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[原料药] 近期的两个FDA警告信都涉及到清洁验证..重点变了?

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发表于 2018-2-16 22:46:57 | 显示全部楼层 |阅读模式

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近期的两个FDA警告信都涉及到清洁验证..重点变了?
上次听某专家现场课,说API专线生产都可以不做清洁验证,好像没事一样的..
检查时,检察官一般听到专线生产,清洁验证的关注度都下降了不少,
但怎么也想不到白云山和拜尔这等大公司会跌在清洁程序,并且现场留下把柄,而非完全的数据完整性的问题?
是FDA的检查风格有变还是个别检查官的事情哈..还是检查手段有变化啊.
清洁的效果关系到GMP的原则,防止污染和交叉污染,话说FDA这样查,清洁程序到底要描述的啥样的程度都有点不好把握了..
个人愚见,不知道大家怎么看..


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药士
发表于 2018-2-17 10:20:57 | 显示全部楼层
清洁验证检查有这么几块:
1、清洁SOP的适用性与执行情况;——清洁的原则、范围、频次等,清洗的程序、次数,检查与接受标准,清洁后的存放,必要时查看清洗记录及设备使用日志。
2、清洁验证方案的合理性和报告完成情况;——重点关注取样点的设置
3、检验方面的,这个可能涉及数据完整性;
4、就是检查过程,现场的发现以及回答人员的回答情况

点评

PDE maco值的计算关注吗 ?  详情 回复 发表于 2018-2-22 11:48
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药士
发表于 2018-2-17 08:04:56 | 显示全部楼层
专线可能不是关注点,但也是重点
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药师
发表于 2018-2-17 08:45:12 | 显示全部楼层
关注SOP的适用性和执行的有效性。
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药士
发表于 2018-2-17 19:23:20 | 显示全部楼层
这两条线都不是专线啊!同时仅两个案例没有代表性
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 楼主| 发表于 2018-2-18 08:02:57 | 显示全部楼层
beiwei5du 发表于 2018-2-17 19:23
这两条线都不是专线啊!同时仅两个案例没有代表性

嗯嗯,具体是否专线不知道
也可能制剂更严格吧
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药士
发表于 2018-2-18 09:27:37 | 显示全部楼层
wfenger 发表于 2018-2-18 08:02
嗯嗯,具体是否专线不知道
也可能制剂更严格吧

你可以再认真核实这两个警告信,文中明确提到的非专线,谢谢!
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药徒
发表于 2018-2-22 09:42:54 | 显示全部楼层
专线的清洁验证就是考虑累积效应(API、杂质、清洁剂都需要考虑)
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药徒
发表于 2018-2-22 10:40:09 | 显示全部楼层
主要看检查官的侧重点吧
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发表于 2018-2-22 11:05:27 | 显示全部楼层
共线带来的风险还是应该充分考虑的
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药徒
发表于 2018-2-22 11:48:22 | 显示全部楼层
zysx01234 发表于 2018-2-17 10:20
清洁验证检查有这么几块:
1、清洁SOP的适用性与执行情况;——清洁的原则、范围、频次等,清洗的程序、次 ...

PDE  maco值的计算关注吗 ?
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药徒
发表于 2018-2-23 10:10:31 | 显示全部楼层
非专线肯定会严格一点的。专线大概会降低一些关注?
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药生
发表于 2018-2-23 12:57:37 | 显示全部楼层
有没有具体的缺陷描述?最好一并发出来
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药徒
发表于 2018-2-23 15:15:25 | 显示全部楼层
还好看完了回复,楼主这个内容差点误导人了啊
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发表于 2018-2-23 21:59:34 | 显示全部楼层
Bayer AG

拜耳股份有限公司

Kaiser-Willhelm-Allee, Building W11, 51368 Leverkusen Germany

德国勒沃库森Kaiser-Willhelm-Allee Building W11

缺陷包括:

设备外表面有产品残留
设备内表面和周围都有产品残留
清洁规程不够详细
投诉调查不充分,未包括对留样的检查,也未审核过去的同类投诉的情况
未确定容器密封缺陷的根本原因
同批次收到3个投诉以后才会将问题升级处理
未保留培训原始记录
垃圾篓中发现遗弃的灯检记录
解释说用灯检设备发现缺陷的程序可能并不是CGMP活动
不合格片重数据未报告
禁止“试针”,但是未对以前的所有历史数据进行审核
缺陷摘译如下:

1. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

贵司未能建立和遵循充分的设备清洁和维护的书面程序(21 CFR 211.67(b))。

Your equipment cleaning practices for non-dedicated equipment are inadequate. Your firm has several (b)(4)that can be used for more than one product.

你们的对非专用设备的清洁做法是不充分的。贵公司几个XX是用于多个产品的。

A. Equipment exterior surfaces

设备外表面

During the production of yourdrug product (b)(4), which was in a (b)(4), our investigatorobserved a (b)(4) residue on the (b)(4) exterior surfaces. Yourmanufacturing area personnel stated that the residue was probably from a (b)(4)drug product, (b)(4), which was previously processed in the same room.

你们的药品XX在XX的生产期间,我们检查人员发现在XX外表面有XX残留物。你们的生产区域人员说该残留可能是来自XX药品XX,该产品之前在同一房间生产。

After our inspection, youtested samples of tablets produced with (b)(4) manufactured in the same (b)(4)to assess the potential for cross-contamination. Your testing confirmed thepresence of (b)(4) in (b)(4) tablets, which you had produced as acontract manufacturer for your customer, (b)(4). (b)(4) recalledseveral lots of (b)(4) on (b)(4), due to the cross-contaminationproblem.

在我们检查之后,你们测试了使用XX在相同XX生产的片剂,以评估交叉污染可能性。你们的测试确认了XX片剂中含有XX,这是你们之前为你们的客户XX合同生产的产品。由于交叉污染问题,XX召回了在XX上的几批XX。

B. (b)(4) on manufacturing equipment

生产设备上的XX

In three different rooms, our investigator observed white residues in and around the (b)(4) of three (b)(4)identified as “clean.” Your cleaning procedure did not include provisions for cleaning (b)(4) in (b)(4).

在三个不同房间,我们的检查人员在三个标识为“清洁”的XX里面和周围均发现了白色残留物。你们的清洁规程没有包含清洁XX里XX的规定。

Residues in and around (b)(4)can lead to the ingress of cross-contaminants into manufacturing equipment.

在XX的里面和周围的残留可能会导致对生产设备的交叉污染侵入。

In your response, youcommitted to a number of corrective actions and preventive actions (CAPA) for (b)(4),including reevaluating cleaning procedures and practices, assessing the effectof residues on quality and safety of products, and retraining personnelinvolved with cleaning.

在你们的回复中,你们承诺了大量针对XX的CAPA,包括重新评估清洁程序和做法,评估残留对产品质量和安全性的影响,以及重新培训清洁相关人员。

Your response was inadequate.You did not sufficiently assess whether U.S.-shipped products manufactured withthe (b)(4) were cross-contaminated. Additionally, you did not reevaluateyour cleaning procedures, practices, and validation for other non-dedicatedmanufacturing equipment.

你们的回复是不充分的。你们没有充分评估使用XX生产的发往美国的产品是否受到交叉污染。另外,你们也没有重新评估你们其它非专用生产设备的清洁程序、做法和验证。

In response to this letter,provide:

在回复此函时请提交:

Your retrospective review supporting the safety and purity of each batch of product manufactured with your (b)(4) that remain within expiry in the U.S. market. Include a summary report of analytical testing results supporting your conclusions. Provide scientific justification if you to propose to exclude any batch that remains within expiry from this retrospective testing.

你们的回顾性审核,支持你们使用XX生产的尚在美国市场仍在有效期的每个批次产品的安全性和纯度。包括支持你们结论的分析检测结果总结报告。如果你们提议在回顾性测试中排除任何仍在有效期内的批次,请提交科学论证。

A comprehensive plan to assess cleaning procedures, practices, and validations for each piece of manufacturing equipment used to manufacture more than one product. Also include your plans to ensure that powder residues are removed from room surfaces as part of product changeovers.

对用于生产不止一个产品的每台生产设备的清洁程序、做法和验证评估的全面计划。还要包括一份计划,用以确保从房间表面清除粉末残留作为更换产品一部分。

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

贵公司未能彻底调查所有已销售和未销售的产品批次成品及其成分任何原因不明的不符合其质量标准的情形(21 CFR 211.192)。

Your investigations into product quality complaints are inadequate. For example, when you investigated two complaints of leaking (b)(4) containing (b)(4) batch (b)(4),you did not determine a root cause for the container-closure defect. Your (b)(4)supplier informed you of a (b)(4) defect that you did not address in your investigation. The investigation also failed to include an examination of retain samples or review past complaints to identify other instances of bag integrity defects.

你们对产品质量投诉的调查是不充分的。例如,你们在调查2个泄漏XX含有XX批次XX时,你们并未确定容器密封缺陷的根本原因。你们的XX供应商告知了你们XX缺陷,但你们在你们的调查中并未解决。调查也未包括对留样的检查,也未审核过去的投诉以发现其它包装袋完整性缺陷的情况。

Your response was inadequate because it lacked sufficient improvements to your investigation systems.

你们的回复是不充分的因未对你们调查体系进行充分的改进。

In response to this letter,provide:

回复此函,请提交:

A list of all complaints received from 2014 to present that indicate potential bag non-integrity, with detailed deions including complaint dates, product names, batch numbers, deion of complaint, exact breach locations, root causes, and CAPA. Include your final, updated investigations into the (b)(4) issues observed in batches (b)(4) and (b)(4).

一份自2014年以来收到的所有投诉清单,展示出潜在的包装袋不完整,详细描述包括投诉日期、产品名称、批号、投诉描述、具体的泄漏点、根本原因以及CAPA。包括你们更新后的对在XX批次和XX批次中发现的XX问题的最终调查。

A retrospective review of all investigations relating to complaints that could impact the quality of products within expiry in the U.S. market. Include an assessment of the depth of investigation, identification of potential root causes, review of related trends, and CAPA.

一份对与可能影响仍在美国市场的有效其内产品投诉有关的所有调查的回顾性审核。包括对于调查深度的评估、潜在根本原因的识别、有关趋势的审核以及CAPA。

A full assessment and remediation of your systems for investigating complaints, failures, and deviations to ensure they are thorough, scientifically sound, and culminate in appropriate and effective CAPA.

对你们投诉、失败和偏差调查系统的全面评估和弥补,以确保该调查的彻底和科学合理性,最终生成恰当有效的CAPA。

Procedures requiring more thorough examination or testing of retention samples during investigations, including both the complaint batch and other potentially affected batches

提供修订后的规程要求在调查期间对留样进行更彻底检查或测试,包括投诉批次和其它可能受影响的批次。

Procedures that ensure each complaint of a critical defect is carefully evaluated to determine whether marketed products may be impacted. Currently, a problem appears to be escalated only after three complaints are received for a batch.

提供修订后的规程确保每个关键缺陷的投诉均经过周密地评估以确定是否影响到上市产品。目前,只有当同一批次收到3个投诉以后才会将问题升级处理。

Improvements in your ongoing monitoring of vendor or contractor acceptability. Explain how you will ensure that vendors notify you about significant deviations or potential defects in materials (e.g., by modifying quality agreements).

提供对供应商或合同商可接受度进行持续监测的改进。解释你们将如何确保供应商会通知你们物料的重大偏差或潜在缺陷(例如,通过修改质量协议)。

3. Your firmfailed to establish an adequate quality control unit with the responsibilityand authority to approve or reject all components, drug product containers,closures, in-process materials, packaging materials, labeling, and drugproducts, and that approves or rejects all procedures or specifications impactingon the identity, strength, quality, and purity of the drug product (21 CFR211.22(a) and (c)).

你们公司未能建立足够的质量控制部门,具备职责和权力批准或拒收所有成分、药品容器、密闭器、中间体、包装物料、标签和药品,批准或拒收所有影响药品鉴定、剂量、质量和纯度的程序或质量标准(21 CFR211.22(a) and (c))。

Your quality control unit didnot sufficiently oversee adequacy of procedures at your facility to assure drugproduct quality.

你们的质量控制部门并未充分监管你们工厂内的规程以确保药品质量。

A. Discarded training records

丢弃的培训记录

Our investigators observed discarded original personnel training records. Your procedure 3-040-127, Use of the Schulungsdatenbank (Learning Management System) in the Supply Center Leverkusen requires these records to be maintained. In your response, you committed to retain original training records. However, you did not reassess your program to ensure that personnel were trained and capable of perform ingtheir assigned functions.

我们的检查人员发现了丢弃的人员培训原始记录。你们的规程3-040-127供应中心的学习管理系统要求保留这些记录。在你们的回复中,你们承诺将保存培训的原始记录。但是你们并未重新评估你们的规程以确保人员经过培训,有能力履行其分配的职责。

B. Discarded automated visual inspection machine parameters

遗弃的自动灯检设备参数

In a (b)(4) department office waste bin, our investigators observed discarded forms used to document and set inspection parameters for your automated tablet visual inspection machinery. These parameters are used to accept or reject tablets. In your response, you noted that you documented and approved final set-up parameters,“but historically the calculations generated in support of those parameters have not been preserved.” You indicate that programming the visual inspection machine to detect defects may not be a CGMP activity. We note that the parameters of this machinery are used to discriminate between acceptable and unacceptable tablets. Accordingly, entering reliable settings into machine programming is part of CGMP.

在XX部门办公室废纸篓中,我们的检查人员发现了丢弃的用于记录和设定你们自动片剂灯检机参数的表格。这些参数是用以接受或拒绝片剂的。在你们的回复中,你们提到你们记录和批准了最终设置参数,“但一直未保留支持这些数据的计算”。你们说用灯检设备发现缺陷的程序可能并不是CGMP活动。我们注意到这些设备参数是用来区分可接受和不可接受片剂的。相应地,录入可靠的设置至设备程序是CGMP的一部分。

In response to this letter:

回复此函:

Reassess any systems or activities associated with drug manufacturing or testing equipment that you consider “non-GMP.” Provide your reassessment and describe improvements in your procedures for document handling, retention, and destruction.

重新评估你们认为“非GMP”的所有与药品生产或检测设备有关的系统或活动。提交你们的重新评估和描述对你们文件处置、保存和销毁程序的改进。

Review your training program’s effectiveness, including but not limited to evaluating the reason(s) that some individuals failed to follow standard operating procedures. Summarize your CAPA.

审核你们培训的有效性,包括但不仅限于评估一些人员未遵守标准操作规程的理由。总结你们的CAPA。

4. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

你们公司未能确保实验室记录包含所有检验完整数据以符合既定规范和标准 (21 CFR211.194(a))。

When reviewing audit trails, our investigator observed unreported data from in-process tablet weight checks. You programmed your in-process weight checker not to report values that varied more than (b)(4)% from the tablet target weight.

在审核审计追踪时,我们的检查人员发现在中控片重检查中有未报告的数据。你们规程规定你们的中控重量检查人员不需报告片重超过XX%目标片重的数值。

In your response, you committed to suspend this procedure, investigate any such values, and perform a retrospective assessment of tablet weight checker data. However, your retrospective tablet weight assessment was limited to all rejected measurements from February 1 to March 15, 2017, and about 8,000 rejected measurements representing an unspecified percentage of the total number of rejected measurements from August 1, 2016, to February 1, 2017. There was no commitment to revisit equipment qualification(s) and process validation(s) to ensure they included complete data.

在你们的回复中,你们承诺中止你们的规程,调查所有这样的数值,对片重检查的数据进行回顾性评估。但是,你们对片重的回顾性评估仅局限于自2017年2月1日至3月15日的所有拒收测量,以及2016年8月1日至2017年2月1日间总拒收测量值中约8000个代表未指定百分比的拒收测量值。也没有承诺重新查看设备确认和工艺验证以确保其中包括完整数据。

In response to this letter, as part of your retrospective tablet weight assessment, explain whether your findings impact data supporting tablet manufacturing equipment qualification and manufacturing process validation studies. Provide a summary listing of equipment qualification and process validation documents that you reviewed.

回复此函,作为片重回顾性评估的一部分,请解释你们的缺陷是否影响支持片剂生产设备确认和生产工艺验证研究的数据。请提交一份汇总清单列出你们审核的设备确认和工艺验证文件。

Data Integrity Remediation

数据完整性弥补措施

FDA acknowledges that, before our inspection, you began a data integrity remediation program. Our investigator documented that, as part of your data integrity remediation program, you discontinued the practice of performing “test” injections as a result of an internal assessment in June 2016. However, we noted that you only reviewed chromatographic data for (b)(4) and (b)(4) generated between January 1, 2015, and June 23, 2016.

FDA知晓在我们检查之前你们已开始了一项数据完整性弥补程序。我们的检查人员记录下了,作为数据完整性弥补计划的一部分,你们中止了实施“试针”的做法,这是2016年6月内部评估的结果。但是我们注意到你们仅审核了2015年1月1日至2016年6月23日之间生成的XX和XX的色谱数据。

Your action plans submitted on May 11, 2017, and August 10, 2017, did not include an assessment of other products manufactured and tested at your facility. Additionally, the retrospective review did not include data generated before January 1, 2015,used in support of drug applications submitted to FDA. Further, your retrospective review only focused on the laboratory. You did not investigate potential data integrity lapses in other manufacturing systems.

你们在2017年5月1日和2017年8月10日提交的行动计划中,未包括对在你们工厂生产和检测的其它产品的评估。另外,回顾性评估并未包括2015年1月1日之前生成的数据,用以支持提交的FDA的药品申报资料。还有,你们的回顾性审核仅关注于实验室。你们没有调查在其它生产系统中潜在的数据完整性问题。

In response to this letter, provide your revised action plan. In your summary report, include otherproducts manufactured and tested at your facility and identify any data generated before January 1, 2015, that was used to support drug applications submitted to FDA. Also, include your protocol and methodology. Summarize all laboratories, manufacturing operations, and systems covered by the assessment. Specify whether a qualified independent consultant performed interviews to ensure that the nature and scope of the problem was fully determined. Discuss the role of the independent consultant in auditing the integrityof your data and assisting with CAPA. Justify why you excluded any part of your operations or systems.

回复此函,请提交你们修订后的行动计划。在你们的总结报告中,请包括在你们工厂生产和检测的其它产品,识别出2015年1月1日生成的用于支持提交给FDA的药品申报资料的所有数据。还有,请包括你们的方案和方法学。总结评估所覆盖的所有化验室、生产操作和系统。说明是否有具备资质的独立顾问执行面谈以确保全面确定问题的属性和范围。讨论独立顾问在审核你们数据和协助CAPA中所起作用。论证为何你们要排除你们操作或系统的任何部分。
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药士
发表于 2018-4-10 08:23:15 | 显示全部楼层
关注点永远不会变,就是你是否会影响到产品的质量
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