/LP)
• It is a drug development tool to justify ‘biowaiver’ in
conjunction with the dissolution of the drug product.
GL Amidon, H Lennernas, VP Shah, JR Crison. A theoretical basis for a
biopharmaceutics classification system: The correlation of in vitro drug
product dissolution and in vivo bioavailability.
Pharm Res. 12: 413-420, 1995
Biopharmaceutics Classification System
Drug Substance
Solubility
Permeability
High
High
Drug Product Dissolution
Very Rapid
Low
Low
Rapid
Slow
Waiver of in vivo BA & BE for
IR drug products based on BCS
• Criteria for biowaiver
– Highly soluble: Highest dose soluble in 250 ml in
pH 1.2 – 6.8
– Highly permeable: extent of absorption greater
than 85%
– Rapidly dissolving: 85% or greater by basket
method 100 rpm or paddle method 50 rpm in 900
ml in pH 1.2, 4.5 and 6.8
• For a waiver of BE, T and R products
should exhibit similar dissolution profile
FDA Guidance - Waiver for Class 1 Drugs
World Health Organization
Multisource (generic) pharmaceutical
products: guidelines on registration
requirements to establish
interchangeability
WHO Technical Report Series, No. 937, 2006
Annex 7, p 347 - 390
Dissolution Test (BCS)
Multisource (test) and
Comparator (reference) product • Paddle method at 75rpm (WHO) or 50rpm (FDA)
or Basket method at 100 rpm in pH 1.2, 4.5, 6.8
• Dissolution profile similarity
Dissolution Characteristics:
• Very rapidly dissolving – 85% in 15 min
• Rapidly dissolving – 85% in 30 min
• Slowly dissolving – more than 30 min for 85%
dissolution
(Bio)-Equivalence Test
Equivalence test is a test that determines the
equivalence between the multisource (test) product
and the comparator (reference) product using in
vivo and/or in vitro approaches.
In Vitro Equivalence Test
In vitro equivalence test is a dissolution test that
includes dissolution profiles comparison between
the multisource product and the comparator product
in three media: pH 1.2, 4.5 and 6.8.
Ref: WHO Technical Report Series, No. 937, 2006, Annex 7, p 347 - 390
BCS Class 1- HS/HP - Biowaiver
• Rapid dissolution
- 85% or greater in 30 minutes or less in
pH 1.2, 4.5 and 6.8 (profile comparison
with reference, similarity factor f2 > 50)
• Very rapid dissolution
- 85 % or greater in 15 minutes or less
in pH 1.2, 4.5 and 6.8 (no need for
profile comparison)
BCS Class 2 – LS/HP - Biowaiver *
(For weak acids)
• Rapid dissolution – 85% or greater in 30
minutes or less in pH 6.8 and
• The test product exhibits similar dissolution
profiles to the reference product in pH 1.2,
4.5 and 6.8
WHO Technical Report Series, No. 937, 2006, Annex 7, p 347 - 390
BCS Class 3 – HS/LP – Biowaiver *
• Test and reference products are very rapidly
dissolving – 85% dissolution in 15 minutes
or less in pH 1.2, 4.5 and 6.8
• The dosage form do not contain any inactive
ingredients that are known to alter GI
motility and permeability
* WHO Technical Report Series, No. 937, 2006, Annex 7, p 347 - 390
BCS Based Biowaiver *
• Well established excipients
• Excipients should NOT alter GI motility and drug
absorption kinetics
– Excipient is also present in comparator or
– Excipient is present in a number of drug products
having a registration in ICH-country
• in amount usual for dosage form
• FDA inactive ingredient database
Ref: WHO Technical Report Series no. 937, 2006. Annex 7, pages 347 - 390.
Biopharmaceutics Classification System
A Tool For Risk Management
• BCS is a framework for identifying low-risk products based on
solubility, intestinal permeability (absorption) and dissolution.
• Minimize the risks associated for decisions on biowaivers
• Assessment of Risk
– Risk of bioinequivalence
– Likelihood of bioinequivalence occurrence and severity of
consequences
• Risk Factors
– Failure to emulate in vivo dissolution process
– Excipient modify GI motility/gastric emptying
The Biowaiver Project - Overview
• Genesis of biowaiver monographs
• Biowaiver – In vitro assessment to waive the need for in vivo bio-studies.
• Risk assessment
• Best scientific judgment about eligibility for BCS based biowaiver
• No direct implication, it provides a good starting point for the applicant – also as a source of information to regulators
• Eligibility for BCS-based biowaivers
– Solubility, Permeability and Dissolution
• Drug substances on WHO’s List if Essential Medicines
Biowaiver Monographs • Literature review – Solubility, permeability, dissolution,
bioequivalence data
– Review can suggest feasibility of biowaiver for a generic formulation
– Indicates criteria for in vitro equivalence test.
– Examples include BCS Class 1, 2, 3. About 30 monographs are published.
– Review can also indicate when biowaiver is not recommended, e.g.,
ciprofloxaxin, furosemide, mefloquin
• No formal regulatory status, but represents the best
scientific judgment
• Published in J Pharm Sci after peer review process
• Also made available on FIP web page and be downloaded www.fip.org
• API selected based on WHO list of essential drugs + other
important drugs
Biowaiver Monograph
• Process of developing Biowaiver monograph
– Document summarizing all known information
relevant to the application of biowaiver of API.
– Critical review - evaluation and reliability of all
relevant data in open scientific literature by core
authors
– Published as a commentary in Journal of
Pharmaceutical Sciences after peer review
process
– Also published/available on FIP website
Biowaiver Monographs
• More than 30 biowaiver monographs, ranging
from BCS class 1-4 have been prepared and
published.
• Biowaiver monographs are useful to applicants
as well as to regulators as a source of
information
• Reduces the cost of bringing generic product
into the market
• Improves patient access to affordable medicines
BCS Based Biowaivers*
• BCS Class 1: HS/HP
- VRD or RD in pH 1.2, 4.5 and 6.8
• BCS Class 2: LS/HP/Weak Acids
– Rapid dissolution in pH 6.8 and similar dissolution
profile in pH 1.2, 4.5 and 6.8
• BCS Class 3: HS/LP/VRD
– contains no inactive ingredients that are known to
alter GI motility and/or absorption
For biowaivers Test (multisource) and Reference (comparator)
products must have similar dissolution profile (f2) in all 3 media
*WHO Technical Report Series, No. 937, 2006, Annex 7, p 347 - 390
Dissolution Based Biowaivers
• Conventional Release Products
- Lower strengths, proportional formulations, f2
- BCS Class 1: HS/HP/RD
- BCS Class 2: LS/HP, Weak acids, HS in pH 6.8
- BCS Class 3: HS/LP/Very Rapidly dissolving
• Extended Release Products
- Lower strengths, proportional formulations
and same release mechanism
- Beads in a capsule - Profile comparison in
one medium
- Tablets - Profile comparison in pH 1.2, 4.5, 6.8
Quality by Design (QbD)
• QbD is essential part of modern approach to pharmaceutical
quality – it combines critical manufacturing process and
operating parameters.
• Space that encompasses combination of product design,
manufacturing process parameters and component
attributes that provide assurance of acceptable product
quality and performance.
• QbD means that product and process performance
characteristics are scientifically designed to meet specific
objectives, not merely empirically derived from performance
of test batches
– Janet Woodcock (2004)
Conclusions
• BCS principles provide a reasonable approach for
drug product approval without sacrificing the
drug product quality.
• BCS applications for Class 2 and 3 are challenging,
but at the same time provides opportunities for
lowering regulatory burden with scientific rational.
• BCS is used as a tool in product development to aid
decision making and risk assessment.
• BCS also provides an avenue to predict drug
disposition (BDDCS) - transport, absorption,
elimination.
Conclusions
Biowaiver
• Lowering regulatory burden,
provide regulatory relief without loss of
drug product quality
• Product approved based on in vitro data
Thank You for
Your Attention