FDA警告信_泰华医药案例

kslam

FDA于2016年9月26-29日检查了位于杭州萧山的泰华医药。

FDA列2个违规。其中之一是"未能根据科学合理的取样规范建立取样计划"。


FDA要求:

- 具体说明贵公司将如何改善XX API的批取样来确保你们可以在商业生产过程中发现批内和批间变异。
- 评价其他API取样计划的充分性。
- 提供总体质量体系的改善以确保贵公司执行的所有的取样具有代表性并能够检测到质量属性可能发生的变异。

在检查期间FDA是如何确定样本量呢？

参阅ASTM E122使用精密度计算样本量以估计批次或工艺的平均值


从估计误差推导出样本量的计算公式。





以此求出样本量为

xqliu

这是梯瓦的工厂吧。

kslam

xqliu 发表于 2017-4-28 14:23
这是梯瓦的工厂吧。

TEVA

syhorchid

了解一下

一片红云

谢谢分享

kslam

Questions and Answers on Current Good Manufacturing Practices—Production and Process Controls


16.  Why is FDA concerned about proper sampling of powder blends?

The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110).  Between- and within-location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors.  However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance).  If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.



补充内容 (2017-5-2 22:35):
15. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment.  What were the Agency’s major concerns with this guidance?

FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.

Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least 3 replicate samples be taken from at least 10 locations in the powder blender, but that only 1 of the 3 replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis.  

Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in General Chapter <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release.  Currently, there are several standard statistical practices that, if used correctly, can help to ensure compliance with CGMP regulations, including 21 CFR 211.110, 21 CFR 211.160, and 21 CFR 211.165.

kslam

不论使用什么类型的混合容器，取样都必须有代表性。

要达到具有代表性的取样点，其总要在总混混合桶的上中下三层分别取样, 取样点要求≥10。每一层的中心点、边缘等取样才能说明其代表性。

每个取样点重复取样3份。

kslam

参考ASTM E2810 Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units (剂量单位含量均一性试验符合能力证明规程

xinhuawbo

kslam 发表于 2017-5-2 11:34
不论使用什么类型的混合容器，取样都必须有代表性。

要达到具有代表性的取样点，其总要在总混混合桶的上 ...

这是什么资料里讲到的

kslam

FDA 规定在工艺确认过程中需要比常规生产进行更加强化的取样和监测，以更好地确认工艺性能及确证产品质量的一致性，且这种取样和监测水平需延续到商业化生产中，直到获得足够的数据以支持日常商业化生产中取样、监测水平的合理性。

meiyududu

谢谢分享。。。

meiyududu

谢谢分享。。。

zysx01234

kslam 发表于 2017-5-2 11:34
不论使用什么类型的混合容器，取样都必须有代表性。

要达到具有代表性的取样点，其总要在总混混合桶的上 ...

这个混合也太满了吧，还取3层，你取的到吗，理论上讲讲吧了。

meiyududu

谢谢分享。。。

歪打正着

文中列的文件有吗？

sunliangjian

看多了一脸懵逼

小金库

谢谢分享。