Why Impurity Deficiencies Keep Repeating: AAPS PharmSci 360 2026

At AAPS PharmSci 360 in New Orleans, which occurred from October 25-28, Subathra Ramamoorthy, MS, RPh, associate principal scientist in analytical R&D, Veranova discusses how impurity-related deficiencies in regulatory submissions tend to repeat themselves, and most can be caught before a filing reaches the agency.

“See, the deficiencies that we come across, they seem to be remarkably consistent from one submission to another,” Ramamoorthy says. Recurring gaps include unidentified impurities above the identification threshold, quantitation limits set above the reporting threshold, missing relative response factors, and methods that are not stability indicating. She also points to specifications built only on batch data instead of on qualification and safety data. Another gap is mutagenic impurity control strategies that claim an impurity is purged without data to back it up.

Nitrosamine findings usually come from overlooked nitrosamine drug substance-related impurities, or from missing risk assessments for excipients that contain nitrite. Elemental impurity assessments draw scrutiny when teams treat them as a checklist. Reviewers expect a full evaluation of manufacturing equipment, water, and every other source, in line with the risk-based approach of ICH Q3D. For extractables and leachables, the weak points are:

• inadequate evaluation thresholds
• extraction conditions that don’t reflect real product use
• no correlation between extractables and leachables
• incomplete toxicological assessment

Ramamoorthy’s fix is one consistent account for each impurity: where it comes from, how the process controls or removes it, which stability-indicating method detects it, and what limit is safe. “So the idea is the story should be consistent across, for all impurities, across both the drug substance and drug product sections of the submissions,” she says. Ramamoorthy also recommends keeping an impurity log and a justification table for every specified impurity.

“My rule of thumb is always to review our own submission as if we are the reviewers and make sure if there is any number that doesn’t make sense to us, then that’s a red flag that needs to be addressed immediately before you even give it to the agency for submission.”