(Dr). Santosh Kumar Narla, Formulation Regulatory Affairs,

Genotoxic impurities Impurities are unwanted chemicals, have no therapeutic value and are potentially harmful. Therefore they need to be controlled in API and DP. Impurities can be classified into: Organic impurities (process- and drug-related) Inorganic impurities Residual solvents Genotoxic impurities Sources of impurities: Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts

Evidence of genotoxicity: Genetic damage, Cell death neoplastic transformation. Regulatory Expectations: January 2007 EMEA CHMP Guideline on the Limits of Genotoxic Impurities February 2008 EMEA letter requesting evaluation of sulfonic esters in all marketed products June 2008 and December 2009 EMEA Questions & Answers Documents on the CHMP Guideline on the Limits of Genotoxic Impurities December 2008 FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and Products; Recommended Approaches

Genotoxic potential “alert structures”

Genotoxins: EMEA/CHMP/QWP/251344/2006 Are considered unsafe at any level. A limit for a genotoxin with an understood toxicity can be calculated based upon the known PDE. A limit for a genotoxin without sufficient toxicity information must determine based upon a TTC of 1.5 ug/day. Max limit = TTC/maximum dose. Levels above this limit need to justified toxicologically. Limits for genotoxins like aflatoxins, N-nitroso-, and azoxy-compounds are considered so toxic they must be justified using toxicological study data. TTC = Threshold of Toxological Concern

ADI and Daily Dose “A Rationale for Determining, Testing and Controlling Specific Impurities in Pharmaceuticals that Possess Potential for Genotoxicity”, Mueller, et al., Regulatory Toxicology and Pharmacology44(2006)

Categorization, Qualification and Risk Assessment

Relationship Between Staged TTC, Drug Dose and Impurity Concentration Limit

Assessment of Potential Genotoxic Impurities

Decision Tree