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FDA警告信22/03/31--实验室控制和数据完整性不符合cGMP(中英文)

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实验室控制、OOS调查以及数据完整性不符合cGMP,FDA发出警告信。
WARNING LETTER

Vi-Jon, LLC

MARCS-CMS 622087 — MARCH 31, 2022
Dear Mr. Koulouris:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Vi-Jon, LLC, FEI 1941150, at 8515 Page Avenue, St. Louis, MO, from October 4 to October 13, 2021.
美国食品和药物管理局(FDA)于2021年10月4日至10月13日检查了企业位于密苏里州圣路易斯Page Avenue 8515的药品生产工厂Vi-Jon, LLC, FEI 1941150。
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
本警告信总结了成品药严重违反现行良好生产规范(CGMP)规定的情况。参见《联邦法规法典》第21篇,第210和211部分(21 CFR第210和211部分)。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于生产、加工、包装或贮存方法、设施或控制不符合CGMP,企业的药品在《联邦食品、药品和化妆品法案》(FD&C法案)第501(a)(2)(B)节、《美国法典》第21卷第351(a)(1)(2)(B)节的含义范围内掺假。
We reviewed your November 3, 2021, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
我们详细审查了企业于2021年11月3日对FDA 483表格的回复,并确认收到了后续的信函。企业的回复是不充分的,因为它没有提供足够的细节或证据来证明企业的操作符合CGMP。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在检查过程中,FDA的调查人员发现了具体的违规行为,包括但不限于以下几点。
1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

1.未能建立实验室控制,包括制订科学可靠和合适的质量标准、规格、取样方案和检验规程,以保证组分、药品容器、封闭物、中间体、标签和药品符合适宜鉴别、规格、质量和纯度标准。(21 CFR 211.160(b))

You manufacture over-the-counter (OTC) drug products including benzalkonium chloride-based hand sanitizer1. Water is a component in your OTC hand sanitizer drug product. Your sampling plan for your water system is not representative of the overall system and is not appropriate to provide meaningful results for detecting system variability.
企业生产非处方药品,包括基于苯扎氯铵的洗手液1。水是非处方洗手液药品中的一种成分。企业的水系统取样计划不能代表整个系统,也不适合为检测系统可变性提供有意义的结果。
Specifically, you sample from only (b)(4) point of use (POU) ports for chemical and microbial attributes on (b)(4) of production operations. However, our investigator noted at least (b)(4) POU ports where you obtain water for drug product manufacturing.
具体来说,企业只从xx使用点(POU)端口取样,用于生产操作xx的化学和微生物属性。然而,我们的调查员注意到至少有xx个POU端口,用于药品生产用水。
Additionally, you have detected Burkholderia cepacia (B. cepacia) in your finished drug products on numerous occasions. Since B. cepacia is a waterborne organism, this recurring product contamination further indicates the impact of insufficient monitoring and control of your water system. You did not have appropriate limits to identify an adverse pattern of B. cepacia in your water system, nor did you routinely test your water system for the presence of B. cepacia utilizing validated methods.
此外,在企业的制剂中多次检测到洋葱伯克霍尔德菌(B. cepacia)。由于洋葱芽孢杆菌是一种水生生物,这种反复出现的产品污染进一步表明了企业对水系统监测和控制是不足的。企业没有适当的限制来识别水系统中的不良cepacia菌株,也没有使用经过验证的方法对水系统中的cepacia菌株进行常规检测。
In your response, you stated that you are updating your water system drawings and have identified at least (b)(4) POU ports. You also stated that you will perform a “(b)(4)” to determine the appropriate number of additional water ports that you will sample. Further, you stated that you will add a specification for the absence of B. cepacia to your water testing. Your response is inadequate. You did not provide sufficient details regarding your (b)(4), including how you will ensure that your water system design is appropriate for its intended use, maintained and sampled appropriately, and subject to closer scrutiny to enable prompt detection when the system may be falling out of a state of control.
回复中,企业声称正在更新水系统图纸,并且已经确认了至少xx个POU端口。企业还表示,将执行“(b)(4)”来确定取样水口的适当数量。此外,声明企业将在水测试中添加没有cepacia的质量标准。企业的答复不充分。没有提供关于xx的足够详细信息,包括将如何确保企业的水系统设计符合预期用途,如何进行适当维护和取样,以及如何进行更有效的监控,以便在系统可能失控时及时发现。
Because water is used as a component in your non-sterile drug products, the lack of data regarding the state of control of your water system poses a potential risk of introducing objectionable microbial contamination into your products. Pharmaceutical water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
因为水是非无菌药品中是一种成分,所以缺乏关于水系统控制状态的数据可能会导致微生物污染企业的产品。制药用水必须适合其预期用途,并进行常规测试,以确保持续符合适当的化学和微生物属性。
In your response to this letter, provide the following:

针对本函,请提供:

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
•制订化学和微生物质量标准,便于测试和放行用于生产的每一批进厂原料。
• A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
• 水系统监测规程,包括水的常规微生物检测,以确保其可用于企业生产的每批药品。
• The current action/alert limits for total counts and objectionable organisms used for your water system. Ensure that the total count limits for your system are appropriately stringent in view of the intended use of each of the products produced by your firm.
•制订水系统(微生物总数量)的行动/警报限。鉴于贵公司生产的每一种产品的预期用途,确保贵公司系统的总计数限制是适当和严格的。
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets Purified Water, USP monograph specifications and appropriate microbial limits.
• 修订企业的持续控制、维护和监测的程序,确保系统持续生产的水符合纯化水、USP各论规范和适当的微生物限度。
• A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
对企业生产操作的设计和控制进行全面综合的评估,并详细、彻底地审查所有微生物危害。
• A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
•一份详细的风险评估,说明销售可能有微生物污染的药品所造成的危害。指定企业将针对风险评估采取的行动,例如客户通知和产品召回。
• Complete investigations into all batches with potential objectionable microbial contamination or an out-of-specification (OOS) microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
对所有可能存在不良微生物污染或超标(OOS)微生物结果的批次进行全面调查(无论是否失效)。调查应该详细说明污染的根本原因。
• Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
制订适合每个药品的微生物批放行规范(即,总计数,用于检测不良微生物的生物负荷鉴定)。
• All chemical and microbial test methods used to analyze each of your drug products.
• 用于分析每个药品的所有化学和微生物测试方法。
• A summary of results from testing retain samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
•所有在有效期内药品批次的留样的测试结果汇总。应测试所有适当的质量属性,包括但不限于每批的活性成分的鉴别和规格以及微生物质量(检测任何不良微生物的总计数和生物负荷的鉴定)。如果测试结果为OOS,说明将采取的纠正措施,包括通知客户和发起召回。
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

2.未能建立并遵守适当的设备清洁和维护的书面规程。 (21 CFR 211.67(b))

Our investigators documented several deficiencies in your equipment maintenance and cleaning program. For example, a leak was observed from a pump within the water purification system. A work order dated May 7, 2021, documented the leak but as of the date of the inspection, the quality unit (QU) had not been notified of the leak, as required by your procedure. Accordingly, an investigation or deviation had not been initiated. A second leak at the (b)(4) was observed with water absorbent pads in place to contain the leak. That leak was also not documented. Your water system operating procedure states that leak checks should be performed (b)(4). You lacked documentation supporting the occurrence of these water leak checks. Water leaks are potential areas of entry for microbial growth, which may contaminate component water and subsequently have an adverse impact on the quality of your drug products manufactured.
FDA调查人员记录了企业设备维护和清洁程序中的几个缺陷。例如,从水净化系统内的水泵观察到泄漏。一份日期为2021年5月7日的工作订单记录了泄漏情况,但截至检查日期,质量部门(QU)尚未按照程序要求得到泄漏的通知。因此,调查或偏离尚未开始。在xx处观察到第二次泄漏,并放置吸水垫以控制泄漏。该泄露也没有记录。企业的水系统操作规程规定应进行泄漏检查。企业缺乏证明这些漏水检查发生的文件。泄漏位置是微生物生长的潜区域,可能会污染水系统,进而对企业生产的药品质量产生不利影响。
Investigators also observed raw material leaking from a valve in the material transfer manifold located above tank #422. A (b)(4) bucket underneath the leak was nearly half full of what appeared to be a green-blue gelatinous material, and the outside of the bucket appeared to be encrusted with white and brown filth. This material was identified as “the surfactant (b)(4).” Your procedure for the storage of raw materials did not adequately assure the proper cleaning and maintenance of equipment.
调查人员还观察到原料从位于422罐上方的原料输送歧管中的一个阀门泄漏。泄漏下面的A (b)(4)桶几乎装满了一半的东西,似乎是一种蓝绿色的胶质物质,桶的外面似乎覆盖着白色和棕色的污染物。这种材料被确定为“表面活性剂(b)(4)”。企业的原料储存程序没有充分保证设备的适当清洁和维护。
We also observed rust in the laboratory’s laminar air flow hood. The state of maintenance of your laboratory is important to ensure its reliability.
FDA还在实验室的层流通风罩中观察到锈蚀。实验室的维护状态对于确保其可靠性非常重要。
In your response, you stated that new personnel were not assigned or trained on the (b)(4) check as specified in your procedure. Additionally, you stated that your procedure lacked sufficient details regarding responsibilities of your quality monitoring program. You also stated that the leaking (b)(4) and pump were placed out of service and a change control order was submitted for their repairs. Additionally, your water system drawings are being updated and reviewed by your QU and Engineering to prepare for your water system “capital project.” Regarding the leaking of “the surfactant (b)(4)”, you stated that a work order was submitted to replace the valve and that you will be replacing the piping.
回复中,企业表示新人员没有按照程序中规定的xx检查进行分配或培训。另外,企业的程序缺乏足够的关于质量监控程序责任的信息。还表示,泄漏的xx和泵已停止使用,并提交了维修变更指令。另外,水系统图纸正在被企业的QU和工程部更新和审核,为变更水系统项目做准备。关于“表面活性剂(b)(4)”的泄漏,企业表示已经提交了更换阀门的工作指令,并且将更换管道。
Your response is inadequate. Your response lacked sufficient details to ensure that you have fully remediated your water system and that the various leaks did not impact product quality. You also failed to discuss how you will ensure similar issues in the maintenance of your facility and equipment will not recur.
企业的答复不充分。回复缺乏足够的细节来确保已经完全修复了水系统,并且各种泄漏没有影响产品质量。企业也没有讨论将如何确保设施和设备维护方面的类似问题不再发生。
It is important that you demonstrate that your cleaning and maintenance procedures are adequate and that they are followed to prevent contamination of your drug products.
必须证明企业的清洁和维护程序是充分的,并遵循这些程序以防止药品受到污染。
In your response to this letter, provide the following:

针对本函,请提供:

• A comprehensive, independent review and extensive remediation plan for the design, control, and maintenance of the water system.
•对水系统的设计、控制和维护进行全面综合的审查和充分的整改计划。
• A purified water system validation report. Also include the summary of all improvements made to system design and to the program for ongoing control and maintenance.
•纯化水系统验证报告应包括对系统设计、持续控制和维护程序的所有改进的总结。
• A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all lots of drug products currently in the U.S. market.
•详细的风险评估,评估所观察到的水系统故障对目前在美国市场的所有药品质量的潜在影响。
• A detailed description of the water system components, include a piping and instrumentation diagram (P&ID), that your firm used to manufacture drug products. Describe the (b)(4) and state if it was in series or parallel. In addition, include the updated information on P&ID for your remediated water system and an assessment that verifies the P&ID matches the actual water system design.
• 贵公司用于生产药品的水系统的详细描述,包括管道和仪表图(P&ID)。描述(b)(4),并说明它是串联的还是并联的。此外,还应包括修复水系统的P&ID信息的更新,以及验证P&ID是否与实际水系统设计相符的评估。
• Your corrective action and preventive action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
企业的纠正措施和预防措施(CAPA)计划以实施对设施和设备的日常、警惕的运营管理监督。该计划应确保及时发现设备/设施性能问题,有效执行维修,遵守适当的预防性维修计划,及时对设备/设施基础设施进行技术升级,并改进系统以进行持续管理审查。
3. 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).

3. 企业未能彻底调查批产品或其成分与质量标准的不明原因的差异或不符,不管这批是否放行销售(21 CFR 211.192)。

You failed to adequately investigate OOS results and complaints. For example:
企业未能彻底调查OOS结果和投诉。例如:
• B. cepacia was found in your Topical Fungicide Formula lot (b)(4). You destroyed this lot, but you did not adequately investigate the root cause of the microbial contamination. During the investigation, you found B. cepacia in a transfer hose, and Vibrio cholerae in the “(b)(4)” Production Line Bottle Hopper. You ultimately determined that the root cause was a failed sanitization cycle of the water system where it alarmed multiple times during the cycle.
•在企业的局部杀菌剂配方批次(b)(4)中发现了洋葱状芽孢杆菌。企业销毁了该批,但没有充分调查微生物污染的根本原因。在调查过程中,企业在输送软管中发现了洋葱双歧杆菌,在“(b)(4)”生产线的瓶料斗中发现了霍乱弧菌。企业最终确定根本原因是水系统消毒循环失败,在该循环中多次发出警报。
However, you did not determine whether your water system was contaminated with B. cepacia or why your water system sanitization cycle alarmed multiple times. You also did not determine the source of the contamination in your transfer hose and bottle hopper. Your CAPA consisted of retraining employees to only clear alarms (b)(4) during water system sanitization cycles.
然而,企业并没有确定水系统是否受到洋葱双歧杆菌污染,也没有确定为什么水系统消毒周期会多次报警。也没有确定输送软管和瓶料斗中的污染源。企业的CAPA包括对员工进行再培训,在水系统消毒周期内仅清除警报(b)(4)。
• You initiated an investigation of a complaint regarding missing lot codes on (b)(4) FOAM Hand Sanitizer lot 0480285. The root cause was determined to be the overfilling of bottles which resulted in the lot codes being wiped off. However, the root cause for the overfilling of the bottles was not adequately investigated, despite production logs showing that there were approximately nine other stoppage events related to overfilling which resulted in missing lot codes. The QU was unaware of these nine additional stoppage events.
•企业对批号0480285的xx泡沫洗手液代码缺失的投诉进行了调查。根本原因被确定为瓶子过满,导致批号被擦掉。然而,尽管生产日志显示大约有9个其他与溢装相关的停产事件导致漏批号,但瓶溢装的根本原因没有得到充分调查。QU对这9起额外的停产事件并不知情。
• You did not implement an appropriate CAPA during the investigation into a complaint regarding illegible lot codes for Germ-X 1000ML 70% ALC FOAM SANI INS lot 0520546. You concluded that the “most probable cause” for the smeared lot codes was an isolated event due to overfilled units. However, our investigator noted multiple complaints regarding missing or illegible lot codes that were not investigated adequately.
•你们在调查有关细菌- x 1000ML 70% ALC泡沫SANI INS批号0520546的投诉时没有实施适当的纠正预防措施。企业的结论是,批号污损的“最可能原因”是由于过满造成的孤立事件。然而,FDA的调查人员注意到多个关于缺失或难以辨认的批号的投诉,这些投诉没有得到充分的调查。
In your response, you stated that you have updated your user access in your production so that only supervisors have access to “acknowledge the alarms.” Additionally, you stated that you will review your complaint practices, add trend analysis, and will conduct a retrospective review of “critical” complaints covering all products that are within expiration. You will also perform a gap analysis of the current risk assessment process and ensure documentation of the risk. You also stated, that once completed, all procedures will be updated, and your team will be trained on these changes. Your response is inadequate. You did not discuss reviewing the QU roles and responsibilities or notifying your customers of any outcomes of your investigations. Additionally, you should review all complaints, not just “critical” ones, to determine their impact on product quality.
回复中,企业表示已经更新了生产中的用户访问权限,这样只有管理员才能访问“确认警报”。另外,表示将审查企业的投诉程序,增加趋势分析,并将对所有过期产品的“关键”投诉进行回顾性审查。还将对当前的风险评估过程进行差距分析,并确保风险的文档化。企业还表示,一旦完成,所有程序都将更新,企业的团队将接受这些变更方面的培训。企业的答复不充分。没有讨论审核QU的角色和职责,也没有将调查的任何结果通知客户。此外,企业应该审查所有的投诉,而不仅仅是“关键的”投诉,以确定它们对产品质量的影响。
Inadequate investigations may result in not identifying or mitigating the root causes of non-conformances and does not ensure consistent production of safe and effective products.
不充分的调查可能导致无法识别或解释不符合的根本原因,也无法确保安全有效产品的持续生产。
In your response to this letter, provide the following:

针对本函,请提供:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
•对偏差、差异、投诉、OOS结果和故障调查的整体系统进行全面、独立的评估。提供一份详细的行动计划来纠正该系统。企业的行动计划应包括但不限于在调查能力、范围确定、根本原因评估、CAPA有效性、质量监督和书面程序方面的重大改进。说明贵公司将如何确保所有阶段的调查都得到适当执行。
• A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
• 对变更管理系统进行全面、独立的评估。该评估应包括但不限于确保变更得到QU的审核和批准。变更管理程序还应包括确定变更有效性的规定。
• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
•一份全面的评估和整改计划,以确保企业的QU得到有效运作的授权和资源。评估还应包括但不限于:
o A determination of whether procedures used by your firm are robust and appropriate
o确定贵公司的程序是否稳健和适当
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
o在整个生产过程中对QU监督的规定,以评估对适当做法的遵守情况
o A complete and final review of each batch and its related information before the QU disposition decision
o在做出质量投诉处理决定之前,对每批产品及其相关信息进行完整和最终的审核
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
o监督和批准所有其他QU职责的调查和履行,以确保所有产品的鉴别、规格、质量和纯度标准。
4. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in the master production and control records, or other records (21 CFR 211.68(b)).

4.未能对计算机或有关系统采取适当控制,以确保生产及控制主记录或其他记录仅能由授权人员进行更改。(21 CFR 211.68(b))

Your firm failed to implement adequate controls to support the integrity of your electronic data and to ensure that only appropriate individuals had administrative rights. For example, your (b)(4) microbiological testing instrument used for drug product release testing is controlled by a stand-alone computer which does not have appropriate controls in place to prevent deletion of raw laboratory data. All QU users utilized a shared generic account to access the computer which had administrative privileges capable of changing and deleting files. During the inspection, one of your employees opened the computer’s recycle bin and noted that approximately (b)(4) files and folders were deleted. Further, these deleted items included at least (b)(4) files of the “(b)(4)” format which your personnel stated were most likely (b)(4) data files. The names of (b)(4) of those deleted files were similar to drug product formulas produced since 2017.
贵公司未能实施足够的控制来支持电子数据的完整性,并确保只有适当的个人拥有管理权利。例如,企业用于药品放行检测的微生物检测仪器由一台独立计算机控制,该计算机没有适当的控制以防止原始实验室数据的删除。所有QU用户使用一个共享通用帐户来访问计算机,该计算机具有更改和删除文件的管理权限。在检查期间,企业的一名员工打开了计算机的回收站,并注意到大约有xx文件和文件夹被删除了。此外,这些被删除的项目包括至少“xx”格式的xx文件,贵公司人员称该文件极有可能是xx数据文件。被删除文件中xx的名称与2017年以来生产的药品配方相似。
Additionally, for your (b)(4) analytical software, the QU management did not review high-performance liquid chromatography (HPLC) audit trails for drug product testing before release of a batch. The QU reviewed the audit trails only on an (b)(4) basis. This is a repeat violation from the 2017 inspection.
另外,对于xx分析软件,QU在放行前没有对药品测试的高效液相色谱(HPLC)审计追踪进行审核。QU仅在xx基础上审查了审计追踪。这是2017年检查以来的重复违规行为。
In your response, you stated that the common user login was discontinued and administrative rights were assigned to Information Technology personnel outside of the QU. Additionally, you stated that your software is being updated and you will create a new procedure governing user access. Additionally, your response stated that your (b)(4) software is being upgraded to a new version and the audit trail for each sample will be printed and added to the data packet for peer and quality assurance (QA) review.
回复中,企业表示已经禁止普通用户登录,管理权限被分配给了QU之外的信息技术人员。另外,企业表示软件正在更新,将创建一个新的程序来管理用户访问。另外,企业的回复中说xx软件正在升级到一个新的版本,每个样本的审计追踪将被打印并添加到数据包中,以便同行和质量保证(QA)审核。
Your response is inadequate because it did not provide sufficient corrective actions to secure the (b)(4) software and associated stand-alone computer. You did not describe the user access levels, access privileges, and authorized users for the (b)(4) system to collect data, review data, or perform other functions. Your plan to maintain data integrity by allowing only one microbiologist access to the system is not a robust strategy because you have not created a system of access levels and privileges to secure integrity of your data. You also did not describe where data will be stored to prevent inappropriate access or deletion. Additionally, your response lacked a retrospective assessment of drug product release data collected on the (b)(4) instrument or a broader evaluation of how system security vulnerabilities may have impacted data integrity.
回复是不充分的,因为它没有提供足够的纠正措施来确保xx软件和相关的独立计算机的安全。也没有描述用户访问级别、访问权限和xx系统收集数据、审查数据或执行其他功能的授权用户。只允许一个微生物访问系统来维护数据完整性的计划不是一个合格的策略,因为没有创建一个访问级别和权限系统来确保数据的完整性。企业也没有说明数据将存储在何处,以防止不适当的访问或删除。另外,企业的回复中缺乏对xx工具中收集的药品放行数据的回顾性评估,也缺乏对系统安全漏洞如何影响数据完整性的更广泛的评估。
Lastly, we recognize the (b)(4) software upgrade described. However, your proposed data review procedure is inadequate. The use of static copies of laboratory records (of raw chromatograms, processed chromatograms, and audit trails) are inadequate as they do not preserve the dynamic record format of the full analytical test result which should be a part of the QA review process for release. You must ensure that original laboratory records, including paper and electronic records, are subject to QA review to ensure that all test results and associated information are appropriately reported.
最后,FDA认识到所述的(b)(4)软件升级。然而,企业提出的数据审核程序是不充分的。使用实验室记录(原始色谱图、处理色谱图和审计跟踪)的静态副本是不充分的,因为它们没有保存完整分析测试结果的动态记录格式,该结果应成为QA审核放行过程的一部分。企业必须确保原始实验室记录(包括纸质和电子记录)经过QA审查,以确保所有测试结果和相关信息得到适当的报告。
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry.
企业的质量体系不能充分确保数据的准确性和完整性,以支持生产的药品的安全性、有效性和质量可控性。关于建立和遵循符合CGMP的数据完整性规范,请参见FDA的数据完整性与药品CGMP符合性指导文件https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry。
In your response to this letter, provide the following:

针对本函,请提供:

A comprehensive, independent assessment and CAPA plan for computer system security and integrity. Include a report that identifies design and control vulnerabilities, and appropriate remediations for each of your laboratory computer systems. This should include but not be limited to:
对计算机系统的安全性和完整性进行全面、独立的评估和CAPA计划。提供一份报告,指出设计和控制漏洞,以及对每个实验室计算机系统的适当整改措施。这应包括但不限于:
• A list of all hardware that includes all equipment, both standalone and network, in your laboratory.
•所有硬件的清单,包括实验室的所有设备,包括独立设备和网络设备。
• Identification of vulnerabilities in hardware and software, encompassing both networked and non-networked systems.
•识别硬件和软件的漏洞,包括联网和非联网系统。
• A list of all software configurations (both equipment software and laboratory information management system ((b)(4))) and versions, details of all user privileges, and oversight responsibilities for each of your laboratory systems. Regarding user privileges, specify user roles and associated user privileges (including the specific permissions allowed for anyone who has administrative rights) for all staff who have access to the laboratory computer systems, and their organizational affiliation and title. Also describe how you will ensure laboratory staff are not given administrative rights, or other permissions that compromise data retention or reliability.
•所有软件配置(包括设备软件和实验室信息管理系统((b)(4))和版本的列表,所有用户权限的详细信息,以及你们每个实验室系统的监督责任。关于用户权限,为所有能够访问实验室计算机系统的员工,以及他们的组织机构和头衔指定用户角色和关联的用户权限(包括具有管理权限的任何人所允许的特定权限)。还要描述企业将如何确保实验室工作人员不被授予管理权限或其他不利于数据保留或可靠性的权限。
• System security provisions, including but not limited to whether unique user names/passwords are always used and their confidentiality safeguarded.
•系统安全规定,包括但不限于是否始终使用唯一的用户名/密码,以及保密性。
• Detailed procedures for robust use and review of audit trail data, and current status of audit trail implementation for each of your systems.
对审计追踪数据的可靠使用和审查的详细程序,以及对每个系统的审计追踪实施的当前状态。
• Interim control measures and procedural changes for the control, review, and full retention of laboratory data.
•实验室数据的控制、评审和完全保留的临时控制措施和程序变更。
• Technological improvements to increase the integration of data generated through electronic systems from standalone equipment (e.g., balances, pH meters, water content testing) into the (b)(4) network.
•技术改进,以增加独立设备(如天平、pH计、含水量测试)通过电子系统产生的数据到xx网络的集成。
• A detailed summary of your procedural updates and associated training, including but not limited to system security control to prevent unauthorized access, appropriate user role assignments, secondary review of all analyses, and other system controls.
企业的程序更新和相关培训的详细总结,包括但不限于防止未经授权访问的系统安全控制、适当的用户角色分配、对所有检验分析的二次审查,以及其他系统控制。
• Your remediated program for ensuring strict ongoing control over electronic and paper-based data to ensure that all additions, deletions, or modifications of information in your records are authorized, and all data is retained. Provide your full CAPA plan and any improvements made to date.
企业的修订程序确保对电子和纸质数据进行严格的持续控制,以确保记录中所有信息的添加、删除或修改都得到授权,并保留所有数据。提供完整的CAPA计划和迄今为止所做的任何改进。
Adulterated Cosmetics: Insanitary Conditions

掺假化妆品:不卫生条件

The cosmetic products (body wash, lotions, and bubble bath) that you manufacture are adulterated within the meaning of section 601(c) of the Act, 21 U.S.C. 361(c), in that they have been prepared, packed, or held under insanitary conditions whereby they may have become contaminated with filth, or whereby they may have been rendered injurious to health. Specifically, during the inspection of your facility, our investigator noted that the (b)(4) water system used in the manufacture of cosmetics products may be a potential source of Gram-negative bacterial contamination. Stagnant water and leaking processing lines were observed in the production area. Your firm has a history of investigations that do not appear to adequately determine the root cause of the microbial contamination nor implement effective CAPA (e.g., including routine testing for the absence of potentially pathogenic organisms). Further, there is inadequate cleaning and/or sanitization of equipment used in the manufacturing of cosmetics.
根据21 U.S.C. 361(c)法案第601(c)条的含义,企业生产的化妆品(沐浴露、乳液和泡沫浴)是掺假的,因为它们是在不卫生的条件下制备、包装或保存的,它们可能会被污染,或可能会对健康造成损害。具体来说,在对企业设施的检查中,FDA的调查人员注意到用于化妆品生产的xx水系统可能是革兰氏阴性细菌污染的潜在来源。生产现场出现死水和生产线漏水现象。贵公司的调查历史似乎没有充分确定微生物污染的根本原因,也没有实施有效的CAPA(例如,包括不存在潜在致病菌的常规检测)。此外,化妆品生产中使用的设备没有充分的清洁和/或卫生处理。
Objectionable Organisms

有害微生物

For further information regarding the significance of Burkholderia cepacia complex and other objectionable contamination of non-sterile, water-based drug products, see FDA’s advisory notice posted on July 7, 2021, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile
关于洋葱伯克霍尔德菌复合物和其他非无菌水基药品污染的重要性的进一步信息,请参阅2021年7月7日发布的FDA咨询通知,网址为https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderia-cepacia-complex-poses-contamination-risk-non-sterile
Ineffective Quality System

无效的质量体系

These violations demonstrate a failure of your executive management to exercise proper oversight and control over the manufacture of drugs. You should immediately and comprehensively assess your company’s manufacturing operations to ensure that systems, processes, and ultimately, products conform to FDA requirements.
这些违法行为表明企业的执行管理部门未能对药品生产进行适当的监督和控制。企业应该立即全面评估贵公司的生产操作,以确保系统、工艺和最终产品符合FDA要求。
In your response, describe how top management will support QA and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing and quality issues and to assure a continuing state of control.
在企业的回复中,描述最高管理层将如何支持QA和可靠的运营,包括但不限于,及时提供资源,主动解决新出现的生产和质量问题,并确保持续的受控状态。
CGMP Consultant Recommended

CGMP顾问推荐

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
基于FDA在贵公司发现的违规行为的性质,FDA强烈建议聘请21 CFR 211.34中规定的合格顾问协助贵公司满足CGMP要求。企业使用顾问并不能减轻贵公司遵守CGMP的义务。贵公司的执行管理层仍有责任解决所有缺陷,以确保持续遵守CGMP。
Conclusion

结论

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
本函中引用的违规行为并不是企业设施中存在的所有违规行为的清单。企业有责任调查和确定任何违规行为的原因,并防止其再次发生或其他违规行为的发生。
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
请及时纠正违规行为。未能及时并充分地解决该问题可能会导致无需另行通知的监管或法律行动,包括但不限于扣押和禁令。未解决的违规行为也可能妨碍其他联邦机构授予合同。
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
未能解决违规问题还可能导致FDA拒绝签发出口证书。FDA可能会拒绝批准将贵公司列为药品生产商的新申请或补充申请,直到任何违规行为被完全解决,并且FDA确认企业符合CGMP。FDA可能会重新检查,以核实企业是否完成了针对任何违规行为的纠正措施。
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
本函告知企业FDA的发现,并为企业提供解决上述缺陷的机会。收到此信后,请在15个工作日内书面回复本办公室。说明企业已经做了哪些工作来解决任何违规,并防止其再次发生。在回复这封信时,可以提供额外的信息供我们考虑,我们将继续评估企业的活动和做法。如果不能在15个工作日内完成纠正措施,说明延迟的原因和完成计划。
Your written notification should refer to the Warning Letter Number above (622087). Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov
书面通知应参考上述警告信号码(622087)。请通过电子邮件回复:ORAPHARM3_RESPONSES@fda.hhs.gov
Attention: Eric Mueller, Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations Division III
If you have questions regarding the contents of this letter, please contact Eric Mueller, Compliance Officer at (402) 331-8536, ext. 101.
Sincerely,
/S/
Nicholas F. Lyons
Acting Program Division Director
Division of Pharmaceutical Quality Operations III
__________________
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times. The guidance was withdrawn effective December 31, 2021 (86 Fed Reg at 56960). This guidance communicated the Agency’s temporary policy that we did not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepared alcohol-based hand sanitizers for consumer use (or for use as a health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance are present. These circumstances included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of the formulations of the drug products indicates that such products are not prepared consistent with FDA’s temporary policy set forth in the guidance. Because Vi-Jon LLC’s hand sanitizer products are not consistent with the formulations described in these guidances, they do not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer products for violations of section 505 of the FD&C Act.
发布于 2022-08-12 07:58:01 © 著作权归作者所有