工艺风险评估与验证案例

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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

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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

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物理属性(大小和分割性)variability of granule PSD and bulk density between commercial batches were observed. The risk of the

IR granulation process variables to impact the tablet size and splitability is low.

制备与实例IR片剂(ANDA aaaaaa(附件I))中的IR颗粒相同的实例MR片剂中的IR颗粒。之前已经优

化了生产工艺，并观察到市售批之间的颗粒PSD和松密度的变异性低。影响片剂大小和分割性的IR

制粒工艺变量的风险为低。

Assay 含量The approved commercial IR granulation routinely delivers granules with an assay of 95 – 105%. The

risk is low. 已批准的市售IR制粒定期提供的含量为95 – 105%。风险为低。

Content Uniformity 含量均匀度On the commercial scale, the IR granules routinely demonstrate good blend uniformity and Example IR Tablets show acceptable CU. The risk of the IR granulation process variables to impact Example MR Tablet CU is low. 在工业规模中，IR颗粒定期显示了良好的混合均匀度，实例IR片剂显示了可接受的CU。影响实例MR片剂CU的IR制粒工艺变量的风险为低。

Drug Release – whole tablets 药物释放--整片Example IR Tablets manufactured using the approved IR granulation process consistently demonstrate rapid drug release. During formulation development, the drug release from IR granules compressed with placebo beads was unaffected. Therefore, the risk of the IR granulation process variables to impact drug release from the IR portion of Example MR Tablets is low. 用已批准的IR制粒工艺生产的实例IR片剂一贯表现出快速药物释放。处方开发中，和安慰剂微丸一起压制的IR颗粒的药物释放未受影响。因此，影响实例MR片剂的IR部分的药物释放的IR制粒工艺变量的风险为低。

Drug Release – split tablets 药物释放—分割片The commercial IR granulation delivers granules with acceptable BU and the Example IR Tablets have acceptable CU. Additionally, rapid drug release from Example IR Tablets is achieved. Thus, the risk of the IR granulation process variables to impact drug release from split tablets is low. 市售IR制粒提供的颗粒具有可接受的BU，实例IR片剂具有可接受的CU。此外，实现了实例IR片剂的快速药物释放。因此，影响分割片的药物释放的IR制粒工艺变量的风险为低。

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by the ER polymer coating formulation and the ER polymer coating step and is not related to the IR granulation. 酒精引发的剂量倾卸是由ER聚合物包衣处方和ER聚合物包衣步骤决定，与IR制粒无关。

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Physical Attributes (size and splitability)

物理属性(大小和分割性)The impact of drug layering on the size of beads is low due to the low dose (7 mg) in the drug layer. The weight gain is low. Process variables may cause some variability in the coating efficiency; however, the impact on bead size is minimal and the risk of the drug layering process variables to impact tablet physical attributes is low. 层积上药对微丸粒径的影响低由于药物层中的剂量低(7 mg)。增重低。工艺变量可引起包衣率的某些变化；但是，对微丸粒径的影响是最低的，影响片剂物理属性的层积上药工艺变量的风险为低。

Assay 含量Poor adhesion and/or spray drying can have an impact on the potency of the drug-layered beads. The risk

of impact on tablet assay is high. 粘性和/或喷干差可影响层积上药微丸的药效。影响片剂含量的风

险为高。

Content Uniformity 含量均匀度Drug substance and binder are uniformly dissolved and the resulting solution is sprayed onto beads in a fluid bed coater. Suboptimal fluidization may lead to some beads receiving more layering than others. The risk of the drug layering process variables to impact the uniformity of the beads, and therefore the tablet CU, is medium. 主药与粘合剂溶解均匀并将所得的溶液喷于流化床包衣机中的微丸上。未达最优的流化可导致某些微丸比其他微丸接受更多的层积。因此，影响微丸的均匀度和片剂CU的层积上药工艺变量的风险为中。

Drug Release – whole tablets 药物释放--整片Rapid dissolution of the drug-layered beads was achieved during formulation development. The risk of the drug layering process variables to impact drug release from whole tablets is low. 处方开发中实现了层积上药微丸的快速溶出。影响整片的药物释放的层积上药工艺变量的风险为低。

Drug Release – split tablets 药物释放—分割片Although the risk of the drug layering step to impact whole tablet drug release is low, the risk of the step to impact tablet CU is medium. Therefore, the risk of the layering process variables to impact split tablet drug release is also medium. 虽然层积上药步骤对整片药物释放的影响风险为低，但是对片剂CU 的影响风险为中。因此，影响分割片的药物释放的层积工艺变量的风险也为中。

ER beads: drug layering ER微丸：

层积上药

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by the ER polymer coating formulation and the ER polymer coating step and is not related to the drug layering step. 酒精引发的剂量倾卸是由ER聚合物包衣处方和ER聚合物包衣步骤决定，与层积上药步骤无关。

Sieving I Physical Attributes (size and The main purpose of the sieving I step is to screen out agglomerates and fines produced during the drug

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splitability)

物理属性(大小和分割性) Assay 含量

Content Uniformity

含量均匀度

Drug Release – whole tablets 药物释放--整片

Drug Release – split tablets 药物释放—分割片layering process. The risk of this separation procedure to impact the drug product CQAs is low.

过筛I步骤的主要目的是筛出层积上药工艺中产生的聚集颗粒和细颗粒。该分离方法影响药品CQAs的风险为低。

过筛I

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by ER polymer coating formulation and the ER polymer coating step and is not related to sieving I. 酒精引发的剂量倾卸是由ER聚合物包衣处方和ER聚合物包衣步骤决定，与过筛I无关。

Physical Attributes (size and splitability)

物理属性(大小和分割性)The ER polymer coating formulation is optimized and the ER polymer coating thickness is ~ 50 μm. The impact of the ER polymer coating process variables on bead size is minimal. The risk of the ER polymer coating process variables to impact the tablet physical attributes (size and splitability) is low. ER聚合物包衣处方经优化后的ER聚合物包衣厚度为~ 50 μm。ER聚合物包衣工艺变量对微丸粒径的影响最低。ER聚合物包衣工艺变量影响片剂物理属性(大小和分割性)的风险为低。

Assay 含量Assay is mainly determined by the drug layering step. Although attrition of the drug-layered beads may

occur during initial ER polymer coating, the risk of the ER polymer coating process variables to impact

tablet assay is low. 含量主要由层积上药步骤决定。虽然在初始ER聚合物包衣中可发生层积上药微

丸的损耗，但是ER聚合物包衣工艺变量影响片剂含量的风险为低。

Content Uniformity 含量均匀度Drug uniformity of the beads is mainly determined by the drug layering process step and is unaffected by the ER polymer coating process variables. The risk of the ER polymer coating process variables to impact tablet CU is low. 微丸的药物均匀度主要由层积上药工艺步骤决定，不受ER聚合物包衣工艺变量的影响。ER聚合物包衣工艺变量影响片剂CU的风险为低。

ER beads:

polymer coating

ER微丸：聚合物

包衣

Drug Release – whole tablets ER polymer coating is the drug release rate controlling step for the ER coated beads. The risk of the ER

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药物释放--整片polymer coating process variables to impact drug release from whole tablets is high. ER聚合物包衣是

ER包衣微丸药物释放率的控制步骤。ER聚合物包衣工艺变量影响整片的药物释放风险为高。

Drug Release – split tablets 药物释放—分割片Despite the fact that the ER polymer coating process has minimal impact on the drug uniformity of the beads, the process has a high potential to impact whole tablet drug release. For this reason, the risk of the ER polymer coating process variables to impact split tablet drug release is high. 尽管事实上ER聚合物包衣工艺对微丸药物均匀度的影响最低，但是该工艺具有影响整片药物释放的高潜在性。由于这个原因，ER聚合物包衣工艺变量影响分割片药物释放的风险为高。

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by the ER polymer coating formulation which was optimized during development and shown to perform comparably to the RLD. Therefore, the risk of the coating process variability to alter susceptibility to alcohol-induced dose dumping is low. 酒精引发的剂量倾卸是由开发中进行了优化并显示行为与RLD类似的ER聚合物包衣处方决定。因此，包衣工艺变异性改变酒精引发剂量倾卸敏感度的风险为低。

Physical Attributes (size and splitability)

物理属性(大小和分割性) Assay 含量

Content Uniformity

含量均匀度The main purpose of the sieving II step is to screen out agglomerates and fines produced during the ER polymer coating step. The risk of this separation procedure to impact physical attributes, assay, or content uniformity of the tablets is low.

过筛II步骤的主要目的是筛出ER聚合物包衣步骤中产生的聚集颗粒和细颗粒。该分离方法影响物理属性，含量，或片剂含量均匀度的风险为低。

Drug Release – whole tablets 药物释放--整片There is a chance that the polymer film on the ER coated beads may be damaged if excessive force is used during sieving II. This may change the drug release profile. The risk of sieving II to impact the drug release from whole tablets is medium. ER包衣微丸上的聚合物薄膜有可能受到破损如果在过筛II中用力过猛。这可改变药物释放曲线。过筛II影响整片的药物释放风险为中。

Sieving II 过筛II

Drug Release – split tablets 药物释放—分割片Although the risk of sieving II to impact tablet CU is low, the risk of impact on drug release from whole tablets is medium. As such, the risk of sieving II to impact drug release from split tablets is also medium. 虽然过筛II影响片剂CU的风险为低，但是影响整片药物释放的风险为中。因此，过筛II影响分割片药物释放的风险也是中。

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Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by the ER polymer coating formulation and the ER polymer coating step. Prototype tablets were shown to perform comparably to the RLD during formulation development. Therefore, the risk of sieving II to alter susceptibility to alcohol-induced dose dumping is low. 酒精引发的剂量倾卸是由ER聚合物包衣处方和ER聚合物包衣步骤决定。处方开发中显示原型片剂行为与RLD类似。因此，过筛II改变酒精引发剂量倾卸敏感度的风险为低。

Physical Attributes (size and splitability)

物理属性(大小和分割性)Suboptimal blending may impact the distribution of magnesium stearate in the final blend. However, the risk of blending and lubrication process variables to impact tablet physical attributes (size and splitability) is considered low. 未达最优的混合可影响硬脂酸镁在最终混合物中的分布。但是，混合和润滑工艺变量影响片剂的物理属性(大小和分割性)被视为低风险。

Assay 含量Blending process variables will impact BU. However, good flowability of the final blend was achieved

during formulation development which will facilitate BU if process variables are optimized. The risk of

blending and lubrication to impact tablet assay is medium. 混合工艺变量将影响BU。但是，处方开发

中达到了最终混合流动性良好，将改善BU如果工艺变量最优化。混合和润滑影响片剂含量的风

险为中。

Content Uniformity 含量均匀度Segregation is possible during the blending and lubrication step, during holding in the blender and during blender discharge. If segregation occurs, the CU of the final drug product will be impacted. The risk of impact on tablet CU is high. 分离可能在混合和润滑步骤中，在混合机的停留期间和混合机排放期间。如果发生分离，则将影响最终药品的CU。影响片剂CU的风险为高。

Drug Release – whole tablets 药物释放--整片Blending process variables may impact the distribution of the extragranular disintegrant and lubricant. The risk of impact on whole tablet drug release is medium. 混合工艺变量可影响外加崩解剂和润滑剂的分布。影响整片药物释放的风险为中。

Blending and Lubrication 混合和润滑

Drug Release – split tablets 药物释放—分割片The risk of blending and lubrication to impact whole tablet drug release is medium. However, for a tablet with poor CU, the drug release profile of split tablets may differ from that of whole tablets. Since the risk of the blending and lubrication process variables to impact tablet CU is high, the risk of the step to impact split tablet drug release is also high. 混合和润滑影响整片药物释放的风险为中。但是，对于CU差的片剂，分割片的药物释放曲线可能不同于整片。因为混合和润滑工艺变量影响片剂CU的风

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险为高，所以影响分割片药物释放的步骤风险也为高。

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸The ER polymer coating formulation and the ER polymer coating step control alcohol-induced dose dumping. Prototype tablets performed comparably to the RLD. Therefore, the risk of blending and lubrication process variables to impact alcohol-induced dose dumping is low.

ER聚合物包衣处方和ER聚合物包衣步骤控制酒精引发的剂量倾卸。原型片剂行为与RLD类似。因此，混合和润滑工艺变量影响酒精引发的剂量倾卸风险为低。

Physical Attributes (size and splitability)

物理属性(大小和分割性)Through tooling design, the shape and score configuration of the tablets are defined. Compression force may impact the splitability of the scored tablets. The risk of the compression process variables to impact the tablet physical attributes (size and splitability) is high. 通过模具设计，确定了片剂的形状和刻痕形态。压缩力可影响刻痕片的分割性。压缩工艺变量影响片剂物理属性(大小和分割性)的风险为高。

Assay 含量Segregation may occur when the final blend is transferred from the drum into the hopper or when the

blend flows from the hopper to the feed frame and into the die cavity. In addition, tablet press speed and

feeder speed may impact the flow of the blend into the die cavity. Although good flowability was

achieved during optimization of the prototype formulation, the risk of compression process variables to

impact tablet assay is high. 当最终混合物从桶中转移至加料斗或当混合物从加料斗流向传送架并进

入模腔时，可发生分离。此外，压片机速率和加料机速率可影响混合物流入模腔。虽然原型处方

优化期间实现了良好的流动性，但是压缩工艺变量影响片剂含量的风险为高。

Content Uniformity 含量均匀度Segregation may occur during compression due to vibration as well as poor flow from the hopper to feeder frame and, ultimately, into the die cavity. The risk of compression process variables to impact tablet CU is high. 压缩期间可发生分离由于振动和从加料斗向传送架流动并最终进入模腔的流动性差，可发生分离。压缩工艺变量影响片剂CU的风险为高。

Compression 压缩

Drug Release – whole tablets 药物释放--整片Excessive compression force may damage the integrity of the ER polymer coating and impact the drug release profile. As such, dose dumping may be a concern and needs to be evaluated. The risk of compression process variables to impact whole tablet drug release is high. 过量的压缩力可破坏ER聚合物包衣的完整性并影响药物释放曲线。因此，剂量倾卸可能是一个问题并需要进行评估。压缩工艺变量影响整片药物释放的风险为高。

2011年11月11

Drug Release – split tablets 药物释放—分割片Because the risk of compression to impact both tablet CU and whole tablet drug release is high, the risk of this step to impact split tablet drug release is also high. 因为压缩影响片剂CU和整片药物释放的风险为高，所以该步骤影响分割片药物释放的风险也为高。

Drug Release –alcohol-induced dose dumping 药物释放—酒精引发的剂量倾卸Alcohol-induced dose dumping is determined by the ER polymer coating formulation and the ER polymer coating step. Excessive compression force may cause dose dumping but not alcohol-induced dose dumping. The risk of compression process variables to impact alcohol induced dose dumping is low.酒精引发的剂量倾卸是由ER聚合物包衣处方和ER聚合物包衣步骤决定。过量的压缩力可引起剂量倾卸但不是酒精引发的剂量倾卸。压缩工艺变量影响酒精引发的剂量倾卸风险为低。

2.3.2 IR Granule Process Development IR颗粒工艺开发

For complete details of the IR granule development, refer to ANDA aaaaaa (Appendix I). In brief, the granulation process involves dry mixing followed by the addition of granulating fluid, purified water. After wet granulation and milling, the wet mass is transferred to the fluid bed dryer. Granules are then dried to a target product bed temperature of 52 °C, corresponding to a LOD of < 2.0%. Dried granules are passed through a mill where the granule particle size is controlled to have a d50 between 250-350 μm. Batches were scaled-up by maintaining impeller tip speed. Assay of pilot batches was maintained between 95% and 105% and the acceptance value for content uniformity was less than 5. The critical operating parameters are summarized in Table 53.

完整的详细IR颗粒开发，请参阅ANDA aaaaaa (附件I)。简言之，制粒工艺涉及干法混合然后加入制粒液，纯化水。湿法制粒和粉碎后，湿物料转移至流化床干燥机中。然后干燥颗粒达到目标产品床温52 °C，相当于LOD< 2.0%。干燥后的颗粒通过粉碎机使颗粒粒径控制在d50介于250～350μm。通过维持叶轮外缘转速来放大批次。维持中试批的含量在95%～105%，含量均匀度可接受值低于5。关键操作参数总结在表53中。

Table 53. Critical operating parameters for IR granules based on ANDA aaaaaa

表53 基于ANDA aaaaaa 的IR颗粒的关键操作参数

Process Parameters 工艺参数 Lab

Scale

实验室规模 Pilot

Scale

中试规模

Active Powder Mixing 混合活性粉末

Equipment model 设备型号Collette Gral 10 Collette Gral 300

Impeller speed 叶轮转速Low (285 rpm) 低速(285 rpm)Low (125 rpm)低速(125 rpm)

Mixing time 混合时间 5 min 5 min

Granulation using Purified Water 用纯化水制粒

2011年11月12

Equipment model 设备型号Collette Gral 10 Collette Gral 300

Impeller speed 叶轮转速Low (285 rpm) 低速(285 rpm)Low (125 rpm)低速(125 rpm)

Chopper speed 切碎机速度 Low

低速 Off

关闭

Solution addition rate 溶液添加速度60 g/min 1.28 kg/min

Mixing time 混合时间12 min 12 min

Drying 干燥

Equipment 设备 Fluid

Bed

Dryer

流化床干燥机Fluid Bed Dryer 流化床干燥机

Bed air temperature 流化床空气温度52 oC (50 – 55 °C) 52 oC (50 – 55 °C)

Milling 粉碎

Equipment model 设备型号Fitzmill L1A Fitzmill DA6

Screen size: 20 mesh 筛孔大小：20目Screen size: 20 mesh 筛孔大小：20目

Screening mill 筛分机

Speed: 4740 ± 20 rpm 速度：4740 ± 20 rpm Speed: 2500 ± 20 rpm 速度：2500 ± 20 rpm

2.3.3 ER Bead Process Development ER微丸工艺开发

This section addresses the potentially critical material attributes and process parameters involved in the fluid bed drug layering and ER polymer coating process development. 本节讨论了流化床层积上药和ER聚合物包衣工艺开发涉及的潜在关键物质属性和工艺参数。

Figure 29 shows the functional components of bottom spray fluid bed equipment for the pilot scale drug layering operation. Important equipment parameters in the Wurster coating process include the insert diameter, nozzle diameter, and distribution plate and partition gap (distance between distribution plate and the bottom of partition column, also referred to as partition height). These parameters can affect the dynamics of air flow, fluidization pattern, heat transfer and moisture content which are all directly related to the quality of the layered product. Settings for these equipment parameters need to be determined in concert with operating conditions and scale of operation, but can usually remain fixed after optimization if the scale and equipment do not change.

图29显示了用于中试放大层积上药操作的底部喷雾流化床设备的功能部件。Wurster包衣工艺的重要设备参数包括插入腔体孔径，喷嘴孔径，及分布板和分离间距(分布板和分离柱底部之间的距离，也称为分离高度)。这些参数可影响空气流量的动力学，流化模式，热传递和水分含量，这些都直接与层积产品质量相关。设置这些设备参数需由操作条件和操作规模决定，但是优化后通常可保持不变如果规模和设备未发生变化。

2011年11月13

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

Figure 29. Schematic diagram of the bottom spray fluid bed coating equipment

图29 底部喷雾流化床包衣设备的示意图

2.3.3.1 Drug Layering Process Development 层积上药工艺开发

Initial Risk Assessment of the Drug Layering Process Variables

层积上药工艺变量的初始风险评估

The initial risk assessment of the overall manufacturing process presented in Table 51 identified the risk of the drug layering step to impact assay of the drug product as high. Subsequently, assay of the drug-layered beads was identified as a CQA for the drug layering step. Process variables that could potentially impact assay of the drug-layered beads were identified and their associated risk was evaluated. Conducting DOEs to evaluate all the variables is not feasible. Therefore, variables ranked as low to medium risk during the assessment were set constant based on feasibility studies and previous experience. The variables ranked as high risk were evaluated by conducting DOE studies to gain process understanding.

表51呈现的整体生产工艺的初始风险评估确定了层积上药步骤对药品含量的影响风险为高。随后，确定层积上药微丸含量为层积上药步骤的CQA。确定了可潜在影响层积上药微丸含量的工艺变量并评估了它们的相关风险。为评估所有的变量而进行DOEs是行不通的。因此，基于可行性研究和之前的经验，在评估中列为低至中风险的变量设置不变。通过进行DOE 研究来评估列为高风险的变量以达到理解工艺。

Assay of the drug-layered beads will be controlled in the range of 95.0 – 105.0% of label claim. A suboptimal process may generate excessive fines or agglomerates which could adversely affect the drug-layered bead assay. Table 54 summarizes the initial risk assessment of the identified drug layering process variables that may impact the drug-layered bead assay.

控制层积上药微丸含量在95.0～105.0%标示量范围内。未达最优化的工艺可产生过量的细颗粒或聚集颗粒，可对层积上药微丸含量产生不利影响。表54总结了可影响层积上药微丸含量的已确定的层积上药工艺变量的初始风险评估。

Table 54. Initial risk assessment of the drug layering process variables

表54 层积上药工艺变量的初始风险评估

Unit Operation: Drug Layering 单元操作：层积上药

Output Material CQA: Assay of the drug-layered beads 输出物料CQA：层积上药微丸含量

Variables 变量Risk Assessment

风险评估

Justification and Initial Strategy

依据和初步策略

Input Material Attributes 输入物料属性

Drug substance PSD 主药PSD Low

低

The drug substance is dissolved and then sprayed. Its PSD has no impact on the assay of the beads.

溶解主药并喷雾。其PSD对微丸含量无影响。

Drug substance solid state form

主药固态形式Low

低

The drug substance is dissolved and is amorphous after drying on the bead surface. The initial solid state

form of the drug substance has no impact on the drug-layered bead assay.

溶解主药，在微丸表面干燥后为无定形。主药的初始固态形式对层积上药微丸含量无影响。

MCC beads PSD MCC微丸PSD Low

低

MCC beads are sieved and only the fraction between 250-350 μm is used for the layering process. Within this

tight control, the risk of MCC PSD to impact drug-layered bead assay is low. 过筛MCC微丸，仅250～350

μm的部分用于层积工艺。在这种严格控制内，MCC PSD影响层积上药微丸含量的风险为低。

MCC beads friability MCC微丸脆碎度Low

低

MCC beads have low friability (< 0.1%). As such, the risk of friability to impact drug-layered bead assay is

low. MCC微丸脆碎度低(< 0.1%)。因此，脆碎度影响层积上药微丸含量的风险为低。

PVP K30 K-value PVP K30 K值Low

低

PVP K-30 is supplied with a K-value in the range of 29-32. This variability should not impact drug-layered

bead assay. 提供的PVP K-30的K值范围在29～32内。该变异性应不影响层积上药微丸含量。

Drug layering solution viscosity

层积上药溶液粘度Low

低

The drug layering solution viscosity is low (< 5 mPa?s) and can be effectively atomized.

层积上药溶液粘度低(< 5 mPa?s)，可被有效的雾化。

Equipment Variables 设备变量

Equipment 设备Low 低Glatt GPCG-5 selected based on availability. 基于可用性选择Glatt GPCG-5。

Wurster insert diameter Wurster插入腔体孔径Low

低

7″ Wurster HS insert is selected based on its capacity, 8.3 L, and the planned batch size.

选择7″ Wurster HS插入腔体基于其容量，8.3 L和计划的批数量。

2011年11月15

Partition column diameter 分离柱孔径Low

低

Fixed by equipment design: 89 mm in diameter.

通过设备设计固定为：孔径89 mm。

Air distribution plate 空气分布板Low

低

The air distribution plate can impact the fluidization pattern of beads passing through the partition column.

C plate is selected based on the size of the beads and previous experience. 空气分布板可影响微丸通过分

离柱的流化模式。基于微丸粒径和之前的经验，选择C板。

Partition height (gap) 分离高度(间距)Medium

中

Partition gap can impact the circulation rate of beads passing through the coating zone. When the gap is more

than optimal, insufficient differential pressure to draw beads into and up the partition column can be

generated. Spraying cannot commence. When the gap is less than optimal, the circulation rate of beads

increases, but the mass flow of beads is limited. Beads will be lost to the filter or the bed will collapse. This

can be observed and remedied before spraying commences. Thus, the risk of impact on drug-layered bead

assay is medium. 分离间距可影响微丸通过包衣区的循环速率。当间距高于最佳时，将产生不足的压差

可吸入微丸并靠近分离柱。喷雾不能开始。当间距低于最佳时，微丸的循环速率增加，但是限制了微

丸的质量流量。微丸将对过滤器不敏感或床将塌陷。这可观察到并在喷雾开始前进行纠正。因此，影

响层积上药微丸含量的风险为中。

The initial gap is set to 25 mm based on bed fill level and previous experience and may need adjustment for

proper fluidization.

基于流化床填充水平和之前的经验，设定初始间距为25 mm，可能需要调整以用于合适的流化。

Nozzle tip diameter 喷嘴口孔径Medium

中

Improper selection of nozzle tip size may impact atomization and spray rate capability and, ultimately,

drug-layered bead assay.

选择不适宜的喷嘴口大小可影响雾化和喷速能力，并最终影响层积上药微丸含量。

Based on the planned spray rate, a nozzle with a 1.0 mm orifice diameter is selected.

基于计划的喷速，选择孔径为1.0 mm的喷嘴。

Nozzle tip/air cap position

喷嘴口/空气盖位置Low

低

If the nozzle tip and air cap are kept flush, the impact on atomization is minimized. The risk of impact on

drug-layered bead assay is low.

如果喷嘴口和空气盖保持齐平，则对雾化的影响最低。影响层积上药微丸含量的风险为低。

No. of nozzles 喷嘴数量Low 低Fixed by equipment design: one nozzle. 通过设备设计固定为：一个喷嘴。

2011年11月16

Filter type 过滤器类型Medium

中

A filter bag is used to prevent loss of material and to allow air to pass through. If the porosity is higher than

optimal, the loss of material will be high. If the porosity is lower than optimal, the filter will clog and

processing will be interrupted. The risk of impact on drug-layered bead assay is medium.

使用过滤袋以防止物料损失并允许空气通过。如果孔隙率高于最优化，物料的损失高。如果孔隙率低

于最优化，则将堵塞过滤器并阻断加工处理。影响层积上药微丸含量的风险为中。

A filter porosity of 10 μm is selected based on previous experience and differential pressure will be

monitored. 基于之前的经验，选择过滤器的孔隙率为10 μm，并监测压差。

Solution Preparation Variables 溶液制备变量

Drug substance concentration 主药浓度Low

低

The drug substance concentration of the layering solution is just below the solubility limit of the drug

substance and is chosen to maintain a solution. The viscosity of the drug layering solution is low (< 5 mPa?s)

and can be effectively atomized so the risk of impact on drug-layered bead assay is low.

层积溶液的主药浓度略低于主药的溶解度限度并选择以维持溶液。层积上药溶液的粘度低(< 5 mPa?s)

并可被有效雾化，所以影响层积上药微丸含量的风险为低。

Solution viscosity 溶液粘度Low

低

High viscosity may impact the droplet size of the atomized solution. The viscosity is low (< 5 mPa?s) and can

be effectively atomized. 高粘度可影响雾化溶液的液滴大小。粘度低(< 5 mPa?s)并可被有效雾化。

Delivery pump 输送泵Low

低

A peristaltic pump is selected to transfer the drug-layering solution to the column based upon availability and

reliability to deliver consistent flow. The risk of impact on drug-layered bead assay is low. 基于输送稳定流

量的可用性和可靠性，选择蠕动泵以转移层积上药溶液至柱中。影响层积上药微丸含量的风险为低。

Holding time 停留时间Low

低

The microbial limit of the drug layering solution needs to be controlled for patient safety; however, the risk

of holding time to impact assay is low.

出于患者的安全性，需控制层积上药溶液的微生物限度；但是，停留时间影响含量的风险为低。

Drug solution is used within 36 hours based on microbial test results.

基于微生物试验结果，在36小时内使用药物溶液。

Preheating Variables 预热变量

Inlet air dew point 进气露点Medium

中

Dew point needs to be controlled to minimize the static charge on the beads which may cause agglomeration.

需控制露点以最大限度降低可引发微丸表面聚集的静电荷。

2011年11月17

A dew point of 5-15 oC is selected based on previous experience. 基于之前的经验，选择露点为5～15 oC。

Shaking

interval/duration 振动间隔/周期Low

低

Shaking prevents beads from being trapped in the filter bag. The risk of shaking to impact assay is low during

preheating. 振动防止微丸阻塞于过滤袋中。振动在预热期间影响含量的风险为低。

Initial setting is 60 sec/5sec based on previous experience. 基于之前的经验，开始设定为60 sec/5sec。

Inlet air temperature 进气温度Medium

中

Higher than optimal temperature may lead to excessive static charge and processing difficulties.

高于最优温度，可导致过量静电荷和加工处理困难。

Equipment warm up: 50-60 oC. 设备预热温度：50～60 oC。

Product temperature 产品温度Medium

中

Higher than optimal temperature may lead to excessive static charge and processing difficulties.

高于最优温度，可导致过量静电荷和加工处理困难。

Equipment warm up: 40-50 oC. 设备预热温度：40～50 oC。

Air volume 风量Medium

中

Higher than optimal air volume may trap MCC beads in the filter bag. If these beads are shaken loose once

spraying starts, it may result in variable drug-layered bead assay. Lower than optimal air volume may cause

suboptimal bead fluidization and uneven heating. Drug-layered bead assay may be affected.

高于最优风量可使MCC微丸阻塞于过滤袋中。一旦喷雾开始，如果松散地振摇这些微丸，可导致层积

上药微丸含量变化。低于最优风量可引发微丸流化未达最优和受热不均。

The air volume range of 70 – 110 cfm was selected based on visual observation and previous experience.

基于目测和之前的经验，选择风量范围为70 – 110 cfm。

Atomization air pressure 雾化气压Low

低

Set at the minimum to prevent nozzle clog: 0.5 bar.

为防止喷嘴堵塞，设定为最低：0.5 bar。

Preheat time 预热时间Low

低

Assay may be affected if the target bead temperature is not reached or if the bead population temperature is

not uniform. 如果目标微丸温度未达到或如果微丸群温度不均匀，则含量可能受到影响。

Heat until target product temperature is reached. 加热至达到目标产品温度。

Spraying Variables 喷雾变量

Inlet air dew point 进气露点Medium

中

Dew point affects droplet evaporation. If it is not controlled, the drying may be variable and assay may be

impacted. 露点影响液滴蒸发。如果未进行控制，则干燥可能发生变化并可能影响含量。

A set point of 5-15 oC is selected based on previous experience. 基于之前的经验，选择露点为5～15 oC。

2011年11月18

Shaking

interval/duration 振动间隔/周期Low

低

Shaking prevents beads from being trapped in the filter bag. An appropriate interval is necessary to avoid

high differential pressure and processing interruptions.

振动防止微丸阻塞于过滤袋中。为避免高压差和加工处理阻断，适宜的间隔是必需的。

Initial setting is 60 sec/5sec based on previous experience. 基于之前的经验，开始设定为60 sec/5sec。

Inlet air temperature 进气温度Medium

中

Inlet temperature will be adjusted to reach the desired product temperature. If it is set higher than optimal,

spray drying may occur and if it is set lower than optimal, agglomeration may occur. 调整进气温度以达到

理想产品温度。如果设定高于最优温度，则可发生喷雾干燥，如果设定低于最优温度，则可发生聚集。

The range of 50-70 oC is selected based on trial batches in a Glatt GPCG-1.

基于Glatt GPCG-1中的试验批，选择温度范围为50～70 oC。

Product temperature 产品温度High

高

Product temperature is a function of inlet air temperature, air volume, and spray rate. If product temperature

is higher than optimal, spray drying may occur resulting in a large amount of fines. If product temperature is

lower than optimal, agglomeration may occur. 产品温度随着进气温度，风量和喷速而变化。如果产品温

度高于最优，则可发生喷雾干燥并导致大量的细颗粒。如果产品温度低于最优，则可发生聚集。

Investigate with DOE to optimize and reduce risk. 用DOE研究以优化并降低风险。

Air volume 风量High

高

If air volume is higher than optimal, spray drying may occur. Product may also be blown into the filter. If air

volume is lower than optimal, suboptimal fluidization may result and agglomeration may occur.

如果风量高于最优，则可发生喷雾干燥。产品也可能被吹入过滤器中。如果风量低于最优，则可导致

流化未达最优并可发生聚集。

Investigate with DOE to optimize and reduce risk. 用DOE研究以优化并降低风险。

Spray rate per nozzle 每个喷嘴的喷速High

高

If spray rate is higher than optimal, agglomeration may occur. If spray rate is lower than optimal, spraying

time may be long and spray drying may occur. 如果喷速高于最优，则可发生聚集。如果喷速低于最优，

则喷雾时间可能很长并可发生喷雾干燥。

Investigate with DOE to optimize and reduce risk. 用DOE研究以优化并降低风险。

Atomization air pressure

雾化气压High

高

If atomization air pressure is higher than optimal, attrition of the beads may occur. If atomization air pressure

is lower than optimal, agglomeration may occur.

如果雾化气压高于最优，则可发生微丸损耗。如果雾化气压低于最优，则可发生聚集。

2011年11月19

Investigate with DOE to optimize and reduce risk. 用DOE研究以优化并降低风险。Drying Variables 干燥变量

Inlet air dew point 进气露点Medium

中

Dew point needs to be controlled to achieve consistent drying. 需控制露点以达到稳定干燥。

A dew point of 5-15 oC is selected based on previous experience. 基于之前的经验，选择露点为5～15 oC。

Inlet air temperature 进气温度Medium

中

A lower than optimal temperature will increase the drying time. A higher than optimal temperature may

speed up surface drying but will increase the product temperature before diffusion-limited water has

evaporated, resulting in a false endpoint determination. 低于最优温度将增加干燥时间。高于最优温度可

加快表面干燥但在扩散限制水蒸发前，将增加产品温度，导致错误的终点判断。

Range of 50-60 oC was selected based on desired product temperature.

基于理想的产品温度，选择范围为50～60 oC。

Inlet air volume 送风量Medium

中

A lower than optimal air volume will not maintain adequate fluidization to facilitate drying. A higher than

optimal air volume may cause attrition of the drug layer which may impact assay. 风量低于最优将不能维

持用以改善干燥的足够流化。风量高于最优，可引发可影响含量的药物层的损耗。

The air volume range of 70 – 110 cfm was selected based on visual observation and previous experience.

基于目测和之前的经验，选择风量范围为70 – 110 cfm。

Exhaust temperature 排气温度Low

低

Exhaust temperature cannot be controlled directly but is an indicator of the drying endpoint and will be

monitored. 排气温度不能直接控制但可指示干燥终点，并将被监测。

Atomization air pressure 雾化气压Low

低

Minimum setting to prevent nozzle clog: 0.5 bar.

为防止喷嘴堵塞，设定为最低：0.5 bar。

Drying time 干燥时间Medium

中

Water content is controlled to prevent microbial growth. However, unnecessary over-drying may cause

attrition of the drug layer and statically charge the beads

控制水分以防止微生物生长。但是，不必要的过分干燥可引起药物层的损耗和微丸带静电。

The LOD target is 2% based on previous experience. 基于之前的经验，LOD目标为2%。

2011年11月20