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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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Each of these impurity issues are discussed below along with next steps for the toxicologist to address these issues.

ICH Q3A (R2) Impurities in new drug substances | European Medicines Agency

Sponsors are encouraged to master the guidance documents discussed in this mini-review and consult a qualified expert with any questions or for assistance in assessing specific impurity issues. Is the impurity toxic?

An unidentified peak in a drug substance or drug product guidelinss raises many questions. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms eg, endocrine active substances and usually do not jch carcinogenic risk in humans at the level ordinarily present as impurities. 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.

FDA Guidance for Industry: This type of mutagenic carcinogen is usually detected in an Ames assay.

This dose-by-factor strategy is based on guidelnies risk of toxicity rather than minimum pharmacologic activity. Drug substance impurities Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements. What do we do now? 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.

Since body surface area varies with body weight W 0. The k m factor value for various animal species is used to estimate the HED as follows:. No part of this content may be reproduced or transmitted in any form or by any means as per the standard guidelines of fair use. Qualification may include genotoxicity assessments based on QSAR assessments and scientific published gudielines in some cases more extensive genetic toxicity testing may be required. 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.


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. The acceptable daily intake gudielines are presented in Table 3. 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.

Therefore, the k m factor for a human is calculated by dividing 60 by 1. 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. Drug substance impurities and drug product impurities are not the same, and are subject to different regulatory requirements.

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 qualification threshold is the level at which the impurity in the drug product must be qualified for safety. Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review.

The identification threshold is the level at uch an impurity must be structurally identified.

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

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. 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.


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. 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.

When there are 3 or more class 2 or 3 impurities, the total of all mutagenic impurities should be per the values provided Source: The most accurate predictions occur for renally excreted compounds with low hepatic metabolism and a low volume of distribution.

ICH Q3A(R2) Impurities in New Drug Substances

Human Equivalent Dose; Km: Impurities that are also significant metabolites present in animal or human studies are generally considered qualified. Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans.

Click here to submit your manuscript Impurities in drug substances may include starting materials, intermediates, degradation products, etc. Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: 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.

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.