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

santosh_narla@yahoo.com

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FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug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