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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Information in the FDA 5 summary basis of approval cannot be used for this purpose.

Toxicology studies to establish safety should compare the new drug substance or drug product containing a representative amount of the new impurity with previously qualified test q3q or using the isolated impurity only.

How much impurity is there? The battery of nonclinical studies typically required for qualification include two genetic toxicology studies the bacterial reverse mutation [Ames] assay and a chromosomal damage [i. Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of cih review.

Adv Drug Deliv Rev.

Impurities that are also significant metabolites present in animal or human studies are generally considered qualified. Edmond, OK Tel: MedCrave Group Danforth Rd. 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.

For example, the average human body weight is 60 kg, and the body surface area is 1. 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.

In some cases, it may be simpler to decrease impurity levels to no more than the threshold rather than conducting safety studies. These classes range from known mutagenic carcinogens Class 1 guidelnes compounds with no structural alerts or with sufficient data to demonstrate lack of mutagenic or carcinogenic potential Class 5. Genotoxic impurities and degradation products pose an additional risk and should be controlled in accordance with the M7 R1 4 guidances, unless qualified for safety.

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.


This involves converting the no observed adverse effect level NOAEL doses in the most relevant animal species to the human equivalent doses HED based on body surface area, recognizing that larger animals typically have lower metabilic rates. 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.

Qualification of drug substance and drug product impurities are broadly dependent on the maximum theoretical clinical dose, whereas potential mutagenic impurities must be controlled to levels less than the threshold of toxicological concern based on lifetime exposure. What do we do now? In general, since drug product impurities are related to the drug substance, the impurities are typically considered to be less toxic.

If neither option is feasible, empirical toxicology testing will have to be performed to qualify the impurity. Therefore, the k m factor for a human is calculated by dividing 60 by 1. While the guidelines state that they are not intended to apply during the clinical research stage of development, recent trends suggest that sponsors should follow these guidelines more closely, especially at the latter stages of clinical development.

Drug substance and drug product impurities, now what?

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. 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. This dose-by-factor strategy is based on minimum risk of toxicity rather than minimum pharmacologic activity.

Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements. The answers to these questions are typically provided by scientists in chemistry, manufacturing and controls CMC and nonclinical toxicology with the single objective of assuring that unavoidable drug impurities induce no risk or an acceptable level of risk for the intended indication and the stage of development.

Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans. Ideally, mutagenic impurities should be eliminated by modification of the formulation, synthetic route, starting materials, reactants, or through additional purification.


The most accurate predictions occur for renally excreted compounds with low hepatic metabolism and a low volume of distribution.

MedCrave Group is ardent to provide article reprints at an instant affordable Read more FDA Guidance for Industry: These early toxicology studies will then increase the chances that any particular impurity will be present in the drug substance at levels considered qualified, especially when the drug substance impurity is present at multiples higher than clinical exposure.

February 27, Correspondence: The toxicology studies needed to qualify a drug product impurity follow those cited above for impurities in drug substances. 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. Toxicological overview of impurities in pharmaceutical products. Sponsors are encouraged to seek experts qualified to complete these QSAR assessments.

What is the impurity? This information may be based on the label of the listed drug, published articles, or studies conducted using the drug product containing the impurity or the impurity itself. Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: Sponsors are encouraged to seek qualified experts to help address drug impurity issues.

ICH Q3A(R2) Impurities in New Drug Substances – ECA Academy

Potential issues with impurities are one reason why toxicology studies completed early in the development program are often completed with drug substance of lower purity. For species not listed or for weights outside the standard ranges, HED can be calculated from the following formula: Qualification may include genotoxicity assessments based on QSAR assessments and scientific published literature; in some cases more extensive genetic toxicity testing may be required.

Should impurity issues arise later in the development program, q3s presence of the impurity and its specific level in the drug substance used in toxicology studies can support immediate qualification. Since body surface area varies with body weight W 0. The HED is determined as follows:.