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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Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: This involves converting the no observed adverse effect level NOAEL doses in the most relevant animal guidelined to the human equivalent doses HED based on body surface area, recognizing that larger animals typically have lower metabilic rates.

Is the impurity toxic?

Drug substance and drug product impurities, now what?

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 article or using the isolated impurity only. Drug product impurities are defined as, and limited to, degradation products of the drug substance, and reaction products of the drug substance with excipients or the container-closure system.

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. While a thorough bioanalytical assessment of impurities in early drug lots is rare, sponsors should consider devoting resources to these efforts up-front to have this potentially critical information available.

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. Impurities that are also significant metabolites present in animal or human studies are generally considered qualified.

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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.

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 therefore, potentially causing q3n. As per the ICH Q3B R2 2 guideline, impurities in the drug product below the qualification threshold levels do not need to be qualified unless any impurity is expected to be unusually toxic or potent.

This information may be based on the label of the listed drug, published articles, or ghidelines conducted using the drug product containing the impurity or the impurity itself. 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.

Impurities in New Drug Products : ICH

Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans. 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.

February 27, Correspondence: Drug substance and drug product impurities, now what? This approach could potentially save precious time at the latter stages of drug development. 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 guiddlines relative concentration.

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.


In drug substance purity testing, every peak that appears in the chromatogram should be considered a drug substance impurity, unless proven otherwise guideilnes, solvent peaks.

Impurities in New Drug Products

What is the source of the impurity? Therefore, the k m factor for a human is calculated by dividing 60 by 1. February 21, Published: For species not listed or for weights outside the standard ranges, HED can be calculated from the following formula: This is an open access article distributed under the terms of the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and build upon your work non-commercially.

An unidentified peak in a drug substance or drug product chromatogram raises many questions. What is the impurity?

The toxicology studies needed to qualify a drug product impurity follow those cited above for impurities in drug substances.

Drug substance and drug product impurities, now what?

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.

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. Click here to submit your manuscript When an impurity in the drug substance reaches the qualification threshold level, it is the responsibility of the sponsor to establish the safety of the impurity. Information in the FDA 5 summary basis of approval cannot be used for this purpose.

The identification threshold is the level at which an impurity must be structurally identified. The qualification threshold is the level at which the impurity in the drug product must be qualified for safety.

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