The document discusses bioequivalence (BE) and drug product assessment. It defines BE as the absence of a significant difference in the rate and extent to which the active drug becomes available at the site of action when administered at the same dose. BE studies are important for approval of generic drugs and ensure they have similar effects to brand drugs. The document outlines the objectives, need, types, and statistical evaluation of BE data. It also discusses important considerations for BE study design, bioanalysis, analyte selection, BE metrics, and statistical approaches.

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REGULATORY AFFAIRS
BE AND DRUG PRODUCT ASSESSMENT
RR COLLEGE OF PHARMACY
SUBMITTED BY: SUBMITTED TO:
PAWAN DHAMALA ASSOCIATE PROF. SRILATHA KS
1st Sem M.Pharm DEPARTMENT OF PHARMACEUTICS

2. Contents:
 Introduction of BE (Bioequivalence)
 Objectives
 Definition
 Need of Bioequivalence
Type of Bioequivalence
Statistical evaluation of bioequivalence data
Importance of Bioequivalence
 Drug Product Assessment
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Introduction
Bioavailability and bioequivalence studies provide important information in overall
set of data that ensure availability of safe and effective medicines.
The concept of bioavailability and bioequivalence have gained during last 3
decades.
Now it is very important for approval of brand name and generic drugs worldwide.
Bioequivalence is a relative term which denotes that the drug substance in two or
more identical dosage form, reaches the systemic circulation at the same relative rate
and relative extent.

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The sponsors have to include bioavailability (BA) and bioequivalence
(BE) information for drug products in INDs, NDAs, ANDAs, and their
supplements.
Studies to measure BA and/or establish BE of a product are important
elements in support of INDs, NDAs, ANDAs, and their supplements.
NOTE :BA and BE requirements is set forth in part 320 (21 CFR part
320)
Introduction (CONT….)

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Objectives
 The main objective is to measure and compare the
formulation performance between two or more
pharmaceutically equivalent drug product.

6. Definition
Bioavailability is defined in 320.1 (US-FDA) as:
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.
For drug products that are not intended to be absorbed into
the bloodstream, bioavailability may be assessed by
measurements intended to reflect the rate and extent to which
the active ingredient or active moiety becomes available at
the site of action.
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7. Bioequivalence is defined as :
By United State Food And Drug Administration (USFDA):
The absence of significant difference in the rate and extent to which
the active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action
when administered at the same molar dose under similar conditions in
an appropriately designed study.
By World Health Organization (WHO):
Two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent or pharmaceutical alternative, and their bio-
availabilities, in terms of rate (Cmax and Tmax) and extent of
absorption (Area Under Curve),after administration of the same molar
dose under same conditions, are similar to such a degree that their
effects can be expected to be essentially the same.
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8. Need of Bioequivalence
The need of bioequivalence studies is increasing due to the
large growth of the production and consumption of the
generic product,
Bioequivalence studies are conducted if there is:
a) A risk of bioequivalence or
b) A risk of pharmacotherapeutic failure
No clinical studies have been performed in patient with the
generic product to support its efficacy and safety.
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9. Types of equivalance
1. Chemical equivalence: Two or more drug product contain same
labelled chemical in a same amount.
2. Pharmaceutical equivalence: Two or more drug are identical in
strength, quality, purity, content uniformity ,disintegration &
dissolution.
3. Therapeutic equivalence: Indicate that two or more drug product
that contain the same therapeutically active ingredients & identical
pharmacological effect & control the disease to the same extent.
4. Bioequivalance: It is a relative term which denotes that the drug
substance in two or more identical dosage form, reaches the
systematic circulation at the same relative rate & relative extent.
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10. Statistical evaluation of bioequivalence data
• Statistical evaluation studies is based on analysis of drug blood or plasma
concentration.
• Area under the plasma conc. v/s time curve (AUC) is used as a index of extent of
drug absorption.
• In the early 1970s, approval was based on mean data. Mean AUC and Cmax
values for the generic product had to be within 20% of those of the brand name
product.
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11. Importance of Bioequivalence
A major strategy for lowering the cost of medication, and
thereby reducing its contribution to total health care costs, has
been the introduction of generic equivalents of brand-name
drugs (innovator drugs).
BA/BE studies is a strategy to introduce this strategy to
lower the cost of medication through proper assessment as
directed by the international regulatory authorities.
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12. 1. STUDY DESIGN
Successfully determining the BE of generic drugs to their respective
reference drugs depends mostly on design and managing the conduct
of study such that the highest quality samples are obtained.
Some regulatory authorities are provide information about Reference
Listed Drug (RLD) on their websites, which makes it easy to proceed
with BA/BE study design
Attention should be paid to selecting as well as collecting the
appropriate reference product details.
NOTE: Generally the study design depends on the RLD information ,
physico-chemical and pharmacokinetic properties of the drug, and
regulatory requirements of the country.
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2. BIOANALYSIS
Bioanalysis should be the subsequent step following clinical
operations of the study
Bioanalysis is a term generally used to describe the
quantitative measurement of a compound (drug) or its
metabolite in biological fluids
Bioanalysis typically consists of two important components
a)Sample preparation and
b)Detection of the desired compound using a validated method.

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3.SELECTION OF APPROPRIATE ANALYTE
Each regulatory authority has its own specifications for
selection of an appropriate analyte to be measured as well as
consideration for BE.
The investigator should consult the relevant regulatory
agency for guidance on a particular therapeutic agent.
Generally considerations are:
Parent drug v/s metabolite(s)
Enantiomers v/s racemates
Drug products with complex mixtures

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4. BE METRICS AND DATA TREATMENT
The most frequent data treatment involves analysis of
variance using a suitable program such as SAS® (Statistical
Analysis System) or WinNonlin®.
By these methods contributions from subject, period,
formulation, and interactions between these can be examined.
Geometric mean ratios and log transformed data are
examined like interval of extent (AUC 0–t and AUC 0–∞) and
the maximum concentration (Cmax) fall within the acceptance
limits of 80% to 125%.

16. 5. STATISTICALAPPROACHES
The various pharmacokinetic parameters derived from the
plasma concentration–time curve are subjected to ANOVA
The classical null hypothesis test is the hypothesis of equal
means,
H0: μT = μR (ie, products are bioequivalent), where , μT
and μR represent the expected mean bioavailabilities of the
test and reference products, respectively.
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17. References:
1) Biopharmaceutics and Pharmacokinetics by D.M. BRAHMANKAR (Msc. Phd.)
2) www.goggle.com
3) http://en.wikipedia.org/wiki/Bioequivalances
4) https://www.sciencedirect.com/topics/medicine-and-dentistry/bioequivalence
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