Learning from FDA Warning Letters – OOS’s and aborted HPLC runs

FDA Warning Letters as a Compliance Benchmarking Tool

FDA Warning letters are a valuable resource to learn the Agency’s expectations around specific practices.  FDA publishes these regularly on their website. Many of these Warning Letters items issued for critical GMP non-compliances have data integrity implications.  Let’s analyze one such GMP non-compliance issue from December 2017 Warning Letter 320-18-12  to understand the underlying problem, the risk or potential impact to data integrity that it represents and the expectations of FDA detailed in the Warning Letter. Based on such analysis, a QC Lab manager can benchmark their practices and procedures, identify any gaps and define CAPAs to reduce risk.

Case Study Example – Warning Letter 320-18-12 issued in December 2017

In the example following, the GMP compliance issue was classified as failure to properly investigate OOS results in chromatographic analyses. Note that this is a common observation from FDA 483s from many companies. In this case, the SOP reportedly permitted the QC analyst to end an HPLC sequence if they suspected there might be a problem that could lead to an OOS — without first performing an initial investigation of the event to determine an assignable cause (bold highlights are mine):

“c. Your OOS investigation procedure 036/—/QS/QA permits an analyst to abort a chromatographic run if an apparent OOS is observed prior to completing analysis of all samples scheduled to be injected in the sequence. Your quality control (QC) manager confirmed that analysts abort HPLC analyses if they “expect to invalidate” them later for an assignable cause. For example, you aborted the HPLC sequence of (b)(4) API batch (b)(4) while observing the chromatographic run on the screen (“online monitoring”) in which an individual unknown impurity tested at (b)(4)% (specification: NMT (b)(4)%). There was no machine malfunction (e.g., unstable system) that would justify aborting the automated analysis.

Our investigators documented approximately 248 instances of aborted sequences.

Your SOP was inadequate. When performing a sample preparation, it may be possible to identify an obvious manual error at the time of the mistake. In such a limited instance, it can be appropriate to discontinue the sample preparation, immediately document the deviation, and justify a new sample preparation. However, it is not appropriate to stop an in-progress automated analysis because of an assumption that an earlier error may be causing an OOS result. Obtaining an unexpected result does not constitute an “assignable cause” and the assumption of such a cause is not a valid basis for interrupting an analysis. The automated analytical sequence should be allowed to proceed to completion, irrespective of the appearance of undesirable analytical results on the computer screen.”

The key quality compliance expectations from this example:  Where in the regulations are these requirements made?

HPLC sequences must be run to completion, assuming no machine malfunction/unstable system.

An SOP that permits analysts to abort GMP runs in-progress based on observing the data generated on the screen is inadequate. The SOP must detail  procedures that include proper handling of preparation error, equipment malfunction and OOS events.  This would include investigation activities prior to repeating a sample analysis.

An obvious sample preparation error may justify stopping prep and starting over, as long as the error/deviation is immediately documented and justified.

Potential impacts to data integrity illustrated by this example

This is a classic example that is often referred to as “testing into compliance” by aborting  and repeating HPLC runs without proper justification based on clear evidence of a machine and or human error.

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