Stability Considerations for Generic Drugs

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Generic Drugs Stability Considerations for Suhas J. Patankar, Ph. D. Team Leader Division of Chemistry III Office of Generic Drugs, FDA FDA Small Business Webinar November 4, 2013 SJP_01_110413 The opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or the policies of the FDA

Transcript of Stability Considerations for Generic Drugs

Page 1: Stability Considerations for Generic Drugs

Generic Drugs Stability Considerations for

Suhas J. Patankar, Ph. D. Team Leader

Division of Chemistry III Office of Generic Drugs, FDA

FDA Small Business Webinar November 4, 2013

SJP_01_110413

The opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or the policies of the FDA

Page 2: Stability Considerations for Generic Drugs

s Synopsi

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Introduction

Previous Communications

Follow up on Drug Master Files (DMFs)

Follow up on Abbreviated New Drug Applications (ANDAs)

Summary

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Page 3: Stability Considerations for Generic Drugs

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Introduction

TEMPERATURE

HUMIDITY

AIR

TIME

LIGHT

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Introduction Contd.

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Why Stability ? Applicable to all ANDAs

One of the indicators of quality, safety and efficacy

Managed through “Life Cycle” of the drug product

Therefore, a Quality Target Product Profile (QTPP)

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Page 5: Stability Considerations for Generic Drugs

Previous Communications

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Stability Considerations for Generic Drugs

GPhA QbD Workshop

GPhA Meeting

GPhA CMC Workshop

DIA Webinar

Further Communications

May 2011 Oct. 2011 May 2012 Nov. 2012 Future Dates !!!

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GPhA CMC Workshop

June 2013

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Previous Communications Contd.

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Questions at GPhA Workshops/Meeting

Questions to the Office

Questions through Controls

Questions!! Questions!! Questions!!

Follow Up is Helpful

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Follow Up on DMFs

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Completeness Assessment Different standard than full scientific review Demonstration of commencement of stability DMF is amended as additional data becomes

available

Full Scientific Review Stability data on batches manufactured under CGMP Batches representative of commercial manufacturing

process Stability data covering proposed retest period

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Page 8: Stability Considerations for Generic Drugs

Follow Up on ANDAs

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General Discussion

Drug Product Manufacturing Discussion of dosage forms that constitute

bulk of ANDA submissions

Discussion of other dosage forms

Drug Product Packaging

Stability Studies

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Follow Up on ANDAs

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General Discussion Applicable to all new ANDAs and DMFs

(Type II)

NOT applicable to post-approval changes

At submission Six month Accelerated and Long-term data, on Three Primary batches Three pilot scale batches or two pilot scale

batches and one small scale batch

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Follow Up on ANDAs

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General Discussion Contd. At submission if six month accelerated data

shows significant change or failure of any attribute in one or more batches, then six month of intermediate data

ICH time recommendations are only in terms of months

Application needs to be updated with accrued long-term stability data and where applicable Intermediate stability data

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Page 11: Stability Considerations for Generic Drugs

Follow Up on ANDAs

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Drug Product Manufacturing All ANDA Submission Batches

Same Drug Substance Quality intended for Market Product

Same chosen formula based on product development studies for Components and Composition

Same Specifications

Same Drug Product Quality intended for Market Product

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Follow Up on ANDAs

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Drug Product Manufacturing Contd. A minimum of two lots of drug substance to be used to prepare

primary batches (MDI and meter-dose spray pumps three lots) When two sources of drug substance are proposed

Comparison and Justification by the firm of physico-chemical properties and impurities

Three batch data on one source for qualification of first source (preferably used in BE studies)

One batch (bio Strength/s) using second source(s) along with comparative dissolution data

Accelerated, long-term stability data (6 months at filing) on strengths manufactured for each source. Intermediate condition stability data could also be recommended

If first source is withdrawn additional data will be necessary

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Follow Up on ANDAs

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Drug Product Manufacturing Contd. Module 3 should contain all the relevant

information When more than one lot of drug substance is

used

When more than one source of drug substance is used

When more than one lot of excipient/s are used

Executed batch records

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Follow Up on ANDAs

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Drug Product Manufacturing (Discussion of dosage forms that constitute bulk of ANDA submissions)

Solid Oral Dosage Forms: Current Thinking Two Pilot Scale batches of 100,000 units or at least 10%

of proposed production whichever is greater

Third batch can be smaller than 10% of proposed production but NLT 25% of the pilot scale

All submission batches manufactured under CGMP with same formulation, same specifications, and at the commercial site

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Follow Up on ANDAs

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Drug Product Manufacturing (Discussion of dosage forms that constitute bulk of ANDA submissions) Contd. Parenterals: Current Thinking

Two batches at least 10% of proposed commercial size (i.e. pilot scale size) or 50 L whichever is larger

Third batch can be smaller than 10% of proposed production but NLT 25% of the pilot scale

All submission batches manufactured under CGMP with same formulation, same specifications, and at the commercial site

Split filling of bulk solution does not constitute discrete batches

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Page 16: Stability Considerations for Generic Drugs

Follow Up on ANDAs

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Drug Product Manufacturing (Discussion of other dosage forms)

President’s Emergency Plan for AIDS Relief (PEPFAR) ANDAs http://www.fda.gov/downloads/Drugs/GuidanceComplianceR

egulatoryInformation/Guidances/UCM079742.pdf

Positron Emission Tomography (PET) ANDAs http://www.fda.gov/downloads/Drugs/GuidanceComplianceR

egulatoryInformation/Guidances/UCM290024.pdf

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Follow Up on ANDAs

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Drug Product Manufacturing (Discussion of other dosage forms) Contd.

Inhalation Solution/Nasal Spray (non-metered dose) ANDAs http://www.fda.gov/downloads/Drugs/GuidanceComplianceR

egulatoryInformation/Guidances/UCM070111.pdf

Transdermal and Related ANDAs http://www.fda.gov/downloads/Drugs/GuidanceComplianceR

egulatoryInformation/Guidances/UCM220796.pdf

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Follow Up on ANDAs

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Packaging Representative samples from all three batches must

be packaged in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b). Current Thinking: For Tablets and Capsules a minimum of 100,000

units in all proposed presentations is recommended.

Secondary Packaging as per ICH Q1A(R2) Container Closure Section (2.2.4)

Packaging System the same as or similar to proposed for storage and distribution

Variability introduced by packaging should be captured

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Follow Up on ANDAs

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Stability Studies Expectation for Storage Positions

Applicable to liquids, solutions, suspensions, semi-solids etc.

Primary batches placed on stability in both inverted (or horizontal/lateral) and vertical positions

Routine stability on worst case orientation

Preservative Effectiveness One of the primary batches tested for anti-microbial

preservative effectiveness and preservative content at the end of proposed expiration dating

Product specification includes preservative content

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Follow Up on ANDAs

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Stability Studies Contd. Extractable Leachable testing Generally one time studies When product packaged in multiple types of

container/closures additional studies recommended

Reconstitution/Dilution and In-Use Stability studies Studies performed when the product is so labeled Follow the ICH recommendations

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Page 21: Stability Considerations for Generic Drugs

Summary

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Office of Generic Drugs (OGD) has communicated with the industry on emerging stability expectations

Follow up on DMFs

Covered general discussion, stability studies, drug product manufacturing and drug product packaging for ANDAs

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Page 22: Stability Considerations for Generic Drugs

Acknowledgements

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Kathleen Uhl, M.D.

Lawrence Yu, Ph.D.

Susan Rosencrance, Ph.D.

Vilayat Sayeed, Ph.D. and Devinder Gill, Ph.D.

Chemistry Directors

Stability Working Group: Upinder Atwal, Raman Murali, Suhas Patankar, Radhika Rajagopalan, Neeru Takiar