This document discusses concepts related to bioequivalence studies for generic drugs, including: - Generic drugs must be pharmaceutically equivalent and bioequivalent to the reference brand name drug to be considered substitutable. - Bioequivalence studies evaluate the rate and extent of absorption of the generic drug compared to the brand name drug and ensure the generic drug performs in the same manner. - Acceptance criteria for bioequivalence studies specify that the 90% confidence intervals for AUC and Cmax of the generic must fall within 80-125% of the reference drug. - Special study designs may be needed for certain drugs based on their pharmacokinetic properties or ability to be measured in plasma.

1. Claim & Reasonable Probability
Understand Product, Control Process & Demonstrate Quality
Roohi B. Obaid & Obaid Ali
Civil Service Officer
Drugs Regulatory Authority of Pakistan

2. Claim & Reasonable Probability
Understand Product, Control Process & Demonstrate Quality
Part B
Obaid Ali

3. Warm up exercise
Fundamental Scenarios and Bio-studies or Dissolution Studies

4. Drug must be available in the blood stream in the same pattern
on which clinical studies have been performed
Similarity & Equivalency?

5. If a tablet is disintegrated, in which
situations, it will not reach to the blood

6. If a tablet is dissolved, in which
situations, it will not reach to the blood

7. Have you ever imagined a situation
where a tablet can come out from the
body as it is?
If so, can it produce effect

10. Biopharmaceutical Evaluation
From Fiction to Reality

11. Performance
should be the
same way

12. No Worse
Performance
should be the
same way

13. No Worse
No Better
Performance
should be the
same way

14. Please make it clear
They are not
clinical studies
Nothing to do
with Safety &
Efficacy of
molecule
Evaluating the
Similarity of
Trends
&
Kinetics

15. Drug Performance
Dosage
Form
Drug in
solution
Gut wall Blood
Site of
Activity
Therapeutic
Effect
Dosage Form
Performance
Pharmacokinetic
Measurement
Clinical/PD
Measurement

16. Science of Bioequivalence
Developed over the last few decades
Continues to evolve
Specific approaches depend on a number of
factors
Can be simple or highly complex

17. Generic Drug
….. equivalent drug products
that can be substituted at the
pharmacy level for the
reference /innovator drug, and
each other, without any
adjustment in dose or other
additional therapeutic
monitoring

18. Pharmaceutical Equivalence
Same active ingredient
Same dosage form
Same route of administration
Identical in strength or concentration

19. What is Substitutability?
Pharmaceutically
equivalent
1
Bioequivalent
2
Generic Drugs must be

20. Generics not necessarily identical
Excipients Difference
Manufacturing Differences
Formulation Difference
Shape, color difference

21. Bioequivalence & Generic Drugs
Pharmaceutical Equivalent & Bioequivalent
Pharmaceutical Equivalence
Does not mean equivalent performance

22. Label
1 CMC
2 Bio-
studies
3 Plant
GMP
4

23. Brand Name Drug Generic Drug
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies
7. Clinical Studies 6. Bioequivalence
8. Bioavailability

24. Bio-
studies
Dissolution
BioavailabilityBioequivalence

25. PK PD

26. 26
Clinical/PD Dose-
Response
Clinical/PDResponse
Log Dose

27. 27
Plasma
Concentration-Dose
Dose
PlasmaConc.

28. What is Reference/Innovator Drug
Innovator
Brand
Authorized
Brand

29. 29
AUC and Cmax 90% Confidence Intervals (CI) must
fit between 80%-125%

30. To determine rate and extent of absorption of
generic, innovator
From 2009

31. On healthy human volunteers but use patients if
there is a safety concern (Etoposide, Clozapine)
Male, Female both

32. Bio-analytical method must be validated

33. 33
• In vivo measurement of
active moiety or moieties
in biologic fluid
• In vivo pharmacodynamic
comparison
• In vivo limited clinical
comparison
• In vitro comparison

34. Single-dose,
two-way
crossover,
fasted
Single-dose,
two-
waycrossover,
fed
Alternatives

35. 1
• Single-dose,
parallel, fasted
• Long Half-Life
(wash-out)
Amiodarone,
Etidronate
2
• Single-dose,
replicate design
• Highly
Variable Drugs
3
• Multiple-dose,
two-way
crossover,
fasted
• Less Sensitive
Clozapine
(Patient Trials)
Chemotherapy
Trials
4
• Clinical
endpoint study
• Topicals Nasal
Suspensions

36. Urine may be used for measurement when drug cannot
be measured in plasma e.g. Potassium Chloride
Baseline in blood is too high to permit accurate
measurement

37. Special Case: Alendronate Sodium (5 to 70 mg)
Problem with plasma detection because of low
concentration & re-distribution from bone

38. Pharmacodynamics Approach
Generic topical corticosteroid, ability to produce
vasoconstriction

39. Special Case: Tretinoin Acne Gel
Problem with plasma detection, endpoint related to
healing region is considered

40. Special Case:
Highly Variable Drugs
3 period bio-studies TRR, RTR, RRT

41. BioWaivers
IV solutions, Oral solutions, BCS class 1, old drugs
with no bio-equivalency problem

42. Oral Solution
Must not contain an excipient that may significantly
affect absorption of API
e.g. Prednisolone sodium phosphate oral solution
Inactive must not have safety issue

43. Solid Oral Dosage
Dissolution testing on all strengths
Strength proportionality must be similar to the biostrength
In-vivo BE must be established for higher strength
But for safety lower strength
E.g. Terazosin HCl 1, 2, 5 & 10 mg strength, 2 is acceptable

44. Highly Soluble, Highly Permeable, Rapidly Dissolving
e.g. Ofloxacin

45. Dissolution e.g. Omeprazole
Use of dissolution data for biowaiver of non-bio strength
Two stage dissolution testing
(acid medium & buffered medium)

47. Dissolution
as a tool
Batch to
batch
consistency
Quality
Assurance
Formulation
development
Bio-waiver
In vitro BE
studies
Alcohol
induced dose
dumping
Post-approval
manufacturing
changes

48. Dissolution Method Development
Dissolution
Material
Attributes
Process
Parameters
Formulation
Variables

49. REMEMBER
Dissolution
method is
product specific

50. Dissolution Method Development
Product Specific
Method Development Evaluation of
method
Discriminating
Ability
Acceptance
Criteria
1
2
3

51. Evaluation of
method
1
Solubility Profile
Apparatus
Selection
Dissolution/Release
Media
Rotation speed Sink conditions
Supportive data
for surfactant
selection

52. Discriminating
Ability
2
Differentiates DP manufactured under
target conditions vs. formulation with
meaningful variations for the most
relevant manufacturing variables

53. Acceptance
Criteria
3
Bioequivalence
batches
85% of drug is
dissolved or
where plateau of
drug dissolved is
reached
Selection of time
points should be
where Q=80% of
drug is dissolved

54. Common Deficiencies in Regulatory Submissions
Dissolution method
development not
included in
application
Failure to
demonstrate
discriminatory
power (information
lacking on CMA &
PP)
Data not supportive
of proposed
acceptance criteria

55. Common Deficiencies in Regulatory Submissions
No dissolution
data for lower
strength
waivers,
multi-media
testing for MR
products
No method
transfer report
on site change
after method
validation
Dissolution
data collected
on aged lots
Individual
dissolution
data is not
submitted

56. Dissolution Failure
Formulation had not been
properly validated (FDA 2008)
Therapeutic failure reported in
2007
Tropol XL (Sandoz) approved
in 1992
Metoprolol Succinate Tabs ER
Recall due to dissolution
What should we learn?
What do you think?
Recalled due to dissolution
2009 Ethex (KV
Pharmaceuticals)
2014 Wockhardt & Ranbaxy

57. Sometimes Math does not favor
ADHD
• Mallinckrodt
• Methyl Phenidate HCl
tab
• 18, 27, 36, 54 mg dose
Failure
• Fasting & fed had two
different behavior in
extended release

58. Sometimes Math does not favor
Bupripion
HCl tab
• Study on low
dose and
waiver on
high dose
Failure
• Desired
kinetics was
not achieved
Teva
• FDA asked
to stop
distribution
in sep 2012

59. Sometimes Math does not favor
Bupripion
(Wellbutrin)
IR Tab of
SKB 1985
Bupripion SR
Tab 1996
& XL Tab
2003
Based on
evidence
demonstratin
g BE with
low strength
In 2006,
Generic
version Mfg
by
Impax/Teva
were
approved
85 post
marketing
reports from
Jan-Jun 2007
Experienced
undesirable
effects
Increased side
effects,
Decreased
therapeutic
effect
Re-switched
on brand
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60. Sometimes Math does not favor
Temporal
relationship
under
question
FDA re-
examined
BE data
Conducted
study
Withdrawal
of Teva drug
in Mar 2013
against Sep
2012 FDA
advice
Also generic of
Actavis
withdraw their
version
A new
challenge
General
rule will not
work
always
Its life, please
care
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