A brief review of the major global guidelines regarding biowaivers.

1. REGULATORY STATUS OF BIOWAIVERS:
GLOBAL PERSPECTIVE
Ikjot Sodhi
M.S. (Pharmaceutics)
NIPER, Mohali

2. CONTENTS:
 Background: About Biowaivers
 Current Pedestals of Biowaivers
Perspective
Regulatory Status of Biowaivers: Global
 Regulatory Guidelines and Guidances
 Conclusion
2

3. BACKGROUND: ABOUT BIOWAIVERS
Pharmaceutical
Equivalence
Perspective
Regulatory Status of Biowaivers: Global
Bioequivalence
Therapeutic
Equivalence
3

4. CURRENT PEDESTALS OF BIOWAIVERS
Applications for biowaivers are granted on the basis of:
BCS
• Considers the dose:solubility
ratio, permeability and dissolution
Perspective
Regulatory Status of Biowaivers: Global
behaviour.
IVIVC
• Based on correlation between in vitro data
and in vivo profile.
Composition Proportionality
• New product is qualitatively same and 4
quantitatively proportional to bio-batch.

5. BCS BASED BIOWAIVERS
Class I Class II of solid oral
For grants
• High Solubility • Low Solubility of:
dosage forms
• High • High
Perspective
Regulatory Status of Biowaivers: Global
Permeability • Permeability products
SUPAC-IR
• ANDAs
Class III Class IVAspects:
Current
• High Solubility • Low Solubility
• Low •• Low
Extension Potential
Permeability • Permeability
Risk Assessment
• Objections
Along with dissolution behaviour of product 5

6. IN VITRO - IN VIVO CORRELATION
Level A
Perspective
Regulatory Status of Biowaivers: Global
Level B
Level C
Multi-Level C
Level D
Used for biowaiver grants of :
•modified release products or 6
•products subject to change in manufacturing procedure.

7. Regulatory Status of Biowaivers: Global
Perspective
7
1000
mg
COMPOSITION PROPORTIONALITY
500
mg
250
mg
100
mg

8. DISSOLUTION TESTING - SOUL OF BIOWAIVERS
Perspective
Regulatory Status of Biowaivers: Global
CP
BCS
IVIVC
DISSOLUTION TESTING
8

9. Regulatory Status of Biowaivers: Global
Perspective
9
DISSOLUTION TESTING - SOUL OF BIOWAIVERS

10. GUIDELINES OF
REGULATORY AGENCIES
HHS-FDA (USA)
• CFR Sec. 320.22(b) „Criteria for waiver of evidence of
in vivo bioavailability or bioequivalence.‟
Perspective
Regulatory Status of Biowaivers: Global
EMEA (EU)
• Guideline on the Investigation of Bioequivalence, 2010
PMDA (Japan)
• Guideline for Bioequivalence Studies of Generic
Products, 2006
10
…continued

11. GUIDELINES OF
REGULATORY AGENCIES
CDSCO (India)
Perspective
Regulatory Status of Biowaivers: Global
• Guidelines for Bioavailability and Bioequivalence
Studies, 2005
WHO (International)
• Revision of Multi-source (generic) Pharmaceutical
Products: Guidelines on Registration Requirements to
Establish Interchangeability, 2005
11

12. HHS-FOOD AND DRUG ADMINISTRATION
Dosage Forms
• Parenterals, solutions, IR solid oral dosage
forms
Perspective
Regulatory Status of Biowaivers: Global
Drug Efficacy Study Implementation (DESI)
• No past bioINequivalence case
• Example: Hydroxyzine Hydrochloride Tablets
Fed-BE Study
• If taken on empty stomach
• No effect of food
12
„Criteria for waiver of evidence of in vivo bioavailability or bioequivalence‟, CDER, HHS-FDA, CFR Sec. 320.22(b)

13. HHS-FOOD AND DRUG ADMINISTRATION
BCS Based Biowaivers
• Only IR products with class 1 APIs
• Post-change products (for minor changes)
Perspective
Regulatory Status of Biowaivers: Global
Proportional Similarity based biowaivers
• Else additive change must be NMT 10% or
• Change of API compensated by excipients in
different strengths
IVIVC based biowaivers
• For MR products
• Post-change products (SUPAC Level 3)
13
FDA Guidances- 1995, 1997, 1997, 2000, 2003

14. EUROPEANS MEDICINES AGENCY
• For additional strengths
Composition • Some deviations from exact
Proportionality proportionality allowed
Perspective
Regulatory Status of Biowaivers: Global
• Acceptable level A correlation
IVIVC Based • Grants of biowaivers for variations
• Class I and III
BCS based
Biowaivers
• Pediatric Investigation Plan(PIP)
Biowaivers of • Pediatric Committee decides eligibility
Pediatric Study of biowaivers
14
Guideline on the Investigation of Bioequivalence, 2010

15. PHARMACEUTICALS AND
MEDICAL DEVICES AGENCY
BCS not recognised testing
Multimedia dissolution
Perspective
Regulatory Status of Biowaivers: Global
• •McIlvaine buffersANDAsto prepare media
No biowaivers to
used in Japan
• Dissolution experimental duration is defined
IVIVC not recognised
• Passing criteria
• •Low solubility: predictor of in vivo absorption 85% disslution
IVIVC not real Drug product fails to reach behaviour
Wider variations allowed
Japanese Achlorhydic patients
• Upto level D, variations are allowed without BE testing under
• Dosage form performance across physiological pH carefully
certain conditions
reviewed
• Separate qualification requirements for core versus coating
layer for coated products. 15
Guideline for Bioequivalence Studies of Generic Products, PMDA, 2006

16. CDSCO GUIDELINES
BCS based biowaiver: Class I
Dosage forms
• Highly soluble
• Highly permeable nasal sprays, powders
Perspective
Regulatory Status of Biowaivers: Global
• Solutions, gases,
• Dissolution: 85% in 15 min
for reconstitution
Composition proportionality:
Excipient considerations:
• Qualitatively same
• • All dosage forms must
Quantitatively proportionalcontain essentially
• same excipients as comparator
Same method of manufacture
• At least one of the strength has been studied for
its bioavailability
16
Guidelines for Bioavailability and Bioequivalence Studies, CDSCO, 2005

17. WORLD HEALTH ORGANIZATION
BCS Class Dissolution profile Qualification Criteria
High solubility
Class I Rapidly dissolving F2>50
Perspective
Regulatory Status of Biowaivers: Global
• When API shows dose:solubility ratio of less
Very Rapidly dissolving Profile comparison not
than 250mL over pH range of 1.2-6.8 needed
Class II with weak acidic Rapidly dissolving at pH Profile comparison at
High permeability
properties 6.8 pH 1.2, 4.5, 6.8
• WhenIIIAPI is absorbed to the extent of assessment of
Class Very rapidly dissolving Risk 85% or
more bioInequivalency more
critical
17
WHO Multisource Document, 2005

18. Regulatory Status of Biowaivers: Global
Perspective
18
COMPARATIVE APPROACH

19. COMPARATIVE APPROACH
Parameter US EU Japan
Allowed BCS Class I I and III All
Highly permeable >90% >85% Not relevant
Perspective
Regulatory Status of Biowaivers: Global
Rapidly >85% 30 min, 3 >85% 15 min, 3
No requirement
Dissolving pHs pHs
SUPAC allowed- None “Strictly Required if low
Media Surfactant
if justified discouraged” solubility
Type A-E, Type B,
Intramural
SUPAC- All BCS C, E like SUPAC
Composition Variation
Classes level 1, 2, 3 Type D
Change
unique
IVIVC as
Dissolution Allowed for MR
Allowed Not permitted
Regimen/BE SUPAC
Surrogate 19

20. Regulatory Status of Biowaivers: Global
Perspective
20
CONCLUSION

21. Regulatory Status of Biowaivers: Global
Perspective
21

22. Perspective
Regulatory Status of Biowaivers: Global
REGULATORY STATUS OF
BIOWAIVERS: GLOBAL PERSPECTIVE
22
Back-up Slides

23. Regulatory Status of Biowaivers: Global
Perspective
23
BIOWAIVER MONOGRAPHS

24. Regulatory Status of Biowaivers: Global
Perspective
24
RISK ASSESSMENT

25. Regulatory Status of Biowaivers: Global
Perspective
25
DISSOLUTION PROFILE COMPARISON

26. EXCIPIENTS
 Well established
 No interaction with the PK of the active substance
Perspective
Regulatory Status of Biowaivers: Global
expected
 Not affect the rate and extent of absorption
 In case of atypically large amounts of known
excipients or new excipients being used, additional
documentation has to be submitted.
26

27. BIOPHARMACEUTICS CLASSIFICATION
SYSTEM
 Dose-Solubility Ratio (Highly soluble):
 FDA- Highest dose strength is soluble in ≤ 250mL
Perspective
Regulatory Status of Biowaivers: Global
aqueous media over pH range of 1-7.5, 37±1⁰C.
 EMEA- same except for 1-6.8
 Permeability (Highly permeable):
 FDA- 90%
 EMEA- 85%
 Dissolution behaviour:
 FDA - pH 1.0, 4.6, 6.8
27
 EMEA - pH 1.2, 4.5, 6.8