Bioavailability and Bioequivalence

General concepts and overview

WHAT IS IT???

WHY IS IT???

HOW IS IT???

REGULATION VERSUS PHARMACEUTICAL COMP.

 Generic Drug product: Definition
Same active ingredient (s)
Same strength
Same dosage form
Same route of administration
Same indications
 NDA vs. ANDA Review Process
Original Drug Generic Drug
NDA Requirements ANDA Requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies 6. Bioequivalence Study (In Vivo, In
7. Clinical Studies vitro)
(Bioavailability)
Note: Generic drug applications are termed "abbreviated" because they are generally
not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
Instead, generic applicants must scientifically demonstrate that their product is bioequivalent
(i.e., performs in the same manner as the origina; drug).
FDA Definitions Used in Bioequivalence
Determinations
 FDA Determinations of Bioequivalence
Main Terms

Pharmaceutical equivalents
Pharmaceutical alternatives
Therapeutic equivalents
Bioavailability
Bioequivalence
 Pharmaceutical Equivalents
Drug products are considered pharmaceutical
equivalents if they contain the same active
ingredient(s), have the same dosage form and route of
administration, and are identical in strength or
concentration
Equivalent products contain the same amount of
ingredient in the same dosage form but may differ in
characteristics, such as shape, release mechanisms,
and packaging
 Pharmaceutical Alternatives
Drug products are considered pharmaceutical alternatives if
they contain the same therapeutic moiety, are different
salts, esters, or complexes of the same moiety, are different
dosage forms, or are different strengths
Other pharmaceutical alternatives
Different dosage forms and strengths within a single product line by a
single manufacturer
Extended-release formulations when compared with immediate- or
standard-release formulations
 Therapeutic Equivalents
Drug products are considered therapeutic equivalents if they
are all of the following
Pharmaceutical equivalents
Bioequivalent
Approved as safe and effective
Adequately labeled
Manufactured in compliance with current Good Manufacturing Practice
regulations
Therapeutic equivalents are expected to have the same
clinical effect and safety profile
 Bioavailability
(quantifies ABSORPTION = ?, Reasons for poor F)

The extent and rate at which its active moiety is

delivered from pharmaceutical form and becomes
available in the systemic circulation
Pharmacokinetics
conc. vs time
Conc.(mg/L)

0.0
0 25
Time (h)
 Why do we care about BIOAVAILABILITY?
The true dose is not the drug swallowed;
BUT is the drug available to exert its effect.
Dissolution
Absorption
Survive metabolism
May have a drug with very low bioavailability
Dosage form or drug may not dissolve readily
Drug may not be readily pass across biological
membranes (i.e. be absorbed)
Drug may be extensively metabolized during
absorption process (first-pass, gut wall, liver)
Important component of overall variability
Variable bioavailability may produce variable exposure
 Rate versus Extent of Absorption

Extent of absorption is reflected by AUC

Rate of absorption, ka, is reflected by Tmax
Both Rate and Extent of absorption affect Cmax

Leads to 4 possible relative scenarios:

(R) Rapid, (E) Complete Absorption
yields a short Tmax, high Cmax, high AUC
(R) Rapid, (E) incomplete absorption
yields a short Tmax, low Cmax, low AUC
(R) Slow, (E) complete absorption
yields a long Tmax, high Cmax, high AUC
(R) Slow, (E) incomplete absorption
yields a long Tmax, low Cmax, low AUC
 FACTORS INFLUENCING BIOAVAILABILITY:
Three distinct factors are involved to influencing bioavailability. These are:
1.Pharmaceutical factors:
physicochemical properties of the drug.
1. Particle size
2. Crystalline structure
3. Salt form
Formulation and manufacturing variables.
1.Disintegration and dissolution time
2.Pharmaceutical ingredients
3.Special coatings
4.Nature and type of dosage form
 2. Patient related factors:
Physiologic factors.
1.Variations in pH of GI fluids
2.Gastric emptying rate
3. Intestinal motility
4. Presystemic and first-pass metabolism
5. Age, sex
6. Disease states
Interactions with other substances.
1. Food
2. Fluid volume
3. Other drugs
3. Route of administration:
1.Parentral administration
2.Oral administration
3.Rectal administration
4.Topical administration
 Bioequivalence
A comparison of the bioavailability of two or more
drug products.
Two products or formulations containing the same
active ingredient are bioequivalent if their rates
and extents of absorption are the same
Bioequivalence may be demonstrated through in vivo or
in vitro test methods, comparative clinical trials, or
pharmacodynamic studies
 Bioequivalence
90
80
Concentration (ng/mL)

70
60
Tes t/Generic
50
R eference/B rand
40
30
20
10
0
0 5 10 15 20 25 30
Time (hours)
 Regulatory Bioequivalence: An Overview
Self-evident - Biowaivers granted
Solutions Condition- excipients do not alter absorption
(historical data)
Suspensions
Pre-1962 DESI Drugs: In Vivo
SUPAC-IR (1995)
Chewable, etc. evaluation for bio-problem
Dissolution-IR
drugs (TI, PK, P-Chem)
BCS
Conventional Post-1962 Drugs: Generally
(pre-/post approval)
Tablets In Vivo - some exceptions
Capsules (IVIVC..)

MR Products SUPAC-MR
In VIVO
IVIVC
 Bioequivalence: IR Products
Pharmaceutical Equivalent
Products
Reference Test
Possible Differences
Drug particle size, ..
Excipients
Normal healthy subjects
Manufacturing process Crossover design
Equipment Overnight fast
Glass of water
Site of manufacture
90% CI within 80-125%
Batch size . of Ref. (Cmax & AUC)
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, Ajaz
same Hussain, FDA spec.)
dissolution
 FDA Methods to Determine
Bioequivalence
Generic drug manufacturers must demonstrate
that a drug is bioequivalent to a reference drug
product
In order of FDA preference, methods used to
define bioequivalence
Pharmacokinetic studies
Pharmacodynamic studies
Comparative clinical trials
In vitro studies
 Pharmacokinetic Studies
Key Measurements
Study Compound AUC
Reference Compound Area under the concentration- time curve
Cmax Cmax
Maximum concentration
A difference of greater than 20% in Cmax or
Concentration

the AUC represents a significant difference

between the study and reference
compounds
Tmax
Time to maximum concentration
AUC

Tmax Time
 Comparative Pharmacodynamic Studies
Not recommended when:
active ingredient is absorbed into the systemic
circulation
pharmacokinetic study can be conducted
Local action / no systemic absorption
eg. : Topical Corticosteroid

28 Hanoi, 2006-19-01
 Comparative Clinical Studies
Pharmacokinetic profile not possible
Lack of suitable pharmacodynamic endpoint

eg . : (Nasal suspensions)

29 Hanoi, 2006-19-01
 Study Designs

-Single-dose, two-way crossover design

- Single-dose, parallel design

-Multiple-dose studies( in case of :

-Drugs too potent/toxic
Extended/modified release products
 Crossover vs. Parallel Designs
Crossover design preferred
Intra-subject comparison
Lower variability
Generally fewer subjects required
Parallel design may be useful
Drug with very long half-life
Crossover design not practical

32 Hanoi, 2006-19-01
 Disadv. of cross over design
The main problem with the cross over design is :
The carry over effect!?
 Fasted vs. Fed Designs

Fasted study design preferred

Minimize variability not attributable to formulation
Better able to detect formulation differences

34 Hanoi, 2006-19-01
Fed Study Designs may be employed when:

Significant gastrointestinal (GI) disturbance caused

by fasted administration
Product labeling restricts administration to fed state

35 Hanoi, 2006-19-01
 When equivalence studies are NOT
necessary (Biowaivers)

Aqueous parenteral solutions

Solutions for oral use ( syrups, elixirs, tinctures & other
soluble forms but not suspensions)
Pdrs for reconstitution as a solution
Otic or ophthalmic aqueous solutions
Topical aqueous solutions
Aqueous nebulizing inhalations or nasal sprays
 B. For some products bioequivalence may be
demonstrated by evidence obtained in vitro instead
of in vivo data:
The drug product is in the same dosage form, but in a
different strength, and is proportionally similar in its
active and inactive ingredients to another product by
the same manufacturer that was found to be
bioequivalent.
 For high potency drug substances, the same
inactive ingredients are used for all strengths, and
the change in any strength is obtained by altering
the amount of the active ingredients and one or
more of the inactive ingerdients are within the
limits defined by the SUPAC guidances (up to level
II).
 Waiver of Bioavailability and
Bioequivalence Studies for Immediate-
Release Solid Oral Dosage Forms Based on
a Biopharmaceutics Classification System
(B.C.S)
 BCS Classifications
According to the BCS, drug substances
are classified as follows:

Class I - High Permeability, High Solubility

Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
 Solubility
A drug substance is considered highly soluble when
the highest dose strength is soluble in 250 ml or
less of aqueous media over the pH range of 1 - 7.5
(WHO , pH: 1.2 6.8)
 Permeability
A drug substance is considered to be highly
permeable when the extent of absorption in
humans is determined to be 90% or more of an
administered dose ( WHO, 85% ).
Conditions for BCS Bio-waivers
Firms can request waivers of in vivo testing for Class
1 drug substances
Drug products must meet these criteria:
Immediate-release solid oral dosage forms
Highly soluble, highly permeable drug
substance
Rapid in vitro dissolution

Note: Waivers not applicable for narrow therapeutic range therapeutic

range (Digoxin, Lithium, phenytoin, warfarin) drugs
A drug product is considered to be
RAPIDLY DISSOLVING when > 85% of
the labeled amount of drug substance
dissolves within 30 minutes using USP
apparatus I or II in a volume of < 900 ml
buffer solutions.
 BCS Class I: Dissolution
USP Apparatus I (100 rpm) or II (50 rpm)
Three media
0.1 N HCl or SGF USP without enzymes 0.1 N
HCl or SGF USP without enzymes
pH 4.5 buffer pH 4.5 buffer
pH 6.8 buffer or SIF USP without enzymes
NLT 85% dissolves within 30 minutes
Similarity factor (f2) for test (T) v. reference
(R) profile comparisons should > 50
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