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‫بسم الله الرحمن الرحيم‬

Bioavailability and
General concepts and overview




Generic Drug product:
• Same active ingredient (s)
• Same strength
• Same dosage form
• Same route of administration
• Same indications

NDA vs. ANDA Review Process
Generic Drug
 Original Drug
ANDA Requirements
NDA 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
7. Clinical Studies Vivo, In vitro)
 (Bioavailability) •
drug applications are termed " abbreviated " because they are generally
d to include preclinical ( animal ) and clinical ( human ) data to establish safety and effectiveness
ric applicants must scientifically demonstrate that their product is bioequivalent
s 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

Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site.
Available at: Equivalence-Related Terms.
Accessed September 29, 2003.
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,
Approved as shape,
Drug Products With Therapeutic release mechanisms,
Equivalence Evaluations . 23 ed. 2003. FDAand
rd /CDER
Web site . Available
September 29, 2003.
at : http ://www .fda . gov /cder/ob /docs /preface /ecpreface .htm . Accessed
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
• 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
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site.
Available at: Equivalence-Related Terms.
Accessed September 29, 2003.
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
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site.
Available at: Equivalence-Related Terms.
Accessed September 29, 2003.
(quantifies ABSORPTION = ?, Reasons for poor F)

• The extent and rate at which its

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

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
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

• A comparison of the bioavailability of two or
• drug products.
• Two products or formulations containing the
• active ingredient are bioequivalent if their
• and extents of absorption are the same
• Approved may be
Drug Products With Therapeutic demonstrated
Equivalence Evaluations. 23 ed. 2003. FDA/CDER Web
site. through in://www
Available at: http vivo or /cderin vitro
/ob/docs test
/preface methods,
/ecpreface .htm#Therapeutic
Equivalence-Related Terms. Accessed September 29, 2003.
comparative clinical trials, or
Concentration (ng/mL)

0 5 10 15 20 25 30
Time (hours)
Regulatory Bioequivalence: An
“Self-evident” - Biowaivers granted
Solutions Condition- excipients do not alter absorption
(historical data)
Pre-1962 DESI Drugs: In Vivo
SUPAC-IR (1995)
Chewable, etc. evaluation for “bio-problem”
drugs (TI, PK, P-Chem)
Conventional Post-1962 Drugs: Generally
(pre-/post approval)
Tablets In Vivo - some exceptions
Capsules (IVIVC..)

MR Products
Bioequivalence: IR
Pharmaceutical Equivalent
Reference Test
Possible Differences
Drug particle size, ..
N o rm a lh e a lth y
Manufacturing process
su b je cts
Equipment C ro sso ve r d e sig n
Site of manufacture O ve rn ig h t fa st
G la ss o f w a te r
Batch size …. 9 0 % C I w ith in 8 0 -
Documented Bioequivalence
o f R e f. ( C m a x & A U C )
= Therapeutic Equivalence
(Note: Generally, same dissolution
Ajaz Hussain, FDA spec.)
FDA Methods to Determine
• Generic drug manufacturers must
demonstrate that a drug is
bioequivalent to a reference drug
• In order of FDA preference, methods
used to define bioequivalence
– Pharmacokinetic studies
– Pharmacodynamic studies
– Comparative clinical trials
– In vitro
Food and Drug Administration studies
. Code of Federal Regulations. Title 21, Part 320: Bioavailability
and Bioequivalence Requirements. Section 320.24. 2003. Available at:
Pharmacokinetic Studies
Key Measurements
S tu d y C o m p o u n d • AUC
R e fe re n ce – Area under the
C oC mma p o u n d concentration- time curve
• Cmax
– Maximum concentration
C o n ce n tra tio

– A difference of greater than

20% in Cmax or the AUC
represents a significant
difference between the
study and reference
AUC compounds
• Tmax

– Time to maximum
Tmax Tim
Approved Drug Products With Therapeutic e
Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
Pharmacodynamic Studies
• Not recommended when:
– active ingredient is absorbed into the
systemic circulation
– pharmacokinetic study can be
• Local action / no systemic absorption
• eg. : Topical Corticosteroid
29 Hanoi, 2006-19-01
Comparative Clinical
• Pharmacokinetic profile not possible
• Lack of suitable pharmacodynamic

• eg . : (Nasal suspensions)

30 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
• 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

33 Hanoi, 2006-19-01
Disadv. of cross over
• 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
– Better able to detect formulation

35 Hanoi, 2006-19-01
Fed Study Designs may be
employed when:
• Significant gastrointestinal (GI)
disturbance caused by fasted
• Product labeling restricts
administration to fed state

36 Hanoi, 2006-19-01
When equivalence studies are
NOT necessary (Biowaivers)
• A-
• Aqueous parenteral solutions
• Solutions for oral use ( syrups, elixirs,
tinctures & other soluble forms but not
• Pdrs for reconstitution as a solution
• Otic or ophthalmic aqueous solutions
• Topical aqueous solutions
• Aqueous nebulizing inhalations or nasal
• B. For some products bioequivalence
may be demonstrated by evidence
obtained in vitro instead of in vivo
– 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 ingerdientsare 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
Classification System
BCS Classifications
 According to the BCS, drug
substances are classified as follows:

Ø Class I - High Permeability, High Solubility

Ø Class II - High Permeability, Low Solubility
Ø Class III - Low Permeability, High Solubility
Ø Class IV - Low Permeability, Low 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 –
• 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:
n Immediate-release solid oral dosage forms
n Highly soluble, highly permeable drug
n Rapid in vitro dissolution

 Note: Waivers not applicable for narrow therapeutic range therapeutic

range (Digoxin, Lithium, phenytoin, warfarin) drugs

n A drug product is considered to be
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
n USP Apparatus I (100 rpm) or II (50 rpm)
n Three media
Ø 0.1 N HCl or SGF USP without enzymes 0.1
N HCl or SGF USP without enzymes
Ø pH 4.5 buffer pH 4.5 buffer
Ø pH 6.8 buffer or SIF USP without enzymes
n NLT 85% dissolves within 30 minutes
n Similarity factor (f2) for test (T) v. reference
(R) profile comparisons should > 50
Thank you