Description, This document provides guidance on the content and qualification of impurities in new drug products for registration applications. This ICH guideline (draft) provides recommendations for the limits and the qualification of impurities to be observed for the marketing authorization of medicinal. ICH Q3B(R) C. Impurities in New Drug Products ICH Q3AR. 1. Introduction. Objective of the Guideline. Guidance for registration or marketing application .

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Can the impurity level be reduced or eliminated? Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans.

The correction factor k m is estimated by dividing the average body weight kg for the species by that species body surface area m 2. Toxicological overview of impurities in pharmaceutical products. 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.

To ihc a possible human cancer risk associated with the exposure to potentially mutagenic impurities, the Ames assay is used to assess the mutagenic potential.

The most accurate predictions occur for renally excreted compounds with low hepatic metabolism and a low volume of distribution. As the program develops, adherence to ICH impurity guidelines is required. The guidance suggests that an impurity is considered qualified as long as it was present in the drug substance used in nonclinical and clinical studies at guodelines level equal to or higher than levels found in the marketed product s 3 For impurities that need to be qualified, the guidance notes that additional toxicology studies can be avoided by lowering the level of the impurity present in the drug substance to levels below the qualification threshold or by providing safety data from the published scientific literature.


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.

ICH Q3B(R2) Impurities in New Drug Products – ECA Academy

Human Equivalent Dose; Km: 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. The thresholds for reporting, identification, and qualification of impurities in new drug products are more granular than for ifh substance impurities and are presented in Table 2.

Adv Drug Deliv Rev.

Given the apparent increased scrutiny regarding impurities, toxicology programs for molecules early in development should consider using a well-characterized drug substance of lower purity.

Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review. Monkeys c 12 3. Qualification may include genotoxicity assessments based on QSAR assessments and scientific published literature; in ihc cases more extensive genetic toxicity testing may be required.

Qualification of drug substance and drug product impurities are broadly dependent on the maximum theoretical clinical dose, whereas potential mutagenic impurities must be guideliness to levels less than the threshold of toxicological concern based on lifetime exposure.

What is the source of the impurity?

In general, since drug product impurities are related to the drug substance, the impurities are typically considered to be less toxic. Impurities in drug substances may include starting materials, intermediates, degradation products, etc. MedCrave Group is ardent to provide article reprints at an instant affordable Read more However, gguidelines 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.


If neither option is feasible, empirical toxicology testing will have to be performed to qualify the impurity. In addition, structure-based assessments can be useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. This dose-by-factor strategy is based on minimum risk of toxicity rather than minimum pharmacologic activity.

Based on a work at https: In some cases, it may be simpler to decrease impurity levels to no more q3v the threshold rather than conducting safety studies.

Impurities in New Drug Products

Click here to submit your manuscript 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 low levels leading to mutations and guidelimes, potentially causing cancer.

Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements. 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.

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. Drug substance impurities and drug product impurities are not the same, and are subject to different q3 requirements.

Drug substance and drug product impurities are a current hot button issue with regulatory authorities. 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.

Drug substance and drug product impurities, now what? Since body surface area varies with body weight W 0.