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BA/BE Overview:

Continuing Equivalence
Erika Stippler, Ph.D.

Drug Release The Rate Limiting Step

Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003

BCS Concept

Published

by Amidon and co-workers 1995


Biopharmaceutics Classification System is a
scientific framework for classifying drug
substances based on their aqueous solubility
and intestinal permeability
The aim is to optimize the development of oral
dosage forms relying only on rate limiting
factors for absorption

Biopharmaceutical Drug Classification


System (BCS)
Class
I
II
III
IV

Solubility
High
Low
High
Low

Permeability
High
High
Low
Low

Solubility directly influences the dissolution behavior of oral


dosage forms in gastrointestinal tract

Biopharmaceutics Classification System

Human Permeability

10

Gastric emptying
determines on-set of
absorption

II

Dissolution likely
to be rate limiting

1.0

III

IV

Absorption might be:


- incomplete
- sensitive to
certain excipients

0.1

Generally problem
molecules

0.01
1

10

100

1000

10000

100000

Volume of water (ml) required to dissolve the highest dose strength at


pH 1.2 - 8

Dissolution Testing Requirements for in vitro BE


FDA

EMA

WHO

Apparatus

USP App. 1
USP App. 2

Basket
Paddle

Basket
Paddle

Dissolution
media

0.1 N HCl or SGF


Buffer pH 4.5
Buffer pH 6.8 or SIF

Buffer pH 1.0 or SGF


Buffer pH 4.5
Buffer pH 6.8 of SIF

Buffer pH 1.2
Buffer pH 4.5
Buffer pH 6.8

Use of enzymes is allowed


in case of gelatin capsules
or gelatin coated tablets

Absolutely no addition
of surfactant or
enzymes is allowed

Int. Ph. Buffers are


preferred

Volume

900 ml

900 ml or less

900 ml or less

Temperature

37C 0.5C

37C 1C

37C

Agitation

Basket: 100 rpm


Paddle: 50 rpm
alternatives to be justified

Basket: 100 rpm


Paddle: 50 rpm

Basket: 100 rpm


Paddle: 75 rpm

Sampling time

10, 15, 20, 30 min

10, 15, 20, 30, 45 min

10, 15, 20, 30, 45, 60 min

Sample #

12

12

12

Requirements

f2 50

50 f2 100

50 f2 100

Dissolution Characteristics of IR Drug Products


FDA

EMA

WHO

Very rapidly
dissolving

No definition

85%of the labeled


amount dissolves in
15 min

85%of the labeled


amount dissolves in
15 min or less

Rapidly
dissolving

85%of the labeled


amount dissolves in
30 min

No definition

85%of the labeled


amount dissolves in
30 min

Similarly
dissolving
(EMA)

No definition

85%of the labeled


amount dissolves
between 15 and 30 min

No definition

Test conditions

Paddle at 50 rpm or
Basket at 100 rpm in
900 ml or less of
0.1N HCl or SGF
Buffer pH 4.5
Buffer pH 6.8 or SIF

Paddle at 50 rpm or
Basket at 100 rpm in
900 ml or less of
0.1N HCl or SGF
Buffer pH 4.5
Buffer pH 6.8 or SIF

Paddle at 75 rpm or
Basket at 100 rpm in
900 ml or less of
Buffer pH 1.2
Buffer pH 4.5
Buffer pH 6.8

FDA-Requirements for BCS-based Biowaiver


Immediate

release drug products only

BCS-Class

I drug substance
Rapidly dissolving IR drug product
Test and reference drug product are pharmaceutically equivalent
Test and reference drug product exhibit similar dissolution profiles
Exclusions
IR

drug products considered not to have a narrow therapeutic index


Products designed to be absorbed in the oral cavity

EMA-Requirements for BCS-based Biowaiver


Restricted

for immediate release drug products considered not to


have a narrow therapeutic index
Case

Same drug substance BCS-Class I or different salt both BCS-Class I


either very rapid or rapid in vitro dissolution
Same excipients in similar amounts
Similarity of dissolution profiles
Case

II

Same drug substance BCS-Class III


very rapid in vitro dissolution
Same excipients in very similar amounts
Similarity of dissolution profiles

WHO-Requirements for BCS-based Biowaiver


WHO

Model List of Essential Medicines immediate release solid


oral dosage forms
Case

BCS-Class I drugs
very rapidly dissolving drug products (both test and reference)
rapidly dissolving drug products for which similarity of dissolution profiles was
demonstrated
Case

BCS-Class III drugs


very rapid in vitro dissolution
Same composition regarding excipients in both test and reference

WHO-Requirements for BCS-based Biowaiver


WHO

Model List of Essential Medicines immediate release solid


oral dosage forms
Case

BCS-Class II compounds with weak acid properties (high solubility at


pH 6.8 but not at pH 1.2 or 4.5 and with high permeability)
rapidly dissolving in pH 6.8 (both test and reference)
similar of dissolution profiles for both test and reference product in all three
buffer media (pH 1.2, 4.5, and 6.8)
Careful examination of type and amount of surfactant in the formulation

Dosage Form Performance Test - Dissolution


To

label a drug product as Bioequivalent test results must be


compared with an appropriate comparator

About

70% of orally administered immediate release essential


medicines (WHO List) are highly soluble drug products

Using

dissolution criteria as safe haven base, it is possible to develop


drug products with acceptable performance, as in MC <12>

There

will be always instances where dissolution it self may not be


sufficient, and may require clinical or bioequivalent study

Medicines Compendium, General Chapter <12>

NEW

CONCEPT for drug product performance

Non-solution

orally administered immediate release drug products


A partial solution for well-behaved IR drug products
Creates a default characterization for most IR drug products
Linked to the BCS classification of the drug substance

Details MC General Chapter <12>


Determine

the Solubility of the Drug Substance

Aqueous

media at pH 1.2 and pH 6.8


Maximum unit dose in 250 mL media
Room temperature, gentle stirring
High or low solubility
Determine
4

Dissolution Conditions

cases possible
Conduct dissolution tests

Dissolution Cases according to MC GC <12>


High

solubility in both pH 1.2 and 6.8

Conduct dissolution according to USP-NF <711> in each pH 1.2 and 6.8


App. 1@100 rpm or App. 2@50 rpm in 900 mL
Q=85% in 30 minutes
High

solubility in pH 1.2 only

Conduct dissolution according to USP-NF <711> in pH 1.2


App. 1@100 rpm or App. 2@50 rpm in 900 mL
Q=85% in 15 minutes
High

solubility in pH 6.8 only

Conduct dissolution according to USP-NF <711> in pH 6.8


App. 1@100 rpm or App. 2@50 rpm in 900 mL
Q=85% in 15 minutes
Low

solubility in both pH values

Product specific development needed


Suggestions on surfactant usage could be included

Evaluation of Drug Product Performance


Products

that meet the acceptance criteria may be considered:

To

perform optimally or
To be optimally available for in vivo absorption

Products that do not meet the acceptance criteria are


not

necessarily bad products,


require additional studies (i.e. in vivo studies) to demonstrate proper
performance

API with high solubility over the entire pH range formulated in


rapidly dissolving solid oral dosage forms can be considered
optimally bioavailable (OBA)

no need for a reference product to evaluate performance


17

What Would This Further Look Like?

Pharmaceutically equivalence

Highly soluble drug substance (API)

Then optimally bioavailable (OBA)


All O-BA are also BE
No comparator product; no comparison studies
Registration only
No regulatory review
Periodic inspection to assure conformity
Label OBA