Statistics and Process Validation: current Findings of the FDA

    統計和工藝驗證：FDA現在發現的缺陷

    The “new” FDA's process validation guideline has been effective since January 2011. One considerable change was made to the original validation guideline from 1987 to put a significantly greater emphasis on statistics in the context of process validation. So far, relatively few inspection deficiencies had been observed by the FDA with regard to statistics. At a conference in September 2015 co-sponsored by the FDA, Grace McNally - Senior FDA official - reported about current “findings” in the 483s deficiency reports and in Establishment Inspection Reports （EIR）。 Now, deficiencies regarding statistical problematics can also be found here.

    “新的”FDA工藝驗證指南自2011年1月開始生效。它與1987年指南相比有一個重大的變化，就是重點強調了工藝驗證中的統計。到目前為止，FDA在統計方面并沒有報告出更多的缺陷。在2015年9月由FDA的GRACE MCNALLY---FDA資深官員---主持的會議中總結了目前在483缺陷表和現場檢查報告EIR中的缺陷。其中也有關于統計的缺陷。

    For example, it has been criticised that a （statistical） sampling plan had be misinterpreted. Wrong AQL values with regard to the number of samples have been noted based on MIL-STD-105D. Moreover, it has been criticised that the company didn't know the operation characteristics of its sampling plan.

    例如，有一個缺陷是說（統計學）取樣方案被錯誤解釋。一個取樣量AQL值，根據MIL-STD-105D，這個AQL值是錯誤的。另外，公司并不知道其取樣方案的操作特點。

    Another criticised “finding” was that PPQ batches had been considered as “accepted” when all in-process controls and release specifications were met. It has also been criticised that no intra-batch variabilities have been examined. In addition, it has been noticed that there was no information available in the validation plan concerning the assessment of the process itself. There was also no indication about the objective of the determination of inter-batch variabilities.

    另一個缺陷是在當符合所有中控和放行批準時PPQ批被“接受”。還有缺陷是沒有檢查批間差異。另外，檢查還注意到在驗證計劃中沒有關于工藝本身的評估，也沒有批間差異的確認目標說明。

    Although OOS results had been found in 2 out of 4 PPQ batches, reduced IPC tests have been recommended in the PPQ report giving the justification that this was a standard procedure. Regarding this point, the FDA criticises the lack of scientific rationales for reduced sampling and monitoring. Interestingly, Grace McNally mentions possibilities for rationales of IPC sampling plans and the adaptation to a reduced size. In this context, she refers to the ANSI/ASQ Z1.4 norm and ISO 2859 wherby it is expressly pointed out that the ANSI norm recommends the production of at least 10 successful batches before reducing testing. According to the ISO norm even 15 successful batches are necessary.

    盡管在4個PPQ批中發現了2個OOS結果，在PPQ報告中還是建議減少IPC測試，論證說這是一個標準程序。關于此點，FDA批評說這樣減少取樣和監測是缺陷科學合理性的。有意思的是，GRACE MCNALLY提到IPC取樣方案合理性，和減少樣品量的合理性的可能性。在此，她引用了ANSI/ASQ Z1.4標準和ISO2859，指出ANSI標準建議在減少測試之前至少生產10個成功批次。如果根據ISO標準就需要有15個成功的批次。

    The FDA notified a tablet process, criticising the fact that no rationales for warning and action limits were available. Furthermore, it has been criticised that no analyses on variabilities were available although they had been required internally and no capacity indices had been determined. There have been no analyses on the distribution of data, neither planned nor performed. The FDA also remarked that the calculation of variabilities is necessary to be able to make statements about process capacities.

    FDA報告了一個片劑工藝，批評其警戒限和行動限沒有合理性。另外，還批評其沒有對變量進行分析，雖然內部有這個要求，并且也沒有確定產能指標。沒有制訂計劃或實施對數據分布情況的分析。FDA還說需要進行變更計算從而能夠說明工藝能力。

    Conclusion: Reinforcing the emphasis on statistics in the US FDA Process Validation Guideline from 2011 hasn't been really often addressed in the official deficiencies reports. This seems to be changing.

編輯：foodnews