我们做在清洁验证/确认的时候,是否需要考虑上各产品中的基因毒杂质的残留吗?
清洁验证

我们做在清洁验证/确认的时候,是否需要考虑上各产品中的基因毒杂质的残留吗?

CFDI指南中竟然说也要考虑上个产品基因毒杂质的残留,这个是否有必要呢?

因为如果有基因毒,它本身已经在上个产品中是合格的,那么它残留到设备上,到下一个产品中,肯定更小啊。, 还是说有一种可能,同一个基因毒杂质在不同的产品中的允许残留限度有可能不一样?

据我了解,类似这样的问题,在欧美是根本就不允许共线的,但是在中国嘛....

各位老师如何理解的呢?

2024-09-19 10:14 匿名     
蓝调 2024-09-29 13:10

不需要考虑,基因毒性杂质本身就是微量杂质在上批主成分中已经控到了相当低的水平,在下批产品清洁过程中,已经考虑了该基因毒性杂质相关的主成分API的限度在较低水平,更不用说基因毒性杂质会远低于限度值。

2个回答

题主您好,首先需要纠正一点,对于欧美法规,并不是完全不允许共线的。欧洲GMP中是这样规定的:

EudraLex  The Rules Governing Medicinal Products in the European Union

Volume 4  EU Guidelines for  Good Manufacturing Practice for  Medicinal Products for Human and Veterinary Use

Part 1 -  Chapter 3: Premises and Equipment

3.6 Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities. The measures to prevent cross-contamination should be commensurate with the risks. Quality Risk Management principles should be used to assess and control the risks.

Depending of the level of risk, it may be necessary to dedicate premises and equipment for manufacturing and/or packaging operations to control the risk presented by some medicinal products.

Dedicated facilities are required for manufacturing when a medicinal product presents a risk because:

i. the risk cannot be adequately controlled by operational and/ or technical measures,

ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta

lactams) or

iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.

Further guidance can be found in Chapter 5 and in Annexes 2, 3, 4, 5 & 6.

此外,关于题主所说的CFDI指南要求考虑上个产品基因毒性杂质残留,不清楚是出自哪里?如果是国家药品监督管理局食品药品审核查验中心在2024年7月发布的清洁验证技术指南 (征求意见稿),通篇只提到毒理学评估,并没有提及基因毒性杂质评估。毒理学评估并不等同于基因毒性杂质评估。

就现有法规来看,清洁限度计算无需特别考虑上个产品的基因毒性杂质残留。如下欧洲法规,也只是提到了需要进行毒理学的评估:

EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use - Annex 15: Qualification and Validation

10.6.  Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria  should consider the potential cumulative effect of multiple items of equipment in the process equipment train.

10.6.1. Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.

10.6.2. If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity.

2024-09-29 11:03 Z_     
陆云 2024-10-21 11:09

在CFDI发布的共线指南里面,确实有提到的,要考虑

陆云 2024-10-21 11:13

老师,这个是GMP中说的,您可以查看相关的欧美指南以及缺陷集,具体我是记不得了,但是有小伙伴的所在企业,上个产品有基因毒没有详细的评估而被提缺陷了

Z_ 回复 陆云 2024-10-23 09:51

谢谢回复,CFDI的共线指南中确有提到“基因毒性”,但该项是列在“技术转移阶段的共线生产策略”下,也就是说,共线品种的基因毒性是在共线风险评估时需要考虑,而不是如题主所问的“在清洁验证/确认的时候,是否需要考虑上各产品中的基因毒杂质的残留”,二者是不同的阶段,不同概念。

此外我理解你所说的企业收到缺陷应该也是基于共线评估不充分提出的。

不需要的,主要考虑活性物质,你可以在你选择活性物质的逻辑时候风险评估一下,你的活性物质是原料药,在制剂里面原料药的含量都不高,主要是辅料,那原料药带过来的各种杂质更少的可怜,另外经过清洁之后,残留的有效成分都非常少,杂质就更加更加少,如果这个时候再去追求杂质的MACO,这个从风险的角度看,就非常低。so这些杂质可以忽略不计的~

2024-09-30 10:42 共产国际特困生