ICH Q3 Impurities

Question 1

What is the ICH Q3A Impurities in new drug substance threshold

Answer 1

Maximum daily dose <2g/day, reporting threshold 0.05%, identification threshold 0.10% or 1.0 mg per day intake (whichever is lower), qualification threshold 0.15% of 1.0mg per day intake (whichever is lower)

Maximum daily dose >2g/day, reporting threshold 0.03%, identification threshold 0.05%, qualification threshold 0.05%

The quantitation limit for the analytical procedure should be not more than (<) the reporting threshold.

Question 2

For each batch of the new drug product described in the registration application, the documentation should include

Answer 2

• Batch identity, strength, and size
• Date of manufacture
• Site of manufacture
• Manufacturing process
• Immediate container closure
• Degradation product content, individual and total
• Use of batch (e.g., clinical studies, stability studies)
• Reference to analytical procedure used
• Batch number of the drug substance used in the new drug product
• Storage conditions for stability studies

The registration application should include documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products. In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products.

Question 3

Any degradation product observed in stability studies conducted at the recommended storage condition should be

Answer 3

identified when present at a level greater than (>) the 1 Impurities in New Drug Products identification thresholds given in Attachment 1. Degradation products present at a level of not more than (<) the identification threshold generally would not need to be identified.

Question 4

For degradation studies, as appropriate, this validation should include samples stored under relevant stress conditions

Answer 4

light, heat, humidity, acid/base hydrolysis, and oxidation. When an analytical procedure reveals the presence of other peaks in addition to those of the degradation products, these peaks should be labelled in the chromatograms and their origin(s) discussed in the validation documentation.

Question 5

The new drug product specification should include, where applicable, the following list of degradation products:

Answer 5

• Each specified identified degradation product
• Each specified unidentified degradation product
• Any unspecified degradation product with an acceptance criterion of not more than (<) the identification threshold
• Total degradation products.

Question 6

What are the different classes of residual solvents

Answer 6

Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limited Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.

Question 7

Exposure limits for Class 1 solvents could be determined with:

Answer 7

the use of a large safety factor (i.e., 10,000 to 100,000) with respect to the no-observed-effect level (NOEL). Detection and quantitation of these solvents should be by state-of-the-art analytical techniques.