Perspectives on Bioregulations (Bioavailability, Bioequivalence and

Biopharmaceutics Classification System)

Vinod P. Shah. Ph.D.

Pharmaceutical Consultant

Symposium

“New Frontiers in Manufacturing

Technology, Regulatory Sciences and

Pharmaceutical Quality System”

Organized by Sindusfarma, ANVISA and FIP/IPS

Brasilia, Brazil. June 25 and 26, 2012

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 …”

Bioequivalence – Drug Regulations

• Pharmaceutical Sciences

- Provided the scientific basis for the 1984 “Drug

Price Competition and Patent Term Restoration Act”

- Provided the statutory authority to FDA for BE

based approval of new generic drugs,

- Provided scientific basis for accepting BE studies

as a surrogate for clinical studies.

• Established present system of generic drug

approval process, ANDA - FDCA 505(j)

• Principles of BCS

- Provided justification for drug approval based on

in vitro dissolution studies.

Generic Drug Products

• The mission of a regulatory authority is to assure

that safe and effective drugs are marketed in the

country and are available to the people.

• FDA ensures that the generic drug products are

safe and effective, are pharmaceutically

equivalent and bioequivalent to the brand-name

counterparts – the same dose of the same active

ingredient, delivered in the same way, and

manufactured according to the same standards

of quality.

Generic Drug Product

• The drug product safety and efficacy for the

generic product is established by it being

pharmaceutically equivalent and

bioequivalent, and thus therapeutically

equivalent.

• The quality of the product is ensured thru

product identity, strength, purity, assay,

potency, content uniformity, dissolution (for

solid oral dosage forms) and being

manufactured under FDA’s good

manufacturing practice.

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

• 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

Lower Strengths - Biowaiver

Waiver based on dissolution profile similarity

• Conventional (Immediate) Release

- Formulation proportional

- Dissolution profile comparison with highest

strength under one condition.

• Extended Release

- Formulation proportional

- Same drug releasing mechanism

- Beaded capsules – dissolution profile comparison

with highest strength under one condition

- Tablets - dissolution profile comparison with

highest strength in pH 1.2, 4.5 and 6.8

Drug Approval Process

• ANDA - Generic Drugs

• Orange Book

– RLD

– Product rating, AB, BA

• Therapeutic Equivalence

The products are considered TE when they

meet regulatory criteria of PE and BE.

TE = Interchangeability between generic

product and reference product.

Guidance for Industry

Bioavailability and

Bioequivalence Studies for

Orally Administered Drug

Products General

Considerations http://www.fda.gov/cder/guidance/index.htm

March 2003

Multiphasic Modified Release

• For multiphasic modified release products

designed to have a rapid onset of drug action

followed by sustained response, an additional

metric of partial AUC is required. e.g., for Zolpidem

Tartrate Extended Release - (Ambien CR)

– The cutoff for partial AUCs may be determined on the

basis of the PK/PD or PK/response characteristics of the

product.

– BE requirement fir a generic product include: Cmax,

AUC0-last or AUC0-∞ and pAUC

BCS

Biopharmaceutics Classification System

Biopharmaceutics Classification System

• It is a framework for classifying drug substance based on its solubility and permeability

• It is a drug development tool to justify ‘biowaiver’ in conjunction with the dissolution of the drug product.

• It is a drug classification scheme that provides a basis for establishing IVIVC

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

• BCS is a scientific framework for classifying

drug substances based on their aqueous

solubility and intestinal permeability.

• BCS takes into account three major factors

that govern the rate and extent of

absorption from IR solid oral dosage

forms: dissolution, solubility and

intestinal permeability.

• BCS Guidance:

For IR drug products ;

Not applicable to NTI drug products

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

• BCS Class 1: Highly soluble/Highly permeable

• 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

Dissolution Test (BCS)

Test and Reference product

• Paddle method at 50rpm 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

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

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

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

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

BCS BDDCS

• Class 1: HS/HP

- Undergo metabolism

- Transporter effects

minimal

• Class 2: LS/HP

- Undergo metabolism

- Efflux transporter

effects predominate

• Class 3: HS/LP

- Mostly unchanged

drug in urine/bile

- Absorptive

transporter effects

predominate

• Class 4: LS/LP

- Mostly unchanged drug

in urine/bile

- Absorptive and efflux

transporters

predominate

Ref: C-Y Wu and LZ Benet, Pharm Res. 22: 11-23, 2005

BCS: Food Effect

• Class 1: HS/HP

- Extent: No change

- T max: Increase

• Class 2: LS/HP

- Extent: Increase

- T max: ?

• Class 3: HS/LP

- Extent: Decrease

- T max: Increase

• Class 4: LS/LP

- Extent: ?

- T max: ?

Ref: C-Y Wu and LZ Benet, Pharm Res. 22: 11-23, 2005

Conclusions

• Bioavailability and Bioequivalence Regulations

are science based

• Regulatory requirements have changed as

science has evolved.

• BCS principles provide a reasonable drug approval

approach by lowering regulatory burden without

sacrificing drug product quality.

• BCS also provides an avenue to predict drug

disposition (BDDCS) - transport, absorption,

elimination.

Thank You