Identification and quantification of impurities in active ingredients and drugs products is a crucial aspect in pharmaceutical development to ensure the quality and safety of the product. Any component present in an active ingredient or in a finished product which is neither the active ingredient nor an excipient is considered an impurity. The presence of impurities, even in small amounts, may influence the efficacy and / or safety of the drug, hence the importance of their toxicological assessment and control.
According to ICH regulations, impurities are classified as organic and inorganic impurities as well as residual solvents. Organic impurities may arise from the starting materials, by-products or reaction intermediates and from degradation products which may arise after synthetic accomplishment. Inorganic impurities generally come from the synthetic process elements, such as some inorganic reagents, inorganic salts, metals, catalysts, ligands, etc…, while residual solvents are impurities derived from the use of solvents in the synthesis and purification steps.
While inorganic impurities or residual solvents are readily identified and their toxicity is known, in the case of organic impurities, their number and structural variability is unlimited and their toxicity generally unknown.
Analytical control and Qualification of organic impurities
Synthetic and degradation organic impurities analysis is controlled by a series of tests collected in the monographs of the European and / or American Pharmacopoeia1, whereas the ICH regulation establishes its limits according to the quantity of active principle or finished product that is administered to the day.
ICH regulation distinguishes three levels in the evaluation of organic impurities: the reporting threshold, the identification threshold and the qualification threshold. These thresholds are values from which the organic impurities must be reported, identified and qualified respectively. Qualification means the process of acquiring and evaluating the data that define the biological safety and toxicity of the impurity at the specified level. Depending on the maximum daily dose, qualification thresholds for API varies from 0.15% or 1mg (whichever is lower) when maximum daily dose is lower than 2 g/day to 0.05% when doses are higher than 2g/day. Similarly, thresholds for drug products ranges from 1% or 5µg (whichever is lower) for doses lower than 10 mg/day to 0.15% when maximum doses exceed 2 g/day.
Following the decision tree of the ICH Q3A2 and Q3B3 guidelines, when an organic impurity reaches or exceeds the level of qualification, the manufacturer must justify the toxicity of the product. In this sense and based on these guidelines, any impurity that has been adequately evaluated in clinical and / or safety studies will be considered qualified. Impurities that are described as metabolites in human or animal studies will also be qualified. Where levels of an impurity cannot be lowered below the qualification limit, an impurity safety study shall be carried out by means of a toxicological evaluation. In a worst-case scenario, the inclusion of additional experimental data on genotoxicity (Ames test or chromosomal aberration) and general toxicity (14 to 90 days toxicity assays) would be required, also accompanied by a toxicological assessment.
In Azierta, science and health consulting, we have a specialized line in toxicological assessment being also corporate members of EUROTOX. We have accredited toxicologists and experts in the evaluation and qualification of impurities of synthesis and degradation, always in accordance with the existing regulation. If you want to know us better visit…
- EDQM (European Directorate for the Quality of Medicines) EU. European Pharmacopoeia (Ph. Eur.) 9th Edition. (2017).
- ICH HARMONISED TRIPARTITE GUIDELINE. IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2). (2006).
- ICH HARMONISED TRIPARTITE GUIDELINE. IMPURITIES IN NEW DRUG PRODUCTS Q3B(R2). (2006).