Work Sample#1Regulatory_Requirements-BABE-Studies

Bioavailability & Bioequivalence
studies
General Considerations for
Orally
Administered Drugs
KIREETI BHEEMAVARAPU MSc (IPSc), MSc (Chemistry)

CONTENTS
• Background
• Methods to document BA & BE
• Comparison of BA measures in BE studies
• Documentation of BA & BE
• Special Topics

0 1 2 3 4 5 6 7 8 9 10 11 12
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1
2
3
4
5
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Duration of action
Therapeutic range
Minimum effective concentration
Maximum safe concentration
Elimination phaseAbsorption
phase
Averageserumconcntration(mcg/ml)
Time after drug administration (h)
Cmax
SERUM CONC. vs TIME

BACKGROUND
• Bioavailability is defined in § 320.1 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.”

PHARMACO-KINETIC PERSPECTIVE
• Estimate of the relative fraction of the dose in
systemic circulation (vs Solution, suspension
or Intravenous)
• ADME information
• Nutrients effect on absorption
• Dose proportionality
• Linearity of Pharmacokinetics

REGULATORY OBJECTIVE
• The performance of the formulations used in the
clinical trials provide evidence of safety and efficacy
(21 CFR 320.25(d)(1)).
• Focus on using relative BA (referred to as product
quality BA) and, in particular, BE studies as a means to
document product quality.
• In vivo performance in terms of BA/BE, can be
considered to be one aspect of product quality that
provides a link to the performance of the drug product
used in clinical trials and to the database containing
evidence of safety and efficacy.

BIO-EQUIVALENCE
“ the absence of a 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”

• INDs/ NDAs
• ANDAs
• Post Approval Changes
REQUIRED FOR

BE for INDs/NDAs
To establish links between:
(1) early and late clinical trial formulations;
(2) formulations used in clinical trial and stability
studies, if different;
(3) clinical trial formulations and to-be-
marketed drug product; and
(4) any other appropriate comparisons

POSSIBLE OUTCOMES
Note: *
CASE (1)
CASE (2)

REGULATORY CONCERN
Case (1) :
Test product generates plasma levels that are
substantially above those of the reference
product
Concern: Not therapeutic failure, but the
adequacy of the safety database from the test
product

REGUATORY CONCERN
Case (2) :
The test product has levels that are substantially
below those of the reference product
Concern: Therapeutic Efficacy
Case (3):
Variability of the test product
Concern: Ensuring safety & Efficacy
Contd..

• Individual dose response Curves
• Population dose response Curves
• Concentration dose response curves
“ Burden is on the sponsor to demonstrate the
adequacy of the clinical trial dose-response or
concentration-response data to provide
evidence of therapeutic equivalence.”
For Case (3) the FDA needs :

ANDA
Purpose:
“To demonstrate BE between a
pharmaceutically equivalent generic drug
product and the corresponding reference
listed drug (21 CFR 314.94 (a)(7)).”
BE + Pharmaceutical equivalence  Therapeutic
equivalence

POST APPROVAL CHANGES
• Immediate release dosage forms
• Modified release dosage forms
“ Requirements of in vitro dissolution & in vivo
BE studies depend on the type (level 1,2,3) –
Ref: corresponding detailed guidance from
FDA”

METHODS TO DOCUMENT BA & BE
§ 320.24 - Invitro & in vivo methods used to
measure product quality and establish BE
1) Pharmaco-kinetic study
2) Pharmacodynamic Study
3)Comparative clinical studies
4)In-vitro studies

Comparison of BA measures in
BE studies
FDA’s Approach:
(1) a criterion to allow the comparison,
(2) a confidence interval for the criterion, and
(3) a BE limit

DOCUMENTATION OF BA & BE
• An in vivo study is generally recommended for
all solid oral dosage forms approved after
1962 and for bioproblem drug products
approved before 1962.

BIO WAIVER
§ 320.22(d)(2):
1) the drug product is in the same dosage form,
but in a different strength;
2) this different strength is proportionally similar in
its active and inactive ingredients to the strength
of the product for which the same manufacturer
has conducted an appropriate in vivo study; and
3) the new strength meets an appropriate in vitro
dissolution test.

PROPORTIONALLY SIMILAR
1) All active and inactive ingredients are in exactly
the same proportion between different
strengths if not,
2) ratios of inactive ingredients to total weight of the
dosage form are within the limits defined by the
SUPAC-IR and SUPAC-MR guidance up to and
including Level II
3) For high potency drug substances, where the
amount of the active drug substance in the dosage
form is relatively low, the total weight of the
dosage form remains nearly the same for all
strengths (± 10 % of the total weight of the
strength on which a biostudy was performed)

DOSAGE FORMS
Solutions:
• For oral solutions, elixirs, syrups, tinctures, or
other solubilized forms, in vivo BA and/or BE can
be waived (21 CFR 320.22(b)(3)(i)).
• Generally, in vivo BE studies are waived for
solutions on
“ release of the drug substance from the drug
product is self-evident and that the solutions do
not contain any excipient that significantly affects
drug absorption” (exceptions - Sorbitol, Mannitol)
Contd....

Suspensions:
• BA BE for immediate release solid orals
• Both Invivo & invitro studies are
recommended.
Capsules & Tablets (Immediate release):
• Single dose fasting study –Focus on release of
DS into Systemic circulation) &
• Invitro dissolution profiles on all strengths of
each product.
• ANDAs: BE Test vs RL product (strength-Orange
book)

DIFFERENCE FACTOR
The difference factor (f 1) calculates the
percent (%) difference between the two
curves at each time point and is a mea-
surement of the relative error between the
two curves:

SIMILARITY FACTOR (f2)
n = number of time points
R(t) = mean % API dissolved of reference product
at time point x
T(t) = mean % API dissolved of test product at
time point x
Range : 0-100

PRE-APPROVAL BIOWAIVERS
In vivo BE demonstration of one or more lower
strengths can be waived based on dissolution
tests and an in vivo study on the highest
strength when
“drug product is in the same dosage form, but
in a different strength, and is proportionally
similar in its active and inactive ingredients to
the strength on which BA or BE testing has
been conducted”
Contd...

Biowaiver for Higher strength for NDA is
based on :
(1) clinical safety and/or efficacy studies
including data on the dose and the
desirability of the higher strength,
(2) linear elimination kinetics over the
therapeutic dose range,
(3) the higher strength being proportionally
similar to the lower strength, &
(4) the same dissolution procedures being used
for both strengths and similar dissolution
results obtained
Contd....

DISSOULTION NOT DEPENDENT ON STRENGTH
• Dissolution profile from one medium are
enough to support waivers or profiles from
three media (PH 1.2, 4.5 & 6.8) are needed
• F2 test is used to compare profilesdifferent
strengths of the product
• F2 ≥ 50 – no further in vivo studies are
needed.
• Not suitable for rapidly dissolving drug prod-
ucts (e.g., > 85% dissolved in 15 minutes or
less).
Contd.....

“Invivo studies are NOT required for high-
est strength” for an ANDA if :
1) Linear elimination kinetics has been shown over
the therapeutic dose range
2) The higher strengths of the test and reference
products are proportionally similar to their
corresponding lower strength.
3) Comparative dissolution testing on the higher
strength of the test and reference products is
submitted and found to be appropriate

POST APPROVAL: NDAs & ANDAs
• SUPAC –IR provides specific guidance.
• Eg: Looking at level 2 change
BCS class II (LS/HP):
In vitro dissolution (pH 1-7.4) Multiple profiles – f2
≥ 50
BCS class IV (LS/LP):
In vivo – AUC & Cmax: 80-125% (90% CI )

MODIFIED RELASE PRODUCTS
• Delayed release products
• Extended (controlled) release products

NDAs : BA –BE
§ 320.25(f)- BA requirements
• Purpose: The drug product meets the controlled-
release claims made for it.
• The BA profile established for the drug product rules
out the occurrence of any dose dumping.
• The product’s steady-state performance is equivalent
to a currently marketed noncontrolled release or
controlled-release drug product that contains the same
active drug ingredient or therapeutic moiety of
approved NDA
• The drug product’s formulation provides consistent
pharmacokinetic performance between individual
dosage units

TYPE OF STUDIES
• A single-dose, fasting study on all strengths of
tablets and capsules and highest strength of
beaded capsules
• A single-dose, food-effect study on the highest
strength
• A steady-state study on the highest strength
• BE studies : “substantial changes in the
components or composition and/or method of
manufacture for an extended-release drug
product occur between the to be-marketed NDA
dosage form and the clinical trial material”

ANDAs: BE Studies
(1) a single-dose, nonreplicate, fasting study
comparing the highest strength of the test and
reference listed drug product and
(2) a food-effect, non replicate study comparing
the highest strength of the test and reference
product

Tablets:
When “Proportionality” applies:
• In Vivo study for the highest strength
• Waiver for lower strengths with comparison
of dissolution with higher strengths
• “Similar” dissolution profiles ( f2 ≥ 50 ) in three
dissolution media (pH 1.2, 4.8 & 6.8)
Post Approval Changes :
• SUPAC- MR guidance applies
• Invitro – Prechange vs Post change product

BIO WAIVERS (BE) : NDAs &
ANDAs
Beaded Capsules:
• Strength – no. of beads
• BE study – for Highest Strength is sufficient.
• Bio Waiver for lower strengths based on
dissolution profiles
• F2 ≥ 50

MISC. DOSAGE FORMS
1) Rapidly dissolving drug products –buccal &
sublingual usage:
2) Both in vivo BA & /BE and in vitro dissolution:
WHY?

SPECIAL TOPICS
FOOD - EFFECT studies:
1) Influence of Co-administation of food with
oral dosage forms
2) BA studies – focus on effect of food drug
release
3) BE demostration – comparable BA (test vs
ref.) when coadministered with food
4) Single dose, two period, two sequence
corssover study.

MOIETIES MEASURED
• Parent drug vs metabolities
• BA Studies- Concentration & Activity
• BE studies –Parent drug preferred. WHY?
Except :
=>Low Parent drug levels –Analysis problems
2) Pre-systemic Metabolism
Contd...

Enantiomers vs Racemates:
“BA studies: Individual enantiomers
BE Studies: Measurement of racemate”
Individual enantiomers are preferred when :
• Enantiomers exhibit different PK /PD
characteristics,
• Primary efficacy and safety activity re-
sides with the minor enantiomer, &
• Nonlinear absorption is present for at least
one of the enantiomers Contd.....

COMPLEX MIXTURES AS “ACTIVE”
• Some or all of the APIs can’t be characterized
with regard to chemical structure /activity
• Case by Case basis
• BA and BE studies be based on a small number
of markers of rate and extent of absorption
• Possibility of pharmacodynamic or clinical
approach

LONG HALF LIFE DRUGS
• Adequate characterization of half life
• Non-replicate single dose cross over
• Parallel study when cross over is not feasible
• Sample collection time – gastro-intestinal
transit (2-3 days )
• Truncated Curve: AUC 0-72 hr
• Intra subject variability issue.

FIRST POINT Cmax
• First point of concentration time curve –
reflects Cmax
• Early sampling times ? insufficient sampling?
Better sampling approach :
• Initial 5-15 min after administration
• Additional 2-3 samples in the first hour

BE LIMITS FOR GENERIC NTI DRUGS

REFERENCES
1) www.FDA.gov
2) * - Taken from the work of LAWRENCE YU,
Acting Director – Office of Pharmaceutical
science FDA.

Work Sample#1Regulatory_Requirements-BABE-Studies

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