Genotoxic Impurities, Background, Controlling of genotoxic impurities.

1. (Dr). Santosh Kumar Narla,
Formulation Regulatory Affairs,
santosh_narla@yahoo.com

2. 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

3. 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FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and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

4. Genotoxic potential “alert structures”

5. 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

6. 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.

7. Categorization, Qualification and Risk Assessment

11. Relationship Between Staged TTC, Drug Dose and Impurity Concentration Limit

12. Assessment of Potential Genotoxic Impurities

19. Decision Tree