ICH Q3A (R2) Impurities in new drug substances Description, This document provides guidance on the content and qualification of impurities. Center for Biologics Evaluation and Research (CBER). June ICH . This is the second revision of the Q3A guidance, which was published in and. This guideline deals with impurities (organic, inorganic and residual solvents) in new active Q3A

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Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: In general, since drug product impurities guicelines related to the drug substance, the impurities are typically considered to be less toxic. As per the ICH Q3A R2 1 guideline, impurities in the drug substance below the qualification threshold levels do not need to be qualified unless the impurity is expected to be unusually toxic or potent Table 1. The situation with impurities potentially needing qualification also underscores the importance of completing a thorough bioanalytical assessment of each drug substance lot to identify the impurities present and their relative concentration.

Therefore, the k m factor for a human is calculated by dividing 60 by 1. To limit a possible human cancer risk associated with the exposure to potentially mutagenic impurities, the Ames assay is used to assess the mutagenic potential. If the daily intake of an impurity is above the acceptable intake levels, the impurity should be identified and a stepwise approach can be taken for qualification. This approach could potentially save precious time at the latter stages of drug development.

This practice increases the chances that any potential impurity will be present in the drug substance and thus considered qualified in that study when the drug substance impurity is present at multiples higher than the clinical exposure.

Should impurity issues arise guidelinee in the development program, the presence of the impurity and its specific level in the drug substance used in toxicology studies can support immediate qualification. Sponsors are encouraged to seek qualified experts guidellnes help address drug impurity issues.

In drug substance purity testing, every peak that appears in the chromatogram should be considered a drug substance impurity, unless proven otherwise eg, solvent peaks. What do we do now? The decision tree for the identification and qualification of drug product impurities see Attachment 3 in the ICH Q3B R2 2 guideline should be closely followed and thoroughly discussed with the regulatory authority to resolve drug product impurity issues.


The reporting threshold is the level at which an impurity must be reported with the analytical procedures indicated. The thresholds are broadly dependent on the daily quantity of drug consumed by the patient with threshold tolerances being lower when the maximum exposure is greater than 2 grams of drug substance per day.

Information in the FDA 5 summary basis of approval cannot be used for this purpose. The battery of nonclinical studies typically required for qualification include two genetic toxicology studies the bacterial reverse mutation [Ames] assay and a chromosomal buidelines [i. The decision tree for the identification and qualification of drug substance impurities see Attachment 3 in the ICH Q3A R2 guideline should be closely followed and thoroughly discussed with the regulatory authority to resolve drug substance impurity issues.

As the program develops, adherence to ICH impurity guidelines is required. However, for the toxicologist the issue for any impurity that exceeds qualification thresholds is whether sufficient safety information exists, either in completed nonclinical or clinical studies or in the literature, to support continued development or whether the impurity needs to be qualified through the conduct of additional safety studies.


The thresholds for reporting, identification, and qualification of impurities in new drug products are more granular than for drug substance impurities and are presented in Table 2. Guieelines ICH recommends that for the latter, a computational toxicology assessment should be performed using two Quantitative Structure-Activity Relationship QSAR prediction methodologies that complement each other; one methodology should be expert rule-based, and the second methodology should be statistical-based.

Each of these impurity issues are discussed below along with next steps for the toxicologist to icj these issues. The qualification threshold is the level at which the impurity in the drug product must be qualified for safety. Q3 an impurity in the drug substance reaches the qualification threshold level, it guidelones the responsibility of the sponsor to establish the safety of the impurity. Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review.


To help address these issues, the International Council for Harmonisation ICH guidelines for impurities in drug substance Q3A and drug product Q3Band for genotoxic impurities M7 have been adopted and implemented in the United States, Europe, and many other countries around the world.

Impurities in the huidelines substance primarily originate during the synthetic process using raw materials, intermediates, and by-products present in the reaction mixture at much lower purity requirements than for the drug substance. Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements.

What is the impurity? Click here to submit your manuscript Human Equivalent Dose; Km: The focus of the M7 R1 2 guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at gudielines levels leading to mutations and therefore, potentially causing cancer.

Impurities in New Drug Substances

Since impurities in the drug substance may not be related to or derived from the drug substance, the impuriites may be more toxic than impurities in the drug product which are related to the active drug substance by definition.

Impurities that are also significant metabolites 3qa in animal or human studies are guideljnes considered qualified. If the impurity is from a class of compounds known to be particularly toxic or nontoxic, the qualification thresholds may be lowered or raised, respectively.

Edmond, OK Tel: Toxicological overview of impurities in pharmaceutical products.

Drug substance and drug product impurities, now what?

An unidentified peak in a drug substance or drug product chromatogram raises many questions. The km value for each species increases with body weight, but a fixed k m factor for each species is preferred for standardization and practical purposes. Based on a work at https: Drug substance and drug guidleines impurities, now what?

Adv Drug Deliv Rev.