FDA Warning letter <Nitrosamine or NOT>

A recent FDA warning letter highlights some investigators observed deviations. While we cannot point out is they were Nitrosamine related, I believe there are valuable learnings:

1. Failure to evaluate the potential effect that changes may have on the quality of your intermediates and API.

Your firm failed to fully evaluate whether increasing your acceptable (b)(4) limit by (b)(4) in an (b)(4) API starting material (b)(4) would impact the quality of (b)(4) API. Following the initial rejection of several lots of the (b)(4) starting material for failing to meet specified (b)(4) limits (e.g., (b)(4) ppm observed, (b)(4) ppm specification), you performed a lab scale study to justify an increase in the acceptable (b)(4) limit. You only evaluated (b)(4) potential impurities formed via (b)(4) where (b)(4) and did not consider the generation of the other substituted potential impurities before increasing the (b)(4) limit in your (b)(4) starting material from (b)(4) ppm to (b)(4) ppm

Further, instead of fully evaluating the effect of increasing the (b)(4) limit in the (b)(4) starting material, you relied on an (b)(4) step as part of your lab scale study, which was not a part of the approved or implemented large scale manufacturing process for the (b)(4) API at the time, to purge potential impurities without demonstrating that any potential impurities would be removed by (b)(4). Lastly, you relied on the existing related substances analytical method to detect the new impurities without determining their relative response factors to assess if this analytical method was appropriate for the new impurities.

  • Intermediate Assessment and Manufacturing changes oversight
  • Data, Data, Data… Necessary data is needed to confirm purging studies
  • Appropriate, robust analytical methods are a must

2. Failure of your quality unit to ensure that critical deviations are investigated and resolved.

Your firm does not fully investigate discrepancies. During method transfer for the gas chromatography–mass spectrometry (GC-MS), method for (b)(4) determination in (b)(4), a starting material for (b)(4), you failed to pass the method transfer acceptance criteria for inter laboratory precision because of observed peak splitting. Although you conducted an investigation, it was not adequate as your investigation failed to consider all potential equipment sources. The failing result was invalidated without a scientific rationale and was not reported in the “problems faced” or “corrective actions taken” sections of the approved method transfer report. Ultimately, you attributed the failing result to a dirty and/or degraded column, replaced the column, and obtained a passing result with a fresh sample. Likewise, after attributing the failure to the deteriorated column, you did not establish controls to ensure that only acceptable columns would be used in future analyses.
You stated that the failing result was an isolated incident. In your second response, you noted that there was an “interaction of [the] sample (b)(4) with the deteriorated (b)(4) of the (b)(4) column” to explain why (b)(4) standards in the failing sample set did not show peak splitting. However, if the assigned root cause is an inherent instability between with the sample and a deteriorated GC-MS column, you failed to provide any equipment controls to prevent peak splitting in the future, nor did you consider whether the analytical method was appropriate for the intended (b)(4) testing.

You be the judge, Nitrosamine related or NOT?

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