Bioavailability and Bioequivalence Study a concept of creating documentation in pharma industry. Students of Regulatory affairs. An explanation of the regulatory requirements while performing BA/BE studies in India. A part of PCI syllabus under subject code 104 for MPharm Sem1.

1. BIOAVAILABILITY AND BIOEQUIVALENCE
STUDIES

2. BIOAVAILABILITY
 Bioavailability is a term used to indicate the FRACTIONAL EXTENT to which a dose of drug
reaches to its site of action or a biological fluid , from which the drug has the access to its site of
action.
Or
 It is defined as an RATE AND EXTENT of absorption of unchanged drugs from its dosage form.
BIOAVAILABILITY FRACTION :
BIOAVAILABLE DOSE
F = -----------------------------------
ADMINISTERED DOSE

3. CONSIDERATIONS IN IN-VIVO BIOAVAILABILITY
DESIGN :
 There are 2 types of Bioavailability :
1) ABSOLUTE BIOAVAILABILITY
2) RELATIVE BIOAVAILABILITY

4. ABSOLUTE BIOAVAILABILITY
 When the systemic availability of the drug after oral administration is compared to its IV
ADMINISTRATION is called as Absolute Bioavailability.
 Absolute Bioavailability after oral drug administration using plasma data can be
determined as following :

5.  It is used to characterize a DRUG INHERENT absorption properties from the extravascular
site.
EXAMPLE :
Absolute Bioavailability of NIMODIPINE for different route of administration
ORAL - 1.17%
NASAL - 67.4%
IV - 100%
An Absolute Bioavailability of 1 or 100% indicates complete absorption by
comparing reference standard as an IV dose.

6.  F may be expressed as fraction ( or ) as percentage multiplying F*100 absolute
availability using urinary excretion data can be determined.
Du : Total amount of drug excreted in urine
(Du)oral dose oral
F = ----------------------------
(Du) iv dose iv

7. RELATIVE BIOAVAILABILITY
 When the systemic availability of the drug after oral administration is compared with that of
ORAL STANDARD OF SAME DRUG ( such as aqueous or non-aqueous solutions ,
suspensions ) is referred as Relative Bioavailability.
 It is used to characterize absorption of drug from its formulation.
( AUC ) A
Fr = ---------------
( AUC ) B

8. EXAMPLE :
 Comparison between CAPSULE AMOXICILLIN and SUSPENSION AMOXICILLIN.
When different doses are administered a correction for the size of dose is made as the
following equation : ‘
(AUC) A / dose A
RELATIVE AVAILABILITY = --------------------------
(AUC) B /dose B

9.  The total amount of drug excreted in the urine is collected as the percentage availability
using urinary excretion data can be determined as follows :
Relative bioavailability 1 or 100% indicates that bioavailability of drug from
both dosage forms is same but does not indicates complete absorption.
% RELATIVE AVAILABILITY = { (Du)A / (Du)B}

10. BIOEQUIVALENCE STUDIES
DEFINITION :
It refers to the drug substance in two or more IDENTICAL DOSAGE FORMS reaches
systemic circulation at the same RATE TO THE RELATIVE EXTENT.
i.e. their plasma concentration time profiles will be identical without significant statistical
difference.

11. ADVANTAGES
 Minimizes the effect of INTER SUBJECT VARIABILITY.
 It minimizes the carry over effect.
 Requires less number of subjects to get meaningful results.
DISADVANTAGES
 Requires LONG TIME to complete the studies.
 Increases in study periods leads to high subject dropouts.
 Completion of studies depends on number of formulations evaluated in the studies.

12. OBJECTIVES
 If a new product is intended to be substitute for an approves medicinal product as a
pharmaceutical equivalent or alternative , equivalence with this product should be
shown or justified.
 Bioequivalence studies are conducted if there is :
 A risk of BIOEQUIVALENCE and / or
 A risk of PHARMACOTHERAPEUTIC FAILURE or diminished clinical safety

13. Some of the important terms relevant in this context will be defined.
EQUIVALENCE : It is a relative term that compares DRUG PRODUCT with respect to a
specific characteristics or function to defined SET OF STANDARDS.
There are several types of equivalence :
1. Chemical Equivalence
2. Pharmaceutical Equivalence
3. Bioequivalence
4. Therapeutic Equivalence
TYPES OF BIOEQUIVALENCE STUDIES
 Bioequivalence can be demonstrated either :
1. In vivo or
2. In vitro

14. IN-VIVO BIOEQUIVALENCE STUDY
1. ORAL IMMEDIATE RELEASE PRODUCTS WITH SYSTEMIC ACTION
• Indicated for serious conditions requiring assured response.
• Narrow therapeutic margin
• Unfavourable physiological properties eg : Low Solubility , Metastable modifications
2. NON ORAL IMMEDIATE RELEASE PRODUCTS
3. MODIFIED RELEASE PRODUCTS WITH SYSTEMIC ACTION
In vivo bioequivalence studies are conducted in the usual manner i.e. pharmacokinetic &
pharmacodynamic methods.
 PHARMACOKINETIC METHODS PHARMACODYNAMIC METHODS
• Plasma level time studies • Acute pharmacological response
• Urinary excretion studies • Therapeutic response

15. The drug product differs only in strength of active substance it contains some of the following
conditions :
i. Pharmacokinetics are linear.
ii. The qualitative composition is the same.
iii. The ratio between the active substances and the excipients is the same.
iv. Both products are produced by the same manufacturer at the same production site.
v. The product contains active ingredient in the same concentrations as the approved
drug product.
IN-VITRO BIOEQUIVALENCE STUDY

16. The drug product meets all the following requirements :
a) The product is in the form of solution or solubilized form.
b) The product contains active ingredient in the same concentration as the approved drug
product.
 The drug product has been slightly reformulated or the manufacturing method has been
slightly modified by the original manufacture.
 An acceptable IVIVC and the invitro dissolution rate of new product is equivalent with that
of already approved medicinal product.

17. DESIGN OF BIOEQUIVALENCE STUDIES
1. Title
2. Study Objective
3. Study Design
4. Study Population
5. Clinical Procedures
6. Ethical Considerations
7. Facilities
8. Data Analysis
9. Drug Accountability
10. Appendix

18. ANALYTICAL METHODS :
• Must be accurate.
• Should be with Appropriate precision.
• Measure the actual concentration of the active drug or active metabolites achieved in the
body.
REFERENCE STANDARDS :
• Reference standard is generally a formulation currently marketed with a FULLY
APPROVED NDA for which there are valid scientific safety and efficacy data.
• Usually innovators or brand drug.

19. EXTENDED RELEASE FORMULATIONS
• Product has claimed controlled release characteristics.
• No occurrence of dose dumping.
• Steady state is equivalent to currently marketed extended release formulation.
COMBINATION OF DRUG PRODUCTS
• To determine the rate and extent of absorption of each active ingredient administered
concurrently as separate single ingredient preparations.

20. STUDY DESIGNS
1. FASTING STUDY
• Done for IMMEDIATE RELEASE AND MODIFIED RELEASE oral dosage forms
• Male and Female subjects may be used.
• Blood sampling is done at appropriate intervals to obtain plasma drug concentration- time
profile.
• Subjects should be fasting condition – atleast 10 hours before drug administration and 4
hours after administration.

21. 2. FOOD INTERVENTION STUDY
• These studies are conducted after high fat and high calorie meal.
• Meal is given 30 minutes before dosing.
• No food is given for atleast 4 hours after administration.
• Done for MODIFIED RELEASE DOSAGE FORMS
3. MULTIPLE DOSE
• Done for EXTENDED RELEASE drug products.
• Done in addition to the fasting and food intervention study.
• Sampling done similar to fasting study

22. CROSS OVER DESIGNS
• Each subject receives the test and reference drug product.
• Eg : LATIN SQUARE DESIGN
• Each subject receives only one drug product.
• Adequate wash out periods is provided between drugs.
ADVANTAGES :
• Subject – to – Subject variation is reduced.
• All patients donot receive same drug product on the same day

23. PERIOD :
• Two period study – performed on 2 different days separated by a washout period -
generally 10 elimination half lives.
SEQUENCE :
• No. of different orders in the treatment groups in a study.
• For eg: two sequence , two period study would be designed.

24. • Concept of bioequivalence has been adopted by the pharmaceutical industry and national
regulatory authorities throughout the world for over 20 years.
• There is continuing attempt to understand and develop more sufficient and scientifically
valid approaches to assess bioequivalence of various dosage forms including some of the
tough complex special dosage forms.
• Absolute and Relative bioavailability shows drug availability according to their standards.