Mutagenic Impurities: Guidances Update w/ CMC Perspectives David DeAntonis July 21, 2011

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Topics to Cover Regulatory History of Mutagenic Impurity Guidance Current status of ICHM7 effort CMC hot topics

Regulatory History 2000-2004: ICH Q3A/B (R) issued in 2002 “Lower thresholds may be appropriate for unusually toxic impurities” Increased awareness and regulatory scrutiny on residual levels of genotoxic impurities in API and drug products EMEA issues draft guidance for genotoxic impurities stressing avoidance vs. acceptance of a low limit 2004 EMEA updates draft guidance and introduces the TTC limit (1.5 micrograms/day) 2005/06 PhRMA Position Paper: PhRMA GTI Task Force in 2005- Muller L. et al, A Rationale for Determining, Testing and Controlling Specific Impurities in Pharmaceuticals that Possess Potential for Genotoxicity Introduces concept of the staged TTC for clinical trial materials

Regulatory History 2007 CHMP Guideline on the Limits of Genotoxic Impurities. CPMP/SWP5199/02 EMEA/CHMP/QWP/251344/2006: became effective on January 1, 2007. Q&A document generated based on industry questions and EMEA answers – latest version published September 2010 now includes 2008 FDA Draft Guidance for Industry. Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches. Center for Drug Evaluation and Research: 2009 November 2009 – Concept paper issued and ICHM7 topic agreed 2010 November 2010 – Initial ICHM7 Expert Working Group (EWG) Meeting in Fukuoka Japan June 2011 – ICHM7 EWG meeting #2 in Cincinnati, Ohio

ICHM7 Expert Working Group

ICHM7: High Level Status Two face to face EWG meetings have been completed Current title: Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Carcinogenic Risk Progress is being made towards a Step 1 document with a completed Step 1 document targeted November 2011 Target Step 2 document released for consultation November 2012

ICHM7: Key topics of Discussion Refining Scope Applies to new products for marketing authorization and products in clinical development Application to existing products in certain instances Changes to existing products (for example, new API synthesis, new dosage forms) Cause for concern – need to define Excipients

ICHM7: Key topics of Discussion Structure Activity Relationship (SAR): Approaches to ID functional groups associated with mutagenic/carcinogenic potential DNA Reactive functional groups well known Expert systems widely used by industry/regulatory agencies Criteria for in-silico system performance Single system vs. two systems vs. expert/literature knowledge

ICHM7: Key topics of Discussion Risk Characterization Compound Specific Limits Class Specific Limits TTC based limits potentially adjusted for less than lifetime exposure Process/Product Control How to determine impurities that require an assessment for genotoxicity Control approaches for impurities in alignment with Q11 Differentiating control strategies for clinical development Assessing degradation products

CMC Hot Topics Determination of impurities to assess that are below standard ICH ID thresholds Well established processes for API related impurities leveraging in-silico SAR systems to inform overall mutagenic impurity risk and the need for lower level control approaches Practices for prediction of low level degradation products is less mature as focus has been on higher risk API reactive impurities

CMC Hot Topics Control approaches for mutagenic impurities Acceptance of chemistry based arguments based on process knowledge/quality by design principles in- lieu of routine analytical testing Alignment with ICHQ11 Differentiating clinical development control approaches vs. new products at the marketing registration phase It is understood that products in the clinical stage will have less development control strategies, but how should this be articulated in guidance

CMC Hot Topics Documentation in regulatory filings A discussion of genotoxic impurities in CTD and clinical filings is needed to enable a proper review by regulators ICHM7 will strive to provide guidance for documenation expectations The importance of a companies overall quality system to manage change (process change, supplier changes etc)

Q&A e-mail: david.m.de.antonis@pfizer.com