FDA Offers Q&As on IS Response Variability in Chromatographic Analytical Data
The US Food and Drug Administration’s (FDA) Office of Study Integrity and Surveillance, Office of Generic Drugs and Office of Clinical Pharmacology on Wednesday published a final question and answer (Q&A) guidance to help sponsors, applicants and contract research organizations with internal standard (IS) response variability in chromatographic analytical data.Such data can be submitted in investigational new drug applications, new drug applications, abbreviated new drug applications, biologics license applications and supplements, and FDA defines an IS response as a measurement of the signal from the IS, typically generated during liquid chromatography-mass spectrometry bioanalysis.
“Depending upon its source, IS response variability may impact the accuracy of analyte concentration measurements,” FDA explains, noting that the five Q&As in the guidance provide the agency’s current thinking on IS response variability and its potential impact on the accuracy of analyte concentration measurements.
“This Q&A also suggests approaches to determine whether observed IS response variability is likely to impact the accuracy of the data such that further investigation into the root cause(s) is warranted,” FDA says.
But the third question notes, with two examples, instances when IS response variability is not likely to impact the accuracy of the data. And the fourth question notes, with three examples, when IS response variability may impact the accuracy of the data “when the range of the IS responses for subject samples is different than the range of IS responses for Cals/QCs [calibration standards/quality controls] in the same run.”
As far as addressing concerns about IS response variability, the last answer offers help for when subject samples with IS responses significantly differ from the responses for Cals/QCs, where a gradual drift or pattern in IS responses is observed between subject samples and there are no IS responses for Cals/QCs within the impacted segment of the run, and when IS responses for subject samples are consistently lower or higher than IS responses for Cals/QCs.
Evaluation of Internal Standard Responses During Chromatographic Bioanalysis: Questions and Answers: Guidance for Industry