近期，FDA发布了关于印度泰米尔纳德邦的Malladi Drugs & Pharmaceuticals Limited的警告信Warning Letter 320-18-40，于于2017年9月4-8日对其进行了检查，了发现其API生产存在严重违反CGMP的行为。

检查缺陷：

1.Failure to use appropriate precautions to minimize the risk of API contamination where open equipment is used. 

使用开放设备时未使用适当的预防措施以降低API污染风险。

Parts of your facility inwhich API production is conducted are open to the outdoors. Our investigator observed vermin, such as birds and insects, in the facility near open equipment used for drug manufacturing. Their presence puts your drugs at risk of contamination.You failed to take adequate precautions to prevent the risk of contamination while producing drugs using open equipment.

你工厂部分API生产区域为露天环境。我们调查人员在药品生产所用的开放设备附近厂区发现有害虫，如鸟和昆虫。这使得你们的药品处于污染风险中。你公司未采取足够的预防措施来防止在开放设备中生产药品时的污染风险。

You committed to corrective and preventive actions (CAPA), but your response is inadequate because you failed to address the potential risk to product quality and safety.

你们承诺采取CAPA，但你们的回复是不充分的，因为你们未解决产品质量和安全的潜在风险问题。

In response to this letter, provide a risk assessment for all drugs within their re-test date manufactured and distributed within the United States. Include an evaluation of all (b)(4), drug intermediates, and drugs potentially contaminated by vermin.

在回复此函时，请提交一份在美国销售且仍在复验期内的所有药品的风险评估。其中应包括对所有XX、药品中间体和可能受到害虫污染的药品的评估。

2.     Failure to have equipment of the appropriate design and suitability for its intended use and cleaning for the manufacture of API. 

设备未进行适当设计，适合其既定用途和API生产清洁。

You use (b)(4) vessels in the (b)(4) and (b)(4) stages of your production process. In your response, you indicate that(b)(4) water is used for cleaning the (b)(4) vessels. However, your cleaning processes are insufficient. You lack justification that you can prevent contamination from foreign matter and other impurities that may seep from the (b)(4). Further, your equipment is difficult to reproducibly clean.

你们在你们生产工艺的XX和XX步骤中使用了XX罐。在你们的回复中，你们说XX罐清洁使用的是XX水。但是，你们的清洁程序是不充分的。你们缺乏论证证明你们可以防止从XX渗入的异物和其它杂质。还有，你们的设备的清洁难以重复。

Your response also states thatthe (b)(4) is kept partially full with water for up to (b)(4) because the (b)(4) when it is fully dry. Using vessels made of (b)(4) and partially filled with standing water may increase the risk of drug contamination. In addition, equipment surfaces should be easily cleanable, and constructed to prevent additive, absorptive, or reactive characteristics.

你们的回复还说保持XX装一部分水直至XX，因为如果全干会XX。使用XX材质的罐并且装一部分静止水，可能会增加药品污染的风险。另外，设备表面应易于清洁，其结构应防止渗出、吸收或反应特性。

3.     Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 

未能证明你们的生产工艺可以重复生产出符合其预定质量属性的API。

During our inspection, you acknowledged that you failed to adequately validate your (b)(4) API drug manufacturing process. In addition, our inspection found that your process lacked adequate control during the (b)(4) step. Twenty-four batches yielded out-of-specification test results for an unspecified impurity over approximately two years. Your firm rejected these nonconforming batches and reprocessed some of them.

在我们检查期间，你们说你们未对你们的XX API药品生产工艺进行足够的验证。另外，我们的检查发现你们的工艺在XX步骤中缺乏足够的控制。约2年中有24批均有OOS结果，检出非特定杂质。你们公司拒收了这些不符合批次，有些批次进行了返工。

Prior to the manufacture of process qualification batches, a manufacturer should identify all significant sources of variability and develop robust controls throughout the operation.Your process validation program failed to sufficiently address process parameters and other variables in the commercial manufacturing operation to support process reproducibility. It is essential that your process validation program provide substantial information and data to determine if the process can consistently produce acceptable quality products under commercial manufacturing conditions.

在生产工艺确认批次之前，生产商应找出所有操作中所有波动的来源，并建立稳健的控制。你们的工艺验证计划未能充分说明商业化生产操作中工艺参数和其它变量以支持工艺可重复性。你们的工艺验证计划必须提供实质性信息和数据来确定工艺是否可在商业化生产条件下一致地生产出具有可接受质量的产品。

In your response, you also acknowledged that your investigations and timeliness of response to the batch failures was inadequate, and that process changes were initiated without formal change management. You also provided data from many batches that met specifications for impurity and identity. However, this data is not are placement for adequate process design, control, CAPA and change management, and does not sufficiently support your claim that your process is robust.

在你们的回复中，你们承认过去你们的调查和时间表是不充分的，工艺变更启动没有正式变更管理。你们还提供了许多杂质和鉴别符合质量标准的批次数据。但是，这些数据并不能取代充分的工艺设计、控制、CAPA和变更管理，不足以支持你们声明说你们的工艺是稳健的。

Your firm does not have anadequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation athttp://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.

你们公司没有充分的持续计划监测工艺控制以确保稳定性生产操作和一致的药品质量。参见FDA工艺验证指南。

转自：Julia法规翻译