工艺风险评估与验证案例

2011年11月 1

2011年11月 2

Figure 28. Process map for Example MR Tablets, 10 mg

图28 实例10 mgMR片剂的工艺图

2011年11月 3

Example QbD MR Tablet Module 3 Quality 3.2.P.2 Pharmaceutical Development

实例QbD MR片剂模块3质量3.2.P.2药物开发

2.3.1 Initial Risk Assessment of the Drug Product Manufacturing Process

药品生产工艺的初始风险评估

A risk assessment of the overall drug product manufacturing process was performed to identify the high risk steps that could affect the final drug product CQAs. Subsequently, the drug product intermediate CQAs that are directly linked to the identified final drug product CQAs were identified. The process variables that could impact the identified drug product intermediate CQAs became the focus of the risk assessment to determine which variables have the highest potential to cause a CQA failure. These variables then needed to be investigated in order to optimize the drug product manufacturing process and reduce the risk of failure. For example, the overall risk assessment of the manufacturing process found assay of the tablets to be at high risk of failure due to the drug layering step.

Subsequently, assay of the layered beads is directly linked to final tablet assay and was identified as the CQA of the drug-layered beads. Process variables that could directly impact the assay of the drug-layered beads were assessed to identify which of the variables could have the highest potential to cause a bead assay failure. This method of identifying process variables for further study was also illustrated previously in Figure 19.

进行整体药品生产工艺的风险评估以确定可能影响最终药品CQAs的高风险步骤。随后，确定直接与已确定的最终药品CQAs相关的药品中间体CQAs。可能影响已确定的药品中间体CQAs的工艺变量成为风险评估的焦点，以确定哪些变量最可能引起CQA不合格。然后需要研究这些变量以便优化药品生产工艺并降低不合格的风险。例如，整体生产工艺的风险评估发现片剂的含量是不合格的高风险由于层积上药步骤。随后，层积微丸的含量直接与最终片剂含量相关，曾被确定为层积上药微丸的CQA。评估可直接影响层积上药微丸含量的工艺变量以确定哪些变量最有可能引发微丸含量不合格。这种确定用于进一步研究的工艺变量的方法之前也在图19中进行了说明。

In the initial risk assessment of the overall manufacturing process shown in Table 51, drug layering, ER polymer coating, blending and lubrication, and compression were identified as high risk steps that could affect the quality of the final product. Justification for each risk assignment is presented in Table 52.

表51所示的整体生产工艺的初始风险评估中，确定层积上药，ER聚合物包衣，混合和润滑，及压缩为可影响最终药品质量的高风险步骤。每个风险分配的依据见表52。

Table 51. Initial risk assessment of the manufacturing process for Example MR Tablets, 10 mg

表51 实例10 mg MR片剂生产工艺的初始风险评估

Process Steps 工艺步骤

Drug Product CQAs

药品CQAs IR

granulation

IR制粒

ER beads: drug

layering

ER微丸：层积上药

Sieving I

过筛I

ER beads: polymer

coating

ER微丸：聚合物包衣

Sieving II

过筛II

Blending and

Lubrication

混合和润滑

Compression

压缩

Physical Attributes (size and splitability)

物理属性(大小和分割性)Low

低

Low

低

Low

低

Low

低

Low

低

Low

低

High

高

Assay 含量Low 低High 高Low 低Low 低Low 低Medium 中High 高

Content Uniformity 含量均匀度Low

低

Medium

中

Low

低

Low

低

Low

低

High

高

High

高

Drug Release – whole tablets 药物释放--整片Low

低

Low

低

Low

低

High

高

Medium

中

Medium

中

High

高

Drug Release – split tablets 药物释放—分割片Low

低

Medium

中

Low

低

High

高

Medium

中

High

高

High

高

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸N/A N/A N/A Low

低

Low

低

Low

低

Low

低

Table 52. Justification for the initial risk assessment of the manufacturing process for Example MR Tablets, 10 mg 表52 实例10 mg MR片剂生产工艺的初始风险评估的依据

Process Steps 工艺步骤Drug Product CQAs

药品CQAs

Justification

依据

IR granulation IR制粒Physical Attributes (size and

splitability)

The IR granules in Example MR Tablets are prepared the same as the IR granules in Example IR Tablets

(ANDA aaaaaa(Appendix I)). The manufacturing process has been optimized previously and low

2011年11月 5