OVERVIEW OF DACA BIOEQUIVALENCE REPORT EVALUATION
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Transcript 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
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