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Genotoxic impurities
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Genotoxic Impurities, Background, Controlling of genotoxic impurities.
Transcript of Genotoxic impurities
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FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug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) 188-211.
Categorization, Qualification and Risk Assessment
Relationship Between Staged TTC, Drug Dose and Impurity Concentration Limit
Assessment of Potential Genotoxic Impurities
Decision Tree
