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 seek experts qualified to complete these QSAR assessments. MedCrave Group Danforth Rd.

February 21, Published: Qualification guideelines include genotoxicity assessments based on QSAR assessments and scientific published literature; in some cases more extensive genetic toxicity testing may be required. Table 4 Conversion of animal doses to human equivalent doses based on body surface area HED: 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 guifelines.

As the program develops, adherence to ICH impurity guidelines is required. The reporting threshold is the level at which an impurity must be reported with the analytical procedures indicated.

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. Can the impurity level be reduced or eliminated? 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.

The answers to these questions are typically provided gukdelines scientists in chemistry, qb3 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.

Each of these impurity issues are discussed below along with next steps for the toxicologist to address these issues. In addition, structure-based assessments ihc be useful for predicting bacterial mutagenicity outcomes based upon the established knowledge.


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.

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. 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 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.

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

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. Impurities in drug substances may include starting materials, intermediates, degradation products, etc.

Drug substance and drug product impurities, now what?

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. Sponsors are also reminded to use allometric scaling to compare impurity exposures in nonclinical species with impurity exposures in humans. Insights regarding acceptable amounts of residual solvents and the calculation of permitted daily exposures will be the subject of another review.

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


Impurities in New Drug Products

For example, the average human body weight is 60 kg, and the body surface area is 1. 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. Potential issues with impurities are one reason why toxicology studies completed early in the development program are often completed with guideliens substance of lower purity.

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 HED is determined as follows:. 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.

Is the impurity toxic? Sponsors are encouraged to seek qualified experts to help address drug impurity issues. Human Equivalent Dose; Km: 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.

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. Information in the FDA 5 summary basis of approval cannot be used for this purpose.

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. Since body surface area varies with body weight W 0.