(dr). santosh kumar narla, formulation regulatory affairs, [email protected]
TRANSCRIPT
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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
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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FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug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
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Genotoxic potential “alert structures”
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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
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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.
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Categorization, Qualification and Risk Assessment
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Relationship Between Staged TTC, Drug Dose and Impurity Concentration Limit
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Assessment of Potential Genotoxic Impurities
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Decision Tree
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