Download OVERVIEW OF DACA BIOEQUIVALENCE REPORT EVALUATION

OVERVIEW OF DACA
BIOEQUIVALENCE REPORT
EVALUATION
Presented by
Solomon Shiferaw
31Augst 2010
Objectives

To provide an overview on the bioequivalence
requirement for registration.

To highlight the application assessment for inter
changeability of multi-source generic product in
FMHACA

To show the constraints for assessment of BE in
FMHACA
Introduction

Regulatory Authority Mission
 “To
assure that Safe and Effective
drugs are marketed in the country
and are available to the people”
Introduction

Multi-source drug products need to conform
to the same standards of quality, efficacy and
safety required of the originator's products.

A reasonable assurance must be provided
that they are, as intended, clinically
interchangeable with nominally equivalent
market products.
Introduction cont.

Assessment of equivalence will normally
require


an in vivo study, or
a justification that such a study not be required in
a particular case.
Documentation of equivalence for MA

Pharmaceutically equivalent multi-source
pharmaceutical products must be shown to
be therapeutically equivalent to one another
in order to be considered interchangeable
Documentation of equivalence for MA
Bioequivalence:
BE study
(In most case)
Comparative CT
Approach for
establishing
equivalence
Comparative PD study
In-vitro dissolution study
Documentation of equivalence for MA
•
Acceptance of any test procedure depends
on factors like characteristics of the active
drug substance and drug product
•
concentrations in an accessible fluid (eg plasma)
•
Evidence on vitro/in vivo correlation
•
Solubility & Permeability of API, etc
General organization of the document
for BE

Names and affiliations of the responsible investigator (s) and
analyst (s)

Site of the study


Accreditation of the BE site by Local DRA

Detailed information on clinical and analytical facilities of the
institution (s)
Period of its execution of BE study
General organization of the document
for BE cont.

The names and B. No. of the products used
in the study as well as the composition of the
test product

Analytical validation report

The responsible investigator (s) should sign
for their respective section of the report
General organization of the document
for BE cont.

The applicant should submit a signed
statement confirming the identity of the test
product with the pharmaceutical product,
which is submitted for registration
The report of In-vivo BE should include

Study Protocol

Summary of the study

Objectives
The report of In-vivo BE should include

Subjects



subjects should be as homogeneous (healthy
volunteers in order to reduce variability other than
in the pharmaceutical products)
a clear criteria for inclusion/exclusion
non smokers & with out a history of alcohol or
drug abuse problems
The report of In-vivo BE should include

Subject cont.

volunteers screening





standard laboratory tests,
a medical history and
physical examination
Age range of 18-55 with a weight with normal
range
In most cases 18-24 subjects but NLT 12
The report of In-vivo BE should include

Design considerations
Compare
performance
of the
two formulations
Minimize variability
except attribute
to formulation
Minimize bias
The report of In-vivo BE should include

Study design






Cross over design Vs Parallel Design
Randomization
Standardization (exercise, diet, fluid intake,
restriction of intake)
Single dose Vs Multiple dose
Number of treatment group
Treatment periods
The report of In-vivo BE should include

Study design cont.

wash out period (NLT 5 t1/2)

Doses, rout of administration

Sampling times and method for collection of
samples
The report of In-vivo BE should include

Chemical Analysis


Method used to determine plasma conc. Of drugs
Should be




Accurate & Precise
Selective & Sensitive and
Reproducible
The results of Bioanalytical Method Validation
The report of In-vivo BE should include

Test Product



Identical to the projected commercial
pharmaceutical product
Bio-batch (industrial (ideal), pilot scale)
Reference Product (comparators)


Innovator product
Market leader product( Registered in Ethiopia)
The report of In-vivo BE should include

Results

All results (raw data)

Sufficiently detailed statistical and/or any other
procedures for calculating the parameters used

Clinical findings

Representative chromatograms
The report of In-vivo BE should include

Results cont.
Pharmacokinetics Parameters
AUC
Measure of the extent of absorption
Criteria: 80 -120
C max
Measure of rate of absorption
Criteria: 80 - 120
T max
Measure of rate of absorption
BE is not required for

Aqueous solutions

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Intravenous solutions
Intramuscular, subcutaneous solutions
Oral solutions
Ophthalmic or otic solutions
Nasal spray
Powder for reconstitution as a solution
Gases
Inhalation & nasal preparation
Topical products
BE study required for

Systemic application of such product require
BE study


Oral immediate release product
Non-oral and Non-parenteral products



Eg. transdermal patches, suppositories
Sustained or modified release products
Fixed combination products
In-Vitro dissolution study

Under certain conditions Like

Highly soluble and permeable


Different strength of the same formulation ( BE
done for 1 strength (usually for higher strength)



BCS class I
Same qualitative composition
Same ratio of active ingredients and excipients
Basket Or Paddle
In-Vitro dissolution study

Media for comparative dissolution



pH 6.8 buffer
pH 4.5 buffer
pH 1.2 buffer or 0.1NHCl
In-Vitro dissolution study

Difference factor(f1)
f1 = sum IRt-TtI/sum Rt x100
f1 should NMT 15

Similarity factor(f2):
f2 = 50.Log( 1/ (1+1/nx sum(Rt-Tt)2)1/2x100)
f2 should NLT 50
Challenges in BE Evaluation




Lack of adequate experience and training on
BE evaluation
Lack of comparators reference products
The guideline is not exhaustive
Limited access to the reference materials