1. Bioavailability and Bioequivalence General concepts and overview

2. WHAT IS IT??? WHY IS IT??? HOW IS IT???
REGULATION VERSUS PHARMACEUTICAL COMP.

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

7. NDA vs. ANDA Review Process
Generic Drug
ANDA Requirements
Chemistry
Manufacturing
Controls
Labeling
Testing
Bioequivalence Study (In Vivo, In vitro)
Original Drug
NDA Requirements
Chemistry
Manufacturing
Controls
Labeling
Testing
Animal Studies
Clinical Studies
(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).

8. FDA Definitions Used in Bioequivalence Determinations
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
FDA Definitions Used in Bioequivalence Determinations

9. FDA Determinations of Bioequivalence Main Terms
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
FDA Determinations of Bioequivalence Main Terms
Pharmaceutical equivalents
Pharmaceutical alternatives
Therapeutic equivalents
Bioavailability
Bioequivalence
FDA Determinations of Bioequivalence. Main Terms.
The Orange Book defines 5 terms that describe the most important concepts for discussing product substitution.1 These terms are:
Pharmaceutical equivalents
Pharmaceutical alternatives
Therapeutic equivalents
Bioequivalence
Bioavailability
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.

10. Pharmaceutical Equivalents
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
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 Equivalents.
The FDA considers 2 drug products 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.1
Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or other applicable standards (eg, strength, quality, purity, and identity). However, these drug products may differ in characteristics, such as shape, release mechanisms, and packaging.
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Accessed September 29, 2003.
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Accessed September 29, 2003.

11. Pharmaceutical Alternatives
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
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
Pharmaceutical Alternatives.
The FDA considers 2 products to be pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or if they have different dosages or strengths, such as quinidine sulfate 200-mg tablets versus quinidine sulfate 200-mg capsules. Other products considered to be pharmaceutical alternatives include different dosage forms and strengths within a product line by a single manufacturer, and extended-release (ER) products when compared with immediate- or standard-release formulations of the same active ingredient.1
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.

12. Therapeutic Equivalents
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
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
Therapeutic Equivalents.
Drug products are considered therapeutic equivalents if they meet the following criteria:1
They are approved as safe and effective and are pharmaceutical equivalents;
They are bioequivalent in that
They do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or
If they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard
They are adequately labeled and are manufactured in compliance with Current Good Manufacturing Practice regulations
Drugs marketed before 1938 and drugs marketed between 1938 and 1962 that are safe but not approved are excluded from FDA evaluations. When administered under conditions specified in the product label, therapeutic equivalents are expected to have the same clinical effect and safety profile.
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.

13. 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)
Time (h) 25
0.0

14. 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

17. 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

20. 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

21. 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

22. ACCESS Medical Group, Ltd. S304 Bioequivalence rev08
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
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.
The FDA considers drug products bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when the products administered to patients or subjects at the same molar dose under similar experimental conditions.1
Bioequivalence may be demonstrated through in vivo or in vitro test methods. An in vitro bioequivalence standard may be used, especially when an in vitro test has been correlated with human in vivo bioavailability data.
In addition, bioequivalency may also be demonstrated through comparative clinical trials or pharmacodynamic studies.
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.

23. Bioequivalence

24. Regulatory Bioequivalence: An Overview
“Self-evident” - Biowaivers granted
Condition- excipients do not alter absorption
(historical data)
Solutions
Suspensions
Chewable, etc.
Conventional
Tablets
Capsules
MR Products
Pre-1962 DESI Drugs: In Vivo
evaluation for “bio-problem”
drugs (TI, PK, P-Chem)
Post-1962 Drugs: Generally
In Vivo - some exceptions
(IVIVC..)
SUPAC-IR (1995)
Dissolution-IR
BCS
(pre-/post approval)
In VIVO
SUPAC-MR
IVIVC

25. Bioequivalence: IR Products
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Normal healthy subjects
Crossover design
Overnight fast
Glass of water
90% CI within %
of Ref. (Cmax & AUC)
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution spec.)
Ajaz Hussain, FDA

26. FDA Methods to Determine Bioequivalence
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
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
FDA Methods to Determine Bioequivalence.
Under the Drug Price Competition and Patent Term Restoration Act of 1984, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the drug product is bioequivalent to the reference (innovator) drug product.1
Methods used to define bioequivalence include PK studies, pharmacodynamic (PD) studies, comparative clinical trials, and in vitro studies.
The choice of study used is based on the site of action of the drug and the ability of the study design to adequately compare the generic and reference drug products.
Reference
1. Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence Requirements. Section Available at: Accessed September 29, 2003.
Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence Requirements. Section Available at: Accessed September 29, 2003.

27. Pharmacokinetic Studies Key Measurements
10/6/03
ACCESS Medical Group, Ltd.
S304 Bioequivalence rev08
Pharmacokinetic Studies Key Measurements
Study Compound
Reference Compound
AUC
Area under the concentration- time curve
Cmax
Maximum concentration
A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds
Tmax
Time to maximum concentration
Cmax
Concentration
Pharmacokinetic Studies. Key Measurements.
To investigate the bioequivalence of 2 drug products or compounds, the FDA considers PK studies that determine the area under the concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax) for the study compound (generic) and a reference compound (innovator).1 Each of these values for the study compound are compared with those of the reference compound.
For the study and reference compounds to be considered bioequivalent, their rates and extents of absorption must not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions.
The red area in the diagram represents the AUC, or the extent of absorption, of the reference compound. The yellow area represents the AUC of the study compound. Cmax is an indicator of the absorption rate and Tmax is influenced by the route of compound administration.
A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds.
Reference
1. Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.
AUC
Tmax
Time
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed FDA/CDER Web site. Available at: Equivalence-Related Terms. Accessed September 29, 2003.

28. 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
Hanoi,

29. Comparative Clinical Studies
Pharmacokinetic profile not possible
Lack of suitable pharmacodynamic endpoint
eg . : (Nasal suspensions)
Hanoi,

30. 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

32. 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
Hanoi,

33. Disadv. of cross over design
The main problem with the cross over design is :
The carry over effect………!?

34. Fasted vs. Fed Designs Fasted study design preferred
Minimize variability not attributable to formulation
Better able to detect formulation differences
Hanoi,

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

36. 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

37. 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.

38. 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).

39. Waiver of Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (B.C.S)

40. 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

41. 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 (WHO , pH: 1.2 – 6.8)

42. 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% ).

43. 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

44. 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.

45. 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