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

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

4. 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EMEA issues draft guidance for genotoxic impurities stressing avoidance vs. acceptance of a low limit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EMEA updates draft guidance and introduces the TTC limit (1.5 micrograms/day)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 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

5. 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FDA Draft Guidance for Industry.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

6. ICHM7 Expert Working Group

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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)

14. Q&A