原料药专用生产设备清洁验证相关问题

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第一问

◆问题259：原料药专用生产设备（单一品种）清洁验证时，是否要测残留量？目测残留可否？

答：无须进行化学残留测量，只需目测洁净及对区域设备的微生物监控。如果中间产品或API（活性成分）的长期残留可能降解，产生有害物质，对此应进行检测。

点评：通常清洁方法的验证需要测试三种残留：

1、清洁前产品API（活性成分）的残留：

2、清洁剂的残留（如清洁过程中使用）；

3、微生物的检测。

如果上述清洁过程中使用到清洁剂，需要额外进行清洁剂残留的检测。

注：本问答摘自2010年版GMP疑难问题解答（国家食品药品监督管理局高级研修学院组织编写）

第二问

Questions：For dedicated equipment, is ‘visually clean’ acceptable for verification ofcleaning effectiveness, (i.e., no expectation for specific analytical determination)?

Answers：‘Visually clean’ may be acceptable for dedicated equipment based on the ability to visually inspect and sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning effectiveness) [ICH Q7, Section 12.76]. Equipment should be cleaned at appropriate intervals (e.g., time or number of batches) to prevent build-up and carryover of contaminants (e.g., degradants or objectionable levels of microorganisms) so that they do not adversely alter the quality of the API [ICHQ7,Sections 5.23, 12.7].

问：对于专用设施，在清洁有效性确认中使用“目视清洁”是否被接受（也就是说没有特定的分析检测）？

答：基于目视检查的能力，并有充分的清洁研究支持性数据（例如，分析检查来证明清洁有效性）时，对专用设备采用“目视检查”是可以接受的【ICH Q7第12.76部分】。设备应根据适当的时间间隔进行清洁（例如，时间或批次），以防止污染物累积和带入（例如，降解物或达到不可接受的水平的微生物），这样保证其不会对原料药的质量产生不良影响【ICH Q7第5.23， 12.7部分】。

注：本问答摘自ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Questions and Answers（2015-06-10）

第三问

Questions：Should acceptance criteria for residues be defined for dedicated equipment?

Answers：Yes. Regardless of whether equipment is dedicated or not, it is expected that acceptance criteria for residues be defined and that the equipment be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants. Intervals can be based on number of

batches, product change-over, time, etc. [ICH Q7, Sections 5.22, 5.23, 5.24, 5.25, 8.50].Cleaning intervals and acceptance criteria should be established based on an understanding of the process/reactions/degradation, taking into account solubility,

potency, toxicity, etc. Establishment of acceptance criteria does not necessarily imply sampling and testing after every cleaning. Visual inspection of equipment for cleanliness is an expectation of [ICH Q7, Section 5.21]. Where validation data has confirmed effective cleaning, cleaning procedures should be monitored at appropriate intervals

[ICH Q7, Section 12.76].

问：专用设备还要定义残留可接受标准？

答：要。不管设备是否专用，期望定义残留可接受标准，并且要对以适当的时间间隔进行清洁，以防止污染物的累积和残留。清洁的间隔可以是根据生产批次、产品更换情况、时间长度等。【ICH Q7第5.22， 5.23， 5.24， 5.25， 8.50部分】。应根据对工艺/反应/降解情况的了解来建立清洁间隔和可接受标准，同时考虑溶解性、效价、毒性等。建立可接受标准并表示就一定要在每次清洁后取样和检测。对清洁后的设备进行目视检查是【ICH Q7第5.21】的期望。如果已经通过验证确认了一个有效的清洁程序，则要对清洁程序以适当的时间间隔进行监测【ICH Q7第12.76部分】。

注：本问答摘自ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Questions and Answers（2015-06-10）

第四问

Question 13: In a case of a dedicated plant with no degradants, is there a need to validate?

Advice: Ref. Section 7.0 Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need. However, consideration should be given to the number of runs being performed prior to full cleaning.

问13：如果使用的是专用车间，且没有降解产物，是否还需要进行验证呢？

建议：参见 7.0 部分。

公司要单独考虑每种情形，如果有潜在污染时则需要验证。在上述情形下，可能不需要验证。但是，要考虑在进行全面清洁前可以生产的轮次。

注：本问答摘自原料药工厂中清洁验证指南（APIC）—2016.09

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哈尔滨-HR

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