Idea about Bioequivalence, biosimilars and BCS

1. BIOEQUIVALENCE, BIOSIMILAR
DRUG PRODUCTS, AND BCS
By
Dr. Chinmaya Keshari Sahoo. M.Pharm, Ph.D
Associate Professor
College of Pharmaceutical Sciences, Puri
1

2. CONTENTS
1. Definitions
2. Types of Bioequivalence (BE)
3. When should BE study conducted
4. Methods of studying BE
5. Design and evaluation of bioequivalence studies
6.BE Experimental Study Designs
7. BE Study Protocol
8. Study Submission and Drug Review Process
9. Clinical Significance of BE studies
10.Special Concerns in Bioavailability and BE Studies
11. Generic Substitution
12. Biosimilar drug products
13. Biopharmaceutics classification system (BCS)
2

3. DEFINITIONS
Bioavailability:
Bioavailabilty is defined 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. (According to FDA 2003)
Bioequivalence:
It is a relative term which denotes that the drug substance in two or more
identical dosage forms, reaches the systemic circulation at the same relative
rates and to the same relative extent i.e their plasma concentration time profiles
will be identical without the significant statistical differences.
Innovator Product:
A drug products that have been approved as new drug or a drug that
corresponds to one. E.g. Efudex (Roche laboratories)
Generic Products:
Products of which active ingredients , strengths, dosage forms and dosage
regimens are the same as those of innovator product. E.g Nicip
Generic nomenclature:
It refers to recognized, nonproprietary or common name of an active drug in a drug
product. E.g Acetaminophen (USA), Paracetamol (UK/India) 3

4. TYPES OF BIOEQUIVALENCE
Chemical equivalence:
It indicates that two or more drug products that contain the same labelled
chemical substance as an active ingredient in the same amount.
Therapeutic equivalence:
This term indicates that two or more drug products that contain the same
therapeutically active ingredient elicit identical pharmacological effects and can
control the disease to the same extent.
Clinical equivalence:
When the same drug from 2 or more dosage forms gives identical in vivo effects
as measured by pharmacological response or by control over a symptom or a
disease.
Pharmaceutical equivalence:
The term implies that two or more drug products are identical in strength,
quality, purity, content uniformity, disintegration and dissolution
characteristics. They may however differ in containing different excipients.
4

5. WHEN SHOULD BE STUDIES CONDUCTED
1. When a generic formulation is tested against an
innovator brand.
2. When the proposed dosage form is different from
that used in clinical trails.
3. When significant changes are made in the
manufacture of the marketed formulation.
5

6. METHODS OF BIOEQUIVALENCE STUDIES
Methods of BE studies
I. In Vivo bioequivalence study
II. In vitro bioequivalence study
III. Pharmacodynamic studies
IV. Comparative clinical trials
I. In Vivo bioequivalence study
1. It requires determination of relative bioavailability after
administration of a single dose of test and reference formulations by the
same route in equal doses, but at different times.
2. The reference product is generally a previously approved product,
usually a innovator’s product or some suitable reference standard.
3. The study is performed in fasting, young, healthy, adult male
volunteers to assure homogeneity in the population & to spare the
patients, elderly or pregnant women from rigors of such a clinical
investigation.
6

7. Contd.
II. In vitro BE study
In following circumstances equivalence may be assessed by the use of in vitro
dissolution testing:
1. Drugs for which the applicant provide data to substantiate all of the
following:
 Highest dose strength is soluble in 250ml of an aqueous media over the pH
range of 1-7.5 at 370C.
 At least 90% of the administered oral dose is absorbed on mass balance
determination or in comparison to an intravenous reference dose.
 Speed of dissolution as demonstrated by more than 80% dissolution within 15
minutes at 370C using IP apparatus 1, at 50 rpm or IP apparatus 2, at 100rpm in
a volume of 900 ml or less in each of the following media:
 a. 0.1 N hydrochloric acid or artificial gastric juice (without enzymes)
 b. A pH 4.5 buffer
 c. A pH 6.8 buffer or artificial intestinal juice (without enzyme)
7

8. Contd.
2.Different strength of the drug manufactured by the same
manufacturer, where all of the following criteria are fulfilled:
1. The qualitative composition between the strengths is essentially the same.
2. The ratio of active ingredients and excipients between the strength is
essentially the same or in the case of small strength, the ratio between the
excipients is the same.
3. The method of manufacture is essentially the same.
4. An appropriate equivalence study has been performed on at least one of the
strength of the formulation (usually the highest strength unless a lower strength
is chosen for reasons of safety); and
5. In case of systemic availability-pharmacokinetics have been shown to be linear
over the therapeutic dose range.
In vitro dissolution testing may also be suitable to confirm unchanged product
quality and performance characteristics with minor formulation or
manufacturing changes after approval.
8

9. Contd.
III. Pharmacodynamic studies
Studies in healthy volunteers of patients using
pharmacodynamic parameters may be used for
establishing equivalence between two pharmaceutical
products. These studies may become necessary
1. If quantitative analysis of the drug and/or
metabolite(s) in plasma or urine cannot be made with
sufficient accuracy and sensitivity.
2. If measurement of drug concentrations cannot be used
as surrogate endpoints for the demonstration of
efficacy and safety of the particular pharmaceutical
product e.g. topical products without an intended
absorption of the drug into the systemic circulation.
9

10. Contd.
IV. Comparative clinical trials
It is carried out when
1. The plasma concentration time-profile date
may not be suitable to assess equivalence
between two formulations.
2. Pharmacodynamic studies cannot be performed
because of lack of meaningful pharmacodynamic
parameters, which can be measured.
3. Pharmacodynamic and pharmacokinetic studies
are not feasible.
10

11. ELEMENTS OF BE STUDY PROTOCOL
1. Title
2. Study Objective
3. Study Design
a. Design
b. Drug Products (Test products, Reference products)
c. Dosage Regimen
d. Sample Collection Schedule
e. Housing
f. Fasting/ meals Schedule
g. Analytical methods
4.Study Population
a. Subjects
b. Subject selection ( Medical history, Physical exam., Lab. Tests)
c. Inclusion criteria/ Exclusion criteria
d. Restrictions/ Prohibitions
11

12. Contd.
5. Clinical procedures
a. Dosage and drug administration
b. Biological sampling schedule
c. Activity of subjects
6. Ethical consideration
a. Basic principles
b. Institutional Review Board
c. Informed consent
d. Indications for subject withdrawal
e. Adverse reactions and emergency procedure
7. Facilities
8. Data analysis
a. Analytical validation procedure,
b. Statistical treatment of data)
9. Drug accountability
10. Appendix
12

13. STUDY DESIGN
Basic design is determined by
Scientific questions to be answered
Nature of the reference material and the
dosage form to be tested
 Availability of analytical methods
 Benefit-risk considerations in regard to
testing in humans
13

14. Contd.
Criteria for human subjects
Studies should be conducted in individuals
representative of the general population, taking
into account age, sex, and race.
 Healthy subjects, above 18 years of age.
 Choice of gender based on usage & safety criteria
Pregnant women or those taking contraceptives
should not be included in the test
The subjects are generally fasted for 10 to 12 h
(overnight) prior to drug administration and may
continue so fast for a 2 to 4 h period after dosing.
14

15. Contd.
Study design for solid oral dosage forms
1. Fasting study
2. Food intervention study
3. Multiple-dose (steady-state) study
1. Fasting study
 Required for all immediate release and modified release dosage
form
 Both male and female are used in study
 Bioequivalence studies are usually resolute by a single-dose, two-
period, two-treatment, two-sequence, and open-label, randomized
crossover design comparing equal doses of the test and reference
products in fasted, adult, healthy subjects.
15

16. Contd.
2. Food intervention study
 Generally conducted using meal condition
 The test meal is high fat and high calorie meal
 Alcohol and any over the counter drug was discontinued
for at least three days before the start of the experiment
and throughout the experiment period
3. Multiple-dose (steady-state) study
 Comparing equal dose of test and reference product
 Performed in adult, healthy subjects
16

17. BE EXPERIMENTAL STUDY DESIGNS
Various types of test designs are used to study of BE such as
1. Parallel design
2. Cross over design
1. Parallel design
 A parallel design is a completely randomized design in which
each subject receives one & only one formulation of a drug in a
random fashion.
 The simplest parallel design is the two- group parallel design,
which compares 2 formulations of a drug.
 Each group contains equal number of subjects.
 Parallel design is useful drugs with long half-lives (longer than 24
h)
17

18. Contd.
18

19. Contd.
2. Cross over design
Arrangements in which each subject receives two
or more different treatments on successive
occasions, are known as cross over designs.
 In this design, the number of treatments is same
as the number of periods.
This design can be used with any number of
treatments, subjects to the restriction that the
number of subjects must be a multiple of the
number of treatments.
19

20. Contd.
A) Latin Square Design
 Each formulation is administered just once to each subject and once in each
study period.
 In order to allocate the treatment to the experimental units in rows and columns,
we take the help from Latin squares.
 A Latin square of order p is an arrangement of p symbols in p2 cells arranged in
p rows and p columns such that each symbol occurs once and only once in each
row and in each column.
 Examples of Latin-square crossover designs for a bioequivalence study in
human volunteers, comparing three different drug formulations (A, B, C).
20
Subjects T1 T2 T3
1 A B C
2 B C A
3 C A B

21. Contd.
B) Replicated Crossover Study Design(RCSD)
 RCSD is used for the determination of individual bioequivalence, to estimate
within-subject variance for both the Test and Reference drug products, and to
provide an estimate of the subject-by-formulation interaction variance.
 Generally, a four-period, two-sequence, two-formulation design is
recommended by the FDA.
 The same reference and the same test are each given twice to the same subject.
Other sequences are possible. In this design, Reference-to-Reference and Test-
to-Test comparisons may also be made.
Where R = Reference , T = Test
21
Period 1 Period 2 Period 3 Period 4
Sequence 1 T R T R
Sequence 2 R T R T

22. Contd.
Advantages of Cross over design:
 Minimize intersubject variability in plasma drug level.
 Minimize intrasubject variability
 Minimize variation due to time effect.
 Make it more possible to focus more on formulation variables which is the key
to success for any bioequivalence study.
Drawbacks of cross-over design:
 Takes long time since appropriate washout period between 2 administrations is
essential.
 Time may be longer if the drug has t1/2 long.
 When the no. of formulations to be tested are more, the study becomes more
difficult and subject dropout rate may increase.
22

23. EVALUATION OF THE DATA
1.Analytical Method:
 The analytical method for measurement of the drug
must be validated for accuracy, precision, sensitivity,
and specificity.
 The use of more than one analytical method during a
bioequivalence study may not be valid, because
different methods may yield different values.
 Data should be presented in both tabulated and
graphic form for evaluation.
 The plasma drug concentration–time curve for each
drug product and each subject should be available.
23

24. Contd.
2.Pharmacokinetic Evaluation of the Data
 For single-dose studies, including a fasting study or a food
intervention study, the pharmacokinetic analyses include
calculation for each subject of the area under the curve to the
last quantifiable concentration (AUC0–t) and to infinity
(AUC0–∞), T max, and C max.
 Additionally, the elimination rate constant (k), the elimination
half-life (t ½), and other parameters may be estimated.
 For multiple-dose studies, pharmacokinetic analysis includes
calculation for each subject of the steady-state area under the
curve, (AUC0–t), T max, C min, C max, and the percent
fluctuation [100 x (C max – C min)/C min].
 Proper statistical evaluation should be performed on the estimated
pharmacokinetic parameters.
24

25. Contd.
3.Statistical Evaluation of the Data
After collection of the data statistical method must be
applied to determine the level of significance of any
observed difference in the rate and extent of absorption in
order to establish BE between two or more drug products.
The commonly adopted approaches to determine statistical
differences are
a) Analysis of Variance (ANOVA)
 ANOVA is a statistical procedure used to test the data for
differences within and between treatment and control
groups.
 A bioequivalent product should produce no significant
difference in all pharmacokinetic parameters tested.
25

26. Contd.
The parameters tested usually include AUC0–t,
AUC0–∞, t max, and C max obtained for each
treatment or dosage form.
A statistical difference between the pharmacokinetic
parameters obtained from two or more drug products
is considered statistically significant if there is a
probability of less than 1 in 20 times or 0.05
probability (p ≤0.05) that these results would have
happened on the basis of chance alone.
The probability (p) is used to indicate the level of
statistical significance. If p < 0.05, the differences
between the two drug products are not considered
statistically significant.
26

27. Contd.
(b) Two One-Sided Tests Procedure/ confidence interval approach
 It is used to demonstrate if the bioavailability of the drug from the Test
formulation is too low or high in comparison to that of the Reference
product.
 The 90% confidence limits are estimated for the sample means based on
a Student's t distribution of the data.
 A 90% confidence interval about the ratio of means of the two drug
products must be within ±20% for measurement of the rate and extent of
drug bioavailability (Parameters AUC or Cmax).
 The lower 90% confidence interval for the ratio of means cannot be less
than 0.80, and the upper 90% confidence interval for the ratio of the
means cannot be greater than 1.20.
 When log-transformed data are used, the 90% confidence interval is set
at 80–125%. These confidence limits have also been termed the
bioequivalence interval . The 90% confidence interval is a function of
sample size and study variability, including inter- and intrasubject
variability
27

28. STUDY SUBMISSION AND DRUG REVIEW PROCESS
The contents of New Drug Applications (NDAs)
and Abbreviated New Drug Applications
(ANDAs) are similar in terms of the quality of
manufacture.
 The submission for an NDA must contain safety
and efficacy studies as provided by animal
toxicology studies, clinical efficacy studies, and
pharmacokinetic/bioavailability studies.
 For the generic drug manufacturer, the
bioequivalence study is the pivotal study in the
ANDA that replaces the animal, clinical, and
pharmacokinetic studies.
28

29. Contd.
Brand Name Drug
(NDA) Requirements
Generic Drug
(ANDA) Requirements
1. Labeling
2. Pharm/Tox
3. Chemistry
4. Manufacturing
5. Controls
6. Microbiology
7. Inspection
8. Testing
9. Animal studies
10.Clinical studies
11.Bioavailability
1. Labeling
2. Pharm/Tox
3. Chemistry
4. Manufacturing
5. Controls
6. Microbiology
7. Inspection
8. Testing
9. Bioequivalence
29

30. Contd.
The investigator should be sure that the study has
been properly designed, the objectives are clearly
defined, and the method of analysis has been
validated (i.e., shown to measure precisely and
accurately the plasma drug concentration).
The results are analyzed both statistically and
pharmacokinetically.
These results, along with case reports and
various data supporting the validity of the
analytical method, are included in the
submission.
30

31. Proposed format and contents of an in vivo BE study
submission and accompanying in vitro data
Title Page
1. Study title
2. Name of sponsor
3.Name and address of clinical laboratory
4.Name of principal investigator (s)
5. Name of analytical laboratory
6. Dates of clinical study (start, completion)
7.Signature of principal investigator (and date)
8. Signature of clinical investigator (and date)
Table of Contents
I. Study Resume
1. Product information
2. Summary of bioequivalence study
3. Summary of bioequivalence data
Plasma
Urinary excretion
4. Figure of mean plasma concentration-time
profile
5.Figure of mean cumulative urinary
excretion
6. Figure of mean urinary excretion rates
II. Protocol and Approvals
1.Protocol
2.Letter of acceptance of protocol from FDA
3. Informed consent form
4. Letter approval of Institutional Review
Board (IRB)
5. List of members of IRB
III. Clinical study
1. Summary of the study
2. Details of the study
3. Demographic characteristics of the
subjects
4. Subject assignment in the study
5. Mean physical characteristics of subjects
arranged by sequence
6. Details of clinical study
7. Deviations from protocol
8. Vital signs of subjects
9. Adverse reaction report 31

32. IV. Assay Methodology and Validation
1. Assay method description
2. Validation procedure
3. Summary of validation
4. Data on linearity of standard samples
5. Data on interday precision and accuracy
6. Data on intraday precision and accuracy
7. Figure for standard curve(s) for low/high
ranges
8. Chromatogram of standard and quality
control samples
9. Sample calculation
V. Pharmacokinetic parameters and Tests
1.Definition and calculation
2.Statistical tests
3.Drug levels at each sampling time and
pharmacolinetic parameters
4. Figure of plasma concentration-time profile
5. Figures of individual subject plasma
concentration-time profiles
6.Figure of mean cumulative urinary excretion
7. Figures of individual subject mean cumulative
urinary excretion
8.Figure of mean urinary excretion rates
9. Figures of individual subject mean urinary
excretion rates
10. Table of individual subject data
arranged by drug , drug/period,
drug/sequence
VI. Statistical Analyses
1.Statistical considerations
2.Summary of statistical significance
3.Summary of statistical parameters
4.ANOVA, least square estimates and least
squares means
VII. Appendices
1.Randomization Schedule
2.Sample identification codes
3.Analytical raw data
4.Chromatogram of at least 20% subjects
5.Medical record and clinical reports
6.Clinical facilities description
7.Analytical facilities description
8. Curricula vitae of the investigators
VIII. In Vitro Testing
1. Dissolution testing
2. Dissolution assay methodology
3. Content uniformity testing
4. Potency determination
IX. Batch size and Formulation
1. Batch record
2. Quantitative formulation 32

33. CLINICAL SIGNIFICANCE OF BE STUDIES
 Two formulations whose rate and extent of absorption differ by
20% or less are considered bioequivalent.
 Differences of less than 20% in AUC and Cmax between drug
products are unlikely to be clinically significant in patients. (BE
Task Force Report)
 The BE Task Force states that clinical studies of effectiveness
have difficulty in detecting differences in dose of even 50-100%.
 A small statistically significant difference in drug bioavailability
from two or more dosage forms is detected if the study is well
controlled and the number of subjects is sufficiently large.
 When the therapeutic objectives of the drug are considered an
equivalent clinical response should be obtained from the
comparison of dosage forms if the plasma drug concentrations
remain above MEC for an appropriate interval and do not reach
minimum toxic concentration (MTC).
33

34. Contd.
 The elderly or patients on drug therapy are not used for BE
studies.
 Normal healthy volunteers are preferred for BE studies due to less
risk.
 The excipients in one of the dosage forms tested may pose a
problem in the patient who uses the generic dosage form.
 For the manufacture of a dosage form specifications are set to
provide uniformity of dosage forms.
34

35. SPECIAL CONCERNS IN BIOAVAILABILITY AND
BIOEQUIVALENCE STUDIES
 The general BE study designs and evaluation such as the
comparison of AUC, Cmax and tmax may be used for
systemically absorbed drugs and conventional oral dosage forms.
However for certain drugs and dosage forms systemic
bioavailability and BE are difficult to ascertain .
 Drugs and drug products( e.g. Cyclosporine, Chloropromazine,
Verapamil etc.) are considered to be highly variable if the
intrasubject variability in bioavailability parameters is greater than
30% by analysis of variance coefficient of variation.
 For drugs with very long elimination half lives or a complex
elimination phase, a complete plasma drug concentration Vs time
curve may be difficult to obtain for a BE study using cross over
design.
35

36. Contd.
 Some drugs e.g benzocaine, hydrocortisone, antiinfectives are
intended for local effect formulated as topical ointments, oral
suspensions, or rectal suppositories. The BE determination for
drugs that are not absorbed systemically from the site of
application can be difficult to assess. For these nonsystemic
absorbable drugs a surrogate marker is needed for BE
determination.
 Various drug delivery system and newer dosage forms are
designed to deliver the drug by nonoral route which may produce
only partial systemic bioavailability.
 Drugs having biotransformation.
36

37. Contd.
Table : Problems in BA and BE
37
Drugs with high intrasubject variability
Long elimination half life drugs
Biotransformation of drugs
Stereoselective drug metabolites
Drugs with active metabolite
Drugs with polymorphic
metabolism
Nonbioavailable drugs(for local effect)
Antacids
Local anesthetics
Antiinfectives
Antinflamatory steroids
Dosage forms for nonoral
administration
Transdermal
Inhalation
Ophthalmic
Intranasal
Bioavailable drugs that should not
produce peak drug levels
Hormone replacement therapy
Potassium supplements
Biotechnology derived drugs
Erythromycin interferon
Protease inhibitors
Complex drug substances
Conjugated estrogens

38. Contd.
Table :Possible surrogate Markers for BE Studies
38
Drug Product Drug Surrogate Marker
Metered dose inhaler Albuterol Forced expiratory
volume
Topical steroid Hydrocortisone Skin blanching
Anion exchange resin Cholestyramine Binding to bile acids
Antacids Magnesium and
aluminium hydroxide
gel
Neutralization of acid
Topical antifungal Ketoconazole Drug uptake into
stratum corneum

39. GENERIC SUBSTITUTION
 To contain drug costs, most state have adopted generic
substitution laws to allow pharmacist to dispense a generic drug
product for a brand- name drug product that has been prescribed.
 Some states have adopted positive formulary, which lists
therapeutically equivalent or interchangeable drug product that
pharmacist may dispense.
 Others use a negative formulary, which lists drug products that
are not therapeutically equivalent or interchange of which is
prohibited.
 And if the drug is not negative formulary , the unlisted generic
drug products are assumed to be therapeutically equivalent and
may not be interchanged.
 They serve as public information and advice to health agencies,
prescribers and pharmacists to promote public education in the
area of drug product selection.
39

40. Contd.
 Orange book which identifies drug products approved on the basis
of safety and effectiveness.
 Orange book contains therapeutic equivalence evaluations for
approved drug products made by various manufacturers. These
marketed drug products are evaluated according to specific
criteria.
 CDER publishes annually a listing of approved drug products ,
Approved drug products with therapeutic equivalence evaluation.
 The drug products are divided into two major categories ‘A’ codes
apply to drug products considered to be therapeutically
equivalent to other pharmaceutically equivalent products, and
‘B’ codes apply to drug products.
40

41. Contd.
41
A Codes
AA- Products in conventional dosage
forms not presenting BE problems
AB-Products meeting BE
requirements
AN-Solutions and powders for
aerosolization
AO-Injectable oil solutions
AP-Injectable aqueous solutions and,
sometimes, intravenous nonaqueous
solutions
AT-Topical products
B Codes
BC- Extended release tablets,
extended release capsule and extended
release injectables
BD-Active ingredients and dosage
forms with documented BE problems
BE-Delayed release oral dosage forms
BN-Products in aerosol-nebulizer
delivery system
BP-Active ingredients and dosage
forms with potential BE problems
BR- Suppositories or enemas for
systemic use
BT-Tropical products with BE issues
BX- Insufficient data

42. GENERIC BIOLOGICS (BIOSIMILAR DRUG PRODUCTS)
Biosimilar Product
A biosimilar is a biological product that is highly similar and has no clinically
meaningful differences from an existing FDA-approved reference product
Biological product
Biological products are regulated by the Food and Drug Administration (FDA)
and are used to diagnose, prevent, treat, and cure diseases and medical conditions.
Biological products are a diverse category of products and are generally large,
complex molecules. These products may be produced through biotechnology in
a living system, such as a microorganism, plant cell, or animal cell, and are often
more difficult to characterize than small molecule drugs.
Reference product
A reference product is the single biological product, already approved by FDA,
against which a proposed biosimilar product is compared. A reference product is
approved based on, among other things, a full complement of safety and
effectiveness data.
Interchangeable product
An interchangeable product is a biosimilar product that meets additional
requirements outlined by the Biologics Price Competition and Innovation Act.
As part of fulfilling these additional requirements, information is needed to
show that an interchangeable product is expected to produce the same clinical
result as the reference product in any given patient.
42

43. Contd.
Table : Comparison of biologic, and biosimilar products
43
Process Biologic Biosimilar
Manufacturing
Clinical
development
Regulation
Produced by biological process in
host cell lines
Sensitive to production process
changes expensive and specialized
production facilities
Reproducibility difficult to
establish
Extensive clinical studies, including
Phase I–III
Pharmacovigilance and periodic
safety updates needed
Needs to demonstrate
comparability
Regulatory pathway defined by
Europe (EMEA)
Currently no automatic substitution
intended
Produced by biological
process in host cell lines
Sensitive to production
process hanges expensive and
specialized production facilities
Reproducibility difficult to
establish
Extensive clinical studies,
including Phase I–III
Pharmacovigilance and periodic
safety updates needed
Needs to demonstrate similarity
Regulatory pathway defined by
Europe (EMEA)
No automatic substitution
allowed

44. Contd.
Regulatory perspectives for Biosimilar Products
 Existing generic definition is not appropriate for
biosimilar
 Approval of the biosimilar product should be based on
the demonstration of similarity to a suitable reference
drug with comprehensive comparative data
 Comprehensive characterization and comparison at
quality level shall provide a basis for a reduction in the
non‐clinical and clinical data
 A final determination of similarity can be based on a
combination of quality, non‐clinical and clinical
evaluation
44

45. Contd.
Requirements for Quality studies
Full CMC and comparability exercise data between biosimilar product
and reference product are required
• Extensive side by side characterization
• Physicochemical properties (including Immunochemical properties)
• Biological activity
• Specification
• Impurities
• Stability
 Analytical techniques should be state of art to detect slight differences
in quality attributes
 Acceptance criteria in setting up the specification should be established
and justified based on the results of a number of representative lot
analyses
45

46. Contd.
Demonstration of Similarity
The demonstration of comparability does not
necessarily mean that the quality attributes of the
two products will be identical, but they are highly
similar with two consequences
 Minor structural differences such as variability in
posttranslational modifications may be acceptable
but, must be justified
 Differences in impurity profiles should be justified
The impact of observed differences in the quality
attributes should be assessed and then non‐clinical
and clinical studies should be designed and
conducted on the basis of the results
46

47. Contd.
Requirements for Non‐clinical Studies
Comparative non‐clinical studies should be designed to
detect significant differences between the biosimilar
product and the reference product
In vitro study
• Receptor binding study
• Cell proliferation assay
In vivo study
• Biological/Pharmacodynamic studies relevant to the
clinical application
Toxicity
• At least one repeat dose toxicity study in a relevant
species, including toxicokinetic study, antibody
measurement
47

48. Contd.
 Requirements for Clinical studies
 Comparative clinical trials are required depending on the data
in terms of quality and nonclinical studies.
• Pharmacokinetic Studies/Pharmacodynamic Studies
• Clinical Efficacy & Safety trials
• Confirmatory PK/PD studies
 Equivalence trial is preferable, and margins should be
pre‐specified and justified
 Extrapolation to other indications of the reference drug may be
possible if similar efficacy and safety established in a
‘sensitive’ test model and scientifically justified
 Pre‐approval safety data from sufficient number of patients and
study duration should be provided to compare the nature,
severity, and frequency of adverse reactions (including
immunogenicity study)
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49. Contd.
Table : Biosimilars approved timeline
49
Biosimilar Reference Approval year
Omnitrope Somatropin 2006
Valtropin Somatropin 2006
Binocrit Epoetin alpha 2007
Retacrit Epoetin zeta 2007
Biograstim Filgrastim 2008
Zarzio Filgrastim 2009
Nivestim Filgrastim 2010

50. THE BIOPHARMACEUTICS CLASSIFICATION
SYSTEM (BCS)
 The BCS is a scientific framework for classifying drug
substances based on their Aqueous Solubility And
Intestinal Permeability.
 When combined with the dissolution of the drug product,
the BCS takes into account three major factors that
govern the rate and extent of drug absorption from IR
solid oral dosage forms. These factors are Dissolution,
Solubility and Intestinal Permeability.
 The aim of the BCS is to provide a regulatory tool for
the replacement of certain BE studies by conducting
accurate in vitro dissolution tests.
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51. Contd.
According to the BCS (Amidon et.al), Drug substances
are classified as follows:
CLASS 1: High Solubility–High Permeability
e.g. Metoprolol, Diltiazem, Verapamil, Propranolol
CLASS 2: Low Solubility–High Permeability
e.g. Glibenclamide, Ezetimibe, Phenytoin, Nifedipine
CLASS 3: High Solubility–Low Permeability
e.g. Cimetidine, Acyclovir, Captopril
CLASS 4: Low Solubility–Low Permeability
e.g Hydrochlorothiazide, Neomycin, Methotrexate
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52. Contd.
High Aqueous Solubility
 An objective of the BCS approach is to determine the equilibrium
solubility of a drug under approximate physiologic conditions.
 A drug substance is considered highly soluble when the highest dose
(in mg) strength is soluble (mg/ml) in 250 ml or less of aqueous
medium over the pH range 1-7.5 at 37°C. (FDA/Indian)
High Permeability
 Studies of the extent of absorption in humans, or intestinal
permeability methods can be used to determine the permeability class
membership of a drug.
 To be classified as highly permeable, a test drug should have an extent
of absorption >90% in humans. (FDA/Indian)
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.
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53. Methods to determine permeability
Some methods to determine the permeability of a drug from
the gastrointestinal tract include
(1) In vivo intestinal perfusion studies in humans;
(2) In vivo or in situ intestinal perfusion studies in animals;
(3) In vitro permeation experiments using excised human or
animal intestinal tissues;
(4) In vitro permeation experiments across a monolayer of
cultured human intestinal cells.
 When using these methods, the experimental permeability data
should correlate with the known extent-of-absorption data in
humans.
 After oral drug administration, in vivo permeability can be
affected by the effects of efflux and absorptive transporters in the
gastrointestinal tract, by food, and possibly by the various
excipients present in the formulation.
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54. DISSOLUTION
 The dissolution class is based on the in vitro dissolution rate of an
IR drug product under specified test conditions and is intended to
indicate rapid in vivo dissolution in relation to the average rate of
gastric emptying in humans under fasting conditions.
 An IR Drug product is considered rapidly dissolving when not less
than 85% of the label amount of drug substance dissolves within
30 minutes using USP apparatus I at 100 rpm or apparatus II at 50
rpm in a volume of 900 ml or less in each of the following media:
(1) acidic media such as 0.1 N HCl or simulated gastric fluid USP
without enzymes,
(2) a pH 4.5 buffer, and
(3) a pH 6.8 buffer or simulated intestinal fluid USP without
enzymes. The FDA is in the process of revising the BCS guidance
to permit biowaivers for generic formulations of class 3 drugs
54

55. Contd.
55

56. Significance of BCS
 Regulatory toll for replacement of certainBE studies.
 It can save both time and money—if the immediate -
release, orally administered drug meets specific criteria,
the FDA will grant a waiver for expensive and time
consuming bio- equivalence studies.
 Valuable tool for formulation scientist for selection of
design of formulated drug substance.
 When integrated with other information provide a
tremendous tool for efficient drug development.
 Reduces cost and time of approving Scale-up and post
approval challenges.
 Applicable in both pre-clinical and clinical drug
development process.
 Works as a guiding tool in development of various oral
drug delivery systems.
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57. THANK YOU
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