ICH Q3A(R2): For NEW DRUG SUBSTANCES
- Guidance provided registration applications on the content and qualification of impurities in new drug substances (synthetic and has not been before registered in a region).
- Not applicable during the clinical research stage of drug development.
- For new drug substance impurities addressed with two perspectives such as chemistry aspects(identification) and safety aspects (qualification).
CLASSIFICATION OF IMPURITIES
Organic impurity: identified or unidentified, volatile or non-volatile
- Starting materials
- By-products
- Intermediates
- degradation products
- Reagents, ligands, and catalysts
Inorganic impurities are normally known and identified.
- Reagents, ligands, and catalysts
- Heavy metals or other residual metals
- Inorganic salts
- Other materials (e.g., filter aids, charcoal)
Residual solvent: generally has a toxicity that may be known to humans. choose suitable controls for easy operations. (Refer. ICH Guideline Q3C on Residual Solvents)
Polymorphic forms, enantiomeric impurities, and outsides contaminants are excluded from this guideline.
REPORTING OF IMPURITIES
- Any impurity having a level greater than the identification threshold should be identified including degradation product also, but at a level lower the identification threshold impurities generally not been considered necessary.
- Any potent impurities observed required to qualify.
- Any impurities arise during manufacturing, development, stability study, stress testing, identified as potential impurities may present.
- Results of analytical procedure required to submit for batches of new drug substance used in the clinical study, safety and stability testing.
- The quantification limit of the analytical procedure should be lower the reporting threshold, in case of higher reporting threshold limits used should be justified.
- Below 1% the result should be written in two decimal (Ex: 0.01,0.015) and above 1% in one decimal (Ex: 1.1,1.9)
Listing of impurities in specification:
Individual impurities with specific acceptance criteria are “specified impurities” can be identified or unidentified. The specification for the new drug substance should include a list of impurities.
- Each specified identified impurity
- Each specified unidentified impurity
- Each unspecified with acceptance criteria not more then identification threshold
QUALIFICATION OF IMPURITY
Qualification Threshold: Qualification is the process of collecting and analyzing data to determine the biological safety of a single impurity.
- Studies employing isolated impurities may also be acceptable.
Table 1: Thresholds for new drug substance
| Max daily dose | Reporting threshold (LOQ Level) | Identification threshold (Unknown Imp.) | Qualification threshold (Known Imp.) |
| < 2g | 0.05% | 0.1% or 1mg (whichever is lower) | 0.15% or 1mg (whichever is lower) |
| > 2g | 0.03% | 0.05% | 0.05% |
Decision tree of identification and qualification as per ICH Q3A(R2):
Related Read:
ICH Q2 (R1): Analytical Method Validation
Refer Guideline :
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