Unexpected Impurities in Drug Products


Unexpected impurities, suddenly arising in e.g. a QC analysis, may create a lot of stress and anxiety within different departments of a pharmaceutical company.

In a lot of cases, these unexpected impurities are – at first – not identified, as they are often initially detected with non-specific detectors in generic analytical methods, such as HPLC-UV Chromatography.

These impurities may be observed throughout the complete life cycle development of the drug product.



As the regulatory department, as well as the quality department get involved in the root cause analysis in order to evaluate the impact of this impurity on the drug quality and safety, the first question that pops up is: “What is it?”. At first this appears to be an easy and straightforward question but it may turn into a nightmare for the analytical chemistry department. For them, it means:

  • That the in-house validated process is not under control.
  • A complete shift in priorities because of the high urgency of the problem.
  • The necessity of having extensive expertise and access to the high-end analytical techniques which allow structure elucidation, such as accurate mass measurements, such as LC-ToF or GC-ToF or other structural elucidation techniques like NMR.
  • A need to the access of analytical standards, even if they are not commercially available. This in order to ultimately confirm the impurities identity in the routine QC analyses (such as confirmation of retention time with HPLC-UV).


Apart from the “What is it?”-question, another question will arise: Where is the unexpected impurity coming from?”, a critical question if the presence of this unexpected impurity needs to be avoided. The origin of the compound may also determine which Guidelines (and associated control limits) to follow in the final evaluation of the drug impurity. Relevant guidelines include ICH Q3A (Impurities in New Drug Substances), ICH Q3B (Impurities in New Drug Products), ICH Q3C (Impurities: Guideline for Residual Solvents), ICH M7 (Assessment and control of DNA reactive impurities in pharmaceuticals to limit potential carcinogenic risk), EMA, PQRI-PODP and PQRI-OINDP.

Impurities may be introduced into the drug product through different potential cause pathways, as described in the root cause approach using the fishbone of Ishikawa.


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Nelson Labs Europe | Unexpected Impurities in Drug Products