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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.

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slide1

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

multisource generic products and interchangeability
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: dr.vpshah@comcast.netVPShah-Ukraine-07

regulatory authority mission
Regulatory Authority Mission

“Assure that SAFE and EFFECTIVE drugs are marketed in the country and are available to the people”

VPShah-Ukraine-07

outline
Outline
  • Definition
  • Profile Comparison
  • Biowaiver
  • Biopharfmaceutics Classification System (BCS)
  • Dissolution test conditions for biowaiver
  • Conclusion

VPShah-Ukraine-07

bcs based biowaiver
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

bcs based biowaiver6
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

equivalence test
EquivalenceTest

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

dissolution profile comparison
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

dissolution profile comparison14
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

dissolution profile comparison15
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

slide17

FDA Guidance for IndustryWaiver 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

biopharmaceutics classification system
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

biopharmaceutics classification system20

Biopharmaceutics Classification System

Solubility

High

Low

DrugSubstance

Permeability

High

Low

Very Rapid

DrugProduct

Dissolution

Rapid

Slow

VPShah-Ukraine-07

biowaiver based on bcs
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

equivalence test22
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

dissolution test
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

dissolution test24
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

slide25
WHOMultisource (generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability

WHO Technical Report Series, No. 937, 2006, Pages 347-390

VPShah-Ukraine-07

dissolution test bcs
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

VPShah-Ukraine-07

Continued … 2

dissolution characteristics test results
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

bcs based biowaivers
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

bcs based biowaiver29
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

bcs based biowaiver30
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

conclusions
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 technical series report
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