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 .
|Published (Last):||14 September 2004|
|PDF File Size:||8.89 Mb|
|ePub File Size:||8.80 Mb|
|Price:||Free* [*Free Regsitration Required]|
Impurities in New Drug Products
Drug substance and drug product impurities, now what? What is the impurity? What is the source of the impurity?
How much impurity is there? Can the impurity level be reduced or eliminated? Is the impurity toxic? What do we do now? 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.
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.
Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review. Drug substance impurities and drug product impurities are not the same, and are subject to different regulatory requirements. Impurities in drug substances may include starting materials, intermediates, degradation products, etc. 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.
Impurities in New Drug Products : ICH
Drug product impurities are defined as, and limited to, degradation products of the drug substance, and reaction products of kch drug substance with excipients or the container-closure system. However, for the toxicologist the issue 3qb any impurity that exceeds qualification thresholds is whether sufficient safety information exists, ivh 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.
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.
As the program develops, adherence to ICH impurity guidelines is required. Each of these impurity issues are discussed below along with next steps for the toxicologist to address these issues.
Sponsors are encouraged to seek qualified experts to help address drug impurity issues. Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements. 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.
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 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. 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.
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.
Impurities that are also significant metabolites present in animal or human studies are generally considered qualified. 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 a 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.
If neither option is feasible, empirical toxicology testing will have to be performed to qualify the impurity. 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.
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 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.
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.
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.
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. 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 gudielines 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. In some cases, it may be simpler to decrease impurity levels to no more than the threshold rather than conducting safety studies.
In general, since drug product impurities are related to the drug substance, the impurities are typically considered to be less toxic. The thresholds for reporting, identification, and qualification of impurities in new drug products are more granular than for drug substance impurities and are presented in Table 2.
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. The reporting threshold is guidelinnes level at which an impurity must be reported with the analytical procedures indicated.
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.
The toxicology studies needed to qualify a drug product impurity follow ic cited above for impurities in drug substances.
ICH Q3B (R2) Impurities in new drug products
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 guidelihes.
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. This type of mutagenic carcinogen is usually detected in an Ames assay. Other types of genotoxicants that are non-mutagenic typically have threshold mechanisms eg, endocrine active substances and usually do not pose carcinogenic risk in humans at the level ordinarily present as impurities.
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 Qb 5. 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.
In addition, structure-based assessments can be useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. The ICH recommends that for the latter, a computational toxicology assessment should be performed using two Quantitative Structure-Activity Relationship QSAR prediction methodologies that complement each other; one methodology should be expert rule-based, and the second methodology should be statistical-based.
Sponsors are encouraged to seek experts qualified to complete these QSAR assessments. The acceptable daily intake values are presented in Table 3. 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.
Qualification may include genotoxicity assessments based on QSAR assessments and scientific published literature; in some cases more extensive genetic toxicity testing may be required. Ideally, mutagenic impurities should be eliminated by modification of the formulation, synthetic route, starting materials, reactants, or through additional purification.
When there are 3 or more class 2 or 3 impurities, the total of all mutagenic impurities should be per the values provided Source: 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. 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.
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. 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.
ICH Q3B(R2) Impurities in New Drug Products – ECA Academy
These early toxicology studies will then increase the chances that any particular impurity will be present in the drug substance gguidelines levels considered qualified, especially when the drug substance impurity is present at multiples higher than clinical exposure.
This information may be based on the label of the listed drug, published articles, or kch conducted using the drug product containing the impurity or the impurity itself. Information in the Ic 5 summary basis of guidelijes cannot be used for this purpose. Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans. This involves converting the no observed adverse effect level NOAEL doses in the most relevant animal buidelines to the human equivalent doses HED based on body surface area, recognizing that larger animals typically have lower metabilic rates.
Since body surface area varies with body weight W 0. This dose-by-factor strategy is based on minimum risk of toxicity rather than minimum pharmacologic activity. The most accurate predictions occur for renally excreted compounds with low hepatic metabolism and a low guidelijes of distribution.
The HED is determined as follows:. The icu factor k m is estimated by dividing the average body weight kg for the species by that species body surface area m 2.
The km value for each species increases with body weight, but a fixed k m factor for each species is preferred for standardization and practical purposes.
For example, the average human body weight is 60 kg, and the body surface area is 1. Therefore, the k m factor for a human is calculated by dividing 60 by 1. Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: Human Equivalent Dose; Km: For species not listed or for weights outside the standard ranges, HED can be calculated from the following formula: FDA Guidance for Industry: The k m factor value for various animal species is used to estimate the HED as follows:.
Drug substance and drug product impurities are a guirelines hot button issue with regulatory authorities. 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. This approach could potentially save precious time at the latter stages of drug development. MedCrave Group is ardent to provide ifh reprints at an instant affordable Read more Click here to submit your manuscript February 21, Published: An unidentified peak in a drug substance or drug product chromatogram raises many questions.
Drug substance impurities Table 1 presents the drug substance impurity thresholds described in ICH Q3A R2 1 which trigger reporting, identification, and qualification requirements. Monkeys c 12 3. Toxicological overview of impurities in pharmaceutical products. Adv Drug Deliv Rev. This is an open access article distributed under the terms of the Creative Commons Attribution Licensewhich permits unrestricted guivelines, distribution, and build upon your work non-commercially.
MedCrave Group Danforth Rd. Edmond, OK Tel: 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. Based on a work at https: February 27, Correspondence: