成品制剂(FPP)申报资料中的常见缺陷和对生产商的附加指导-2

COMMON DEFICIENCIES IN FINISHED PHARMACEUTICAL PRODUCT (FPP) DOSSIERS

 Additional guidance for manufacturers

成品制剂（FPP）申报资料中的常见缺陷和对生产商的附加指导-2

Control of related substances in APIs and FPPs

APIs和FPPs中有关物质的控制

Other commonly identified issues (mostly with regard to FPP specifications but also in relation to the FPP manufacturer’s API specifications) were proposals for unacceptably wide limits for unspecified impurities. Some applicants incorrectly assume that pharmacopoeial monograph limits for any unspecified impurities, which in some cases may be higher than the ICH Q3A/Q3B identification thresholds, are also acceptable regulatory limits.

其他常见的问题（多数与成品质量标准有关，但也涉及成品用原料的质量标准）即未知杂质较宽泛的提议。 一些申请人错误地认为：任何未知杂质的药典专论中限度（然而某些情况下可能高于ICH Q3A / Q3B鉴定阈值）也是可接受的法规限度。

Except for some artemisinin derivative or fermentation APIs or FPPs containing such APIs, limits for any unspecified impurities should correspond to the ICH Q3A/Q3B identification threshold. If this limit cannot be met for a particular unidentified impurity, the impurity should be identified and controlled as follows: All identified impurities should be controlled to the ICH Q3A/Q3B qualification threshold. For any impurity that cannot be controlled to this limit, a higher limit should be qualified according to the guidance provided in section 3.2.S.3.2 of the generic guide (Annex 4, TRS970).

除一些青蒿素衍生物、发酵API或含此类APIs的FPP外，任何未知杂质的限度应符合ICH Q3A / Q3B鉴定阈值。 如果某种特定的未知杂质不能满足这个限度，则该杂质应该进行如下鉴别和控制：所有已鉴别的杂质应控制在ICH Q3A / Q3B定量限内。 对于不能控制到此限度的杂质，应根据通用指南（附件4，TRS970）第3.2.S.3.2节中提供的指导，限定一个更高的限度。

There should be a key below the API/FPP specifications that identifies specified impurities, at a minimum by chemical name. For any specified impurities that are also named in an officially recognized compendial monograph, this name should be included, e.g.:

Impurity A: <chemical name> = USP RC B = Ph.Eur. impurity H

在API / FPP质量标准下面应该有一个关键信息，用于鉴别特定的杂质，至少是化学名称。 对于在官方公认的药典专论中也提及的任何特定杂质，应该包括化学名称，例如：杂质A：<化学名称> = USP RC B = 欧洲药典。 杂质H

Granulation processes

制粒工艺

Inadequate or poorly defined end point for wet granulation process affected about 50% of the reviewed dossiers.

湿法制粒工艺的终点不恰当或不明确而影响了约50％审查的申报资料。

Regardless of the manufacturing process (direct compression, wet/dry granulation, etc.), the manufacturing process and controls proposed for production batches (detailed in the blank Batch Manufacturing Record, BMR) should be in agreement with the process and controls used in the manufacturing of the pivotal clinical batch(es) or biobatch. Differences, if any, should not normally be beyond those that can be attributed to scale differences, for example, slight changes to blending parameters.

无论生产工艺如何（直接压片，湿法/干法制粒等），生产批中的生产工艺和控制（详见空白批生产记录，BMR）应与关键临床批或生物等效性批的工艺和控制一致。差别是，如果有，通常不应超出那些可归因于规模差异的因素，例如混合参数的微小调整。

To this end, differences should be highlighted and discussed in order to avoid further questions from the assessors. For this purpose, the table provided in section 2.3.R.2.1 of the QOS-PD should be used.

因此，应强调和讨论差异，以避免审查人员进一步提出质疑。为此，应使用QOS-PD第2.3.R.2.1节中提供的表格。

Furthermore, statements such as “stop granulation when required consistency is achieved” are not acceptable as a means of end-point determination. As mentioned above, processes should be kept as close as possible to the process that was used for the clinical/biobatch.

此外，诸如“在达到要求时停止制粒”等陈述作为终点确定的手段是不可接受的。如上所述，工艺应尽可能保持与临床/生物等效性批的工艺接近。

Manufacturers are advised to use the following approaches:

建议生产商参考以下方法：

1. When the proposed production batch size is the same as the biobatch size

1.拟定的生产批量与生物等效性批量相同时

The blank BMR for production batches should fully reflect the actual process parameters used for the biobatch, including mixing/addition amounts/times, speeds, amperage targets/limits etc. For example, if additional water and/or mixing were used for the biobatch, then the blank BMR should also require the same without statements such as “if required add additional water and mix…”. Similarly, if no additional water and/or mixing process were used then the blank BMR should not require the use of additional liquid or mixing.

生产批次的空白BMR应该充分反映生物等效性批的实际工艺参数，包括混合/加入的量/时间，速度，电流目标值/限度等。例如，如果生物等效性批使用额外的水和/或混合， 那么空白BMR也应该要求相同的描述，如“如果需要添加额外的水和混合...”。 类似地，如果不需要额外的水和/或混合过程，则空白BMR不应该要求使用额外的液体或混合。

2. When the proposed production batch size is larger than the biobatch size

2.拟定的生产批量大于生物等效性批量时

The blank BMR instructions for manufacture of the production batches should be kept as close as possible to the process used for the biobatch. It is acknowledged that slight changes or a provision for use of additional water or mixing may be required to account for the scale difference. In this case, in addition to fully defining the parameters, manufacturers are requested to include chopper/impeller ampere or torque readings as a means of control, with provisional limits defined.

生产批生产的空白BMR指令应尽可能与生物等效性批所用工艺尽可能接近。应当知晓使用额外的水或混合的微小改变会导致批量差异。因此，除了完全明确参数外，还要求生产商将切割刀/搅拌桨电流或扭矩读数作为控制手段，并规定限度。

The provisional limits should as much as possible reflect the observations recorded for the biobatch. The table provided in section 2.3.R.1.2 of the QOS-PD should be used for this purpose. Note that it is not acceptable to use the process validation of production batches as a means of establishing the parameters for scaled-up batches. Therefore, provisional settings and limits must be included in the blank BMR and it is understood that these will be validated and finalized during the process validation for production batches.

规定的限度应尽可能反映生物等效性批的观察结果。应使用QOS-PD第2.3.R.1.2节中提供的表格。请注意，使用生产批次的工艺验证作为建立放大批次参数的手段是不可接受的。因此，规定的设置值和限度必须包含在空白BMR中，并且应该理解这些将在生产批次的工艺验证期间进行验证和最终确定。

Similarly, compression machine speeds should be defined in the BMR as validated or to be validated with ranges reflected in the process validation protocol. To this end, process validation protocols should also include a provision for machine speed challenge runs.

类似地，压片机的速度应在批生产记录中明确并验证或在工艺验证方案中反映其验证范围。因此，工艺验证方案还应包括针对机器速度挑战运行的规定。