Transcript WHO Prequalification Programme June 2007

Multisource (generic) products
and Interchangeability
Training Workshop on Dissolution,
Pharmaceutical Product Interchangeability
and Biopharmaceutical Classification System.
Hotel Bratislava
1 Malyshko Street
Kyiv, Ukraine
Date: 25 to 27 June 2007
WHO Prequalification Programme
June 2007
Multisource (generic) products
and Interchangeability
Profile Comparison,
BCS Based Biowaiver
Presenter:
Vinod P. Shah, Ph. D.
FIP Scientific Secretary
North Potomac, MD 20878, USA
E-mail: [email protected]
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
Regulatory Authority
Mission
“Assure that
SAFE and EFFECTIVE
drugs are marketed in the
country and are available
to the people”
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Outline
 Definition
 Profile Comparison
 Biowaiver
 Biopharfmaceutics Classification System (BCS)
 Dissolution test conditions for biowaiver
 Conclusion
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS Based Biowaiver
A biowaiver based on solubility and permeability
consideration of active pharmaceutical
ingredient, as well as dissolution profile similarity
of the multisource (test) and the comparator
(reference) product in pH 1.2, 4.5 and 6.8 media.
Ref: WHO Technical Report Series, No. 937, 2006, Page: 347-390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS Based Biowaiver
 When appropriate, in vitro testing and BCS-based
biowaivers for immediate release pharmaceutical
products can assure equivalence between the
multisource product and the comparator product.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Equivalence Test
Equivalence test is a test that determines the
equivalence between the multisource (test)
product and the comparator (reference) product
using in vivo and/or in vitro approaches.
Ref: WHO Technical Report Series, No. 937, 2006, Page: 347-390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Profile Comparison
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Profile Comparison
 Regulatory interest is to know how similar the two curves
are, and for this reason, the f2 comparison has been the
focus in Agency Guidances.
 When the two profiles are identical, f2 = 100. An average
difference of 10% at all measured time points results in a
f2 value of 50. FDA has set a public standard of f2 value
between 50-100 to indicate similarity between two
dissolution profiles.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Profile Comparison
 At least 12 units should be used for each profile determination. To use
mean dissolution data, the % cv at the earlier point should not be more
than 20% and at other time points should not be more than 10%.
 The dissolution measurements of the two products (T and R, pre- and
post- change, two strengths) should be made under the same test
conditions. The dissolution time points for both the profiles should be
the same, e.g., for IR products 15, 30, 45 and 60 minutes, for ER
products 1, 2, 3, 5 and 8 hours.
 Because f2 values are sensitive to the number of dissolution time points,
only one measurement should be considered after 85% dissolution of
the product.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Profile Comparison
 For products which are rapidly dissolving, i.e., more than
85% dissolution in 15 minutes or less, a profile
comparison is not necessary.
 A f2 value of 50 or greater ensures sameness or
equivalence of the two curves and, thus, the performance
of two products.
 For circumstances where wide variability is observed, or a
statistical evaluation of f2 metric is desired, a bootstrap
approach to calculate a confidence interval can be
performed.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS
Biopharmaceutics Classification System
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WHO Prequalification Programme
June 2007
FDA Guidance for Industry
Waiver of in vivo bioavailability and
bioequivalence for immediate-release solid oral
dosage forms based on Biopharmaceutics
Classification System
HHS, US FDA, 2000 (http://www.fda.gov/cder/guidance/index.htm)
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Biopharmaceutics Classification System
• 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, BCS takes into
account three major factors that govern the rate and
extent of absorption from IR solid oral dosage forms:
dissolution, solubility and intestinal permeability.
BCS Guidance:
For IR drug products, non-NTI drug products
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Biopharmaceutics Classification System
Solubility
High
Low
Permeability
High
Low
Dissolution
Very Rapid
Rapid
Slow
Drug Substance
Drug Product
VPShah-Ukraine-07
Biowaiver Based on BCS
A biowaiver based solubility and permeability
consideration of active pharmaceutical
ingredient, as well as dissolution profile similarity
of the multisource (test) and the comparator
(reference) product in pH 1.2, 4.5 and 6.8 media.
Ref: WHO Technical Report Series, No. 937, 2006, Page: 347-390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Equivalence Test
Equivalence test is a test that determines the
equivalence between the multisource (test)
product and the comparator (reference) product
using in vivo and/or in vitro approaches.
Ref: WHO Technical Report Series, No. 937, 2006, Page: 347-390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Test
• In Vitro Quality Control Dissolution Test
Dissolution test procedure identified in the pharmacopeia,
generally a one time point dissolution test for immediate
release products and 3 or more time points dissolution test
for modified release products.
• In Vitro Equivalence Test
In vitro equivalence test is a dissolution test that includes
dissolution profiles comparison between the multisource
product and the comparator product in three media: pH
1.2, 4.5 and 6.8.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Test
 Quality control dissolution test – Generally a single point
compendial test for routine batch-to-batch performance
test.
 Equivalence (BE) dissolution test = QC dissolution test
+ additional dissolution tests
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
WHO
Multisource (generic) Pharmaceutical Products:
Guidelines on Registration Requirements to
Establish Interchangeability
WHO Technical Report Series, No. 937, 2006, Pages 347-390
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Dissolution Test (BCS)
Multisource (test) and
Comparator (reference) product
- Paddle method at 75 rpm or
Basket method at 100 rpm
- Dissolution profile in pH 1.2, 4.5 and 6.8
- Similarity f2 > 50
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WHO Prequalification Programme
June 2007
Continued … 2
Dissolution Characteristics - Test Results
 Very rapidly dissolving – 85% in 15 min
 Rapidly dissolving – 85% in 30 min
 Slowly dissolving – more than 30 min for 85% dissolution
For biowaivers, multisource and comparator (T and R)
products must have similar dissolution profile in all 3
media – pH 1.2, 4.5 & 6.8
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS Based Biowaivers*
 BCS Class 1: HS/HP
- VRD or RD in pH 1.2, 4.5 and 6.8
 BCS Class 2: LS/HP/Weak Acids
- Rapid dissolution in pH 6.8 and similar dissolution profile in
pH 1.2, 4.5 and 6.8
 BCS Class 3: HS/LP/VRD
- Contains no inactive ingredients that are known to alter GI motility
and/or absorption
For biowaivers Test (multisource) and Reference (comparator) products must have
similar dissolution profile (f2) in all 3 media
*Ref: WHO Technical Report Series, No. 937, 2006, Annex 7: Page: 347-390 and
Annex 8: Page 391-438.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS Based Biowaiver *
 Well established excipients
 Excipients should NOT alter GI motility and drug absorption kinetics
– Excipient is also present in comparator or
– Excipient is present in a number of drug products having a registration
in ICH-country
• in amount usual for dosage form
• FDA inactive ingredient database
Ref: WHO Technical Report Series no. 937, 2006. Annex 7, pages 347 - 390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
BCS Based Biowaiver *
 Risk analysis:
– Risk to accept bioinequivalent drug product
&
– Therapeutic consequences of bioinequivalent drug product
*Ref: WHO Technical Report Series no. 937, 2006. Annex 7, pages 347 - 390.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Conclusions
• BCS principles provide a reasonable approach for
testing and approving drug product quality.
• BCS applications for Class 2 and 3 are challenging,
but at the same time provides opportunities for
lowering regulatory burden with scientific
rational.
• BCS also provides an avenue to predict drug
disposition, transport, absorption, elimination.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
WHO Technical Series Report
WHO Expert committee on Specifications for Pharmaceutical
Preparations, Fourtieth Report
WHO Technical Report Series 937, 2006
- Annex 7. Multisource (generic) pharmaceutical products:
guidelines on registration requirements to establish
interchangeability, pages 347 - 390.
- Annex 8. Proposal to waive in vivo bioequivalence requirements
for WHO Model List of Essential Medicines immediate-release, solid
oral dosage forms, pages 391 - 438.
VPShah-Ukraine-07
WHO Prequalification Programme
June 2007
Thank You
WHO Prequalification Programme
June 2007