Sometimes the question asked is “How do ICH Q3A and ICH Q3B apply to cleaning validation?” My simple answer (like many answers provided by consultants) is “It depends”. Let me explain. The confusing thing may be that the titles of these documents are “Impurities in New Drug Substances” (Q3A) and “Impurities in New Drug Products”. One might assume that these documents would apply to impurities found in cleaning validation samples. So, even though the test samples are residues from the cleaned surfaces (and not from drug substance or drug products), those residues in the cleaning validation samples could transfer to a drug substance or a drug product. Under that assumption those ICH guidance might apply to cleaning validation. That conclusion seems consistent with the definitions of “Impurity” in each document.
Q3A Considerations
For Q3A, the glossary definition is “Any component of the new drug substance that is not the chemical entity defined as the new drug substance.” But, for Q3A the emphasis for impurities seems to be those that can arise from the manufacturing process or the storage of drug substance. This is consistent with the glossary definition of “Potential Impurity” (one “that theoretically can arise during manufacture or storage”) as well as the discussion in Section 2 on “Classification of Impurities”. Furthermore, this would seem to exclude applicability of Q3A to “Extraneous Contaminant”, which has a glossary definition of an “impurity arising from any source extraneous to the manufacturing process”. Furthermore, Section 2 includes a statement that extraneous contaminants “are more appropriately addressed as Good Manufacturing Practice (GMP) issues.” As an aside, I should note that sometimes the manufacturing process can be seen as separate from the cleaning process, while others might consider both the manufacturing process and the cleaning process part of the overall manufacturing practice. However, I don’t want to argue those distinctions here since I believe the context for Q3A suggests that cleaning is not part of manufacturing, or at least that cleaning residues are “extraneous contaminants”.
Q3B Considerations
For Q3B, the glossary definition is “Any component of the new drug product that is not the drug substance or an excipient in the drug product.” For Q3B the emphasis for impurities seems to be those that can arise from degradation of the drug substance in the drug product either during the manufacturing process or stability studies (the latter could reflect degradation during the shelf life). Included are reaction products of the drug substance with excipients and /or the container closure system. Excluded are impurities “arising from excipients .. or extracted or leached from the container closure system”. Unlike Q3A, there is no explicit statement in Q3B excluding external contaminants (which are handled by GMP principles). However, other statements in Q3B would seem require that same exclusion for extraneous contaminants.
Thresholds
Both Q3A and Q3B have thresholds for degradation products. For Q3A, the threshold percentages of the drug substance vary based on the maximum daily dose of the drug substance. Thresholds are given in Attachment 1 for “reporting”, for “identification”, and for “qualification”. Qualification involves the evaluation of the biological safety of the impurity. I advise looking carefully at the glossary definitions for “Qualification” and “Qualification Threshold” in Q3A.
For Q3B, the thresholds percentages are also based on the drug substance (and not on the drug product. Those thresholds vary based on the maximum daily dose of the drug substance (and) not the maximum daily dose of the drug product) . “Reporting Thresholds” are based on a percentage of the maximum daily dose of the drug substance. “Identification Thresholds” and “Qualification Thresholds” are expressed as the lower of a percentage of the degradant in the maximum daily dose of the drug substance and a total daily intake (TDI) of the degradant.
These previous paragraphs are given for context as we move into a discussion of how some of the principles in these ICH documents might be applied to extraneous contaminants in cleaning validation studies, specifically for unknown peaks found in chromatograms of swab or rinse samples That topic will be covered in detail in Part 2 next month.
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