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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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Sponsors are encouraged to master the guidance documents discussed in this mini-review and consult guidelinse qualified expert with any questions or for assistance in assessing specific impurity issues. Given the apparent increased scrutiny regarding impurities, toxicology programs for molecules early in development should consider guideliens a well-characterized drug substance of lower purity. 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.

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.

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. Human Equivalent Dose; Km: 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. In drug substance purity testing, every peak that q3v in the chromatogram should be guidelinss a drug substance impurity, unless proven otherwise eg, solvent peaks.

Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review.

Is the impurity toxic? Click here to submit your manuscript In general, since drug product impurities are related to the drug substance, the impurities are typically considered to be less toxic.

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


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 neither option is feasible, empirical toxicology testing will have to be performed to qualify the impurity. The reporting threshold is the level at which an impurity must be reported with the analytical procedures indicated. Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, guidellnes qualification requirements.

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

Edmond, OK Tel: Impurities in drug substances may include starting materials, intermediates, degradation products, etc.

Drug substance and drug product impurities, now what?

These classes range from known mutagenic carcinogens Class 1 to compounds with no structural alerts or with sufficient data to demonstrate lack of mutagenic or carcinogenic potential Tuidelines 5.

Based on a work at https: When there are 3 or more class 2 or 3 impurities, the total of all mutagenic impurities should be per the values provided Source: 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 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. The thresholds for reporting, identification, and qualification of impurities in new drug ugidelines are more granular than for drug substance impurities and are presented in Table 2.

What is the source of the impurity? Should impurity issues arise later 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. February 27, Correspondence: Impurities in the drug 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.


For species not listed or for weights outside the standard ranges, HED can be calculated from the following formula: In addition, structure-based assessments can be useful for predicting bacterial mutagenicity outcomes based guidelihes the established knowledge.

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ICH Q3B (R2) Impurities in new drug products

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.

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 cancer.

The k m factor value for various animal species is used to estimate the HED as follows:. 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. 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.

Since body surface area varies with body weight W 0.

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. 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 icy the conduct of additional safety studies.