Multisource (generic) products and Interchangeability

WHO Prequalification Programme June 2007

Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and

Biopharmaceutical Classification System.

Hotel Bratislava1 Malyshko Street

Kyiv, UkraineDate: 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: [email protected] VPShah-Ukraine-07

mailto:[email protected]


Regulatory Authority Mission

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

to the people”

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Outline

Definition

Profile Comparison

Biowaiver

Biopharfmaceutics Classification System (BCS)

Dissolution test conditions for biowaiver

Conclusion VPShah-Ukraine-

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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.

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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.

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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.


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Dissolution Profile Comparison

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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.

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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.

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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.

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BCSBiopharmaceutics Classification System

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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)

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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

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Biopharmaceutics Classification System

Drug SubstanceSolubility

Permeability

High

High

Drug Product DissolutionVery Rapid

Low

Low

RapidSlow

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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.


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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.


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Dissolution Test• In Vitro Quality Control Dissolution TestDissolution 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 TestIn 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.

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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

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WHOMultisource (generic) Pharmaceutical Products:

Guidelines on Registration Requirements to Establish Interchangeability

WHO Technical Report Series, No. 937, 2006, Pages 347-390VPShah-Ukraine-07


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

Continued … 2

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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

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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.

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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.

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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.

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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.

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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.

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Thank You

Documents

Multisource (generic) products and Interchangeability