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