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Regulators expect drug manufacturers to understand toxicological significance of impurities: Expert
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Shardul Nautiyal, Mumbai
August 26 , 2026
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Regulators increasingly expect manufacturers to understand the toxicological significance of impurities, especially those that may interact with DNA and pose long-term carcinogenic risk, informs Dr. Prashant S. Kharkar, medicinal chemist and Al-enabled drug discovery expert.
He further adds that India's pharmaceutical sector has earned global respect for its ability to manufacture affordable, high-quality medicines at scale. Indian companies supply active pharmaceutical ingredients, intermediates, generics, and finished dosage forms to markets across the world. As this role expands, expectations around pharmaceutical quality are also evolving. Today, quality is not limited to confirming assay, dissolution, impurity levels, or stability.
“Among all impurity classes, mutagenic impurities require special attention. These are compounds capable of inducing genetic mutations, often through direct or indirect interaction with DNA. Even when present at very low levels, such impurities may carry safety concern because mutation is a key initiating event in chemical carcinogenesis. Therefore, their assessment is not simply an analytical chemistry exercise; it is a public-health obligation that links synthetic chemistry, toxicology, process control, and regulatory science,” Dr Kharkar explains.
He further explains that the globally accepted framework for this assessment is ICH M7(R2), which provides guidance on the assessment and control of DNA-reactive mutagenic impurities in pharmaceuticals to limit potential carcinogenic risk. The guideline emphasizes both safety and quality risk management and applies to impurities that reside, or are reasonably expected to reside, in the final drug substance or drug product. The US FDA also describes M7(R2) and its related documents as part of an international harmonization effort for the assessment and control of DNA-reactive mutagenic impurities.
“For Indian pharmaceutical manufacturers, this has practical consequences. A company developing or manufacturing an API must consider not only known impurities but also plausible impurities arising from starting materials, reagents, intermediates, solvents, degradation pathways, carry-over risks, and side reactions. The key question is no longer only 'What impurity is present?' but also 'Could this impurity be mutagenic, and how should it be controlled?',” Dr Kharkar clarifies.
He further informs that experimental AMES testing remains an important tool, but it is not practical or necessary for every theoretical impurity, trace-level species, or early-stage route option. This is where computational toxicology has become extremely valuable. Modern in silico approaches can screen chemical structures for mutagenic potential, detect structural alerts, support analogue-based reasoning, and help prioritize which impurities require further evaluation or tighter control. When properly applied, such methods can reduce unnecessary testing, accelerate decision-making, and support scientifically justified regulatory documentation.
However, mutagenicity prediction should not be treated as a simple software output. A 'positive' or 'negative' result is only the beginning. A regulatory-quality conclusion requires expert review. The assessor must ask whether the chemical structure is within the model's applicability domain, whether structural alerts are relevant, whether analogues support or weaken the prediction, whether the impurity is likely to be purged during manufacturing, and whether an acceptable intake or control threshold is needed. A weakly interpreted computational result can create confusion, while a well-reasoned assessment can improve regulatory confidence.
For manufacturers, early mutagenicity prediction has value across the product lifecycle. During route selection, it can help identify hazardous reagents, intermediates, or side products before the process is locked. During impurity profiling, it can help classify impurities and guide analytical method development. During forced degradation studies, it can support toxicological evaluation of degradants. During post-approval changes, it can help assess whether a new process condition, raw material, or supplier introduces additional mutagenic risk. In regulatory query responses, a structured computational toxicology report can help companies respond with clarity and speed.
“This approach is especially important for small and mid-sized API and formulation manufacturers. Many such companies may not have large in-house toxicology teams, yet they increasingly face global expectations for impurity risk assessment. Access to reliable computational workflows, combined with expert interpretation, can help democratize high-quality regulatory toxicology and reduce the gap between large multinational companies and smaller manufacturers,” Dr. Kharkar concludes.
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