质量管理 自检/审计

FDA警告信21/12/21-生产工艺未验证、偏差调查不彻底、实验室控制不合规以及质量部门职责不完善

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生产工艺未验证、偏差调查不彻底、实验室控制不合规以及质量部门职责不完善等,FDA发出警告信。
WARNING LETTER
Sunstar Americas, Inc.
MARCS-CMS 614058 — DECEMBER 21, 2021
Warning Letter # 614058
December 21, 2021
Dear Mr. McMahon:
The U.S. Food and Drug Administration (FDA) inspected your drug and medical device manufacturing facility, Sunstar Americas, Inc., FEI 1413787, at 301 E. Central Rd., Schaumburg, Illinois, from January 12 to February 18, 2021.
美国食品和药物管理局(FDA)于2021年1月12日至2月18日检查了企业位于伊利诺伊州绍姆堡E. Central Rd 301号的药品和医疗器械制造工厂Sunstar Americas FEI 413787。
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals and Quality System (QS) regulations for medical devices. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211) and Title 21 CFR, part 820, respectively.
本警告信总结了严重违反成品药现行良好生产规范(CGMP)和医疗器械质量体系(QS)的情况。分别参见《联邦法规法典》第21篇第210和211部分(《联邦法规法典》第21篇第210和211部分)和《联邦法规法典》第21篇第820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).
因为生产、加工、包装或贮存方法、设施或控制不符合CGMP要求,企业的药品根据《联邦食品、药品和化妆品法》(FD&C法)第501(a)(2)(B)条、21 U.S.C. 351(a)(2)(B)条被定义为掺假。
Under section 201(h) of the FD&C Act, 21 U.S.C. § 321(h), G•U•M® HYDRAL™ OTC products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body. The HYDRAL™ OTC products are intended for treatment of Xerostomia/dry mouth.
根据FD&C法案第201(h)条,21 U.S.C.§321(h), G•U•M®HYDRAL™OTC产品用于疾病或其他条件的诊断,或用于治疗、缓解、治疗或预防疾病,或用于影响身体结构或任何功能。HYDRAL™OTC产品用于治疗口干舌燥症/口干症。
This inspection also revealed that your devices are adulterated within the meaning of section 501(h) of the FD&C Act, 21 U.S.C. § 351(h) because the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation.
本次检查还发现,企业的设备在FD&C法案第501(h)条、21 U.S.C.§351(h)中被定义为掺假,因为它们的生产、包装、储存或安装所使用的方法或设施或控制不符合质量体系法规的当前良好生产规范要求。
We reviewed your March 11, 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.
我们详细审阅了企业2021年3月11日对我们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纠正措施的证据,使企业的操作符合CGMP。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在我们的检查中,我们的调查人员发现了具体的违规行为,包括但不限于以下情况。
Drug CGMP Violations

药物CGMP违规

1. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to follow all of its written production and process control procedures (21 CFR 211.100(a) and (b)).

1.未能制定并遵守旨在确保所生产的药品具备所声称的或表明拥有的成分、规格、质量和纯度的书面生产和工艺控制规程。(21 CFR 211.100 (a) 和 (b))

Our investigators documented deficiencies in the “(b)(4) system) validation protocol and deviations during its execution. For example:
我们的调查人员记录了xx系统验证协议中的缺陷及其执行过程中的偏差。例如:
• Excursions in the performance parameters of your water system occurred while the system was being validated. For example, the (b)(4) concentration, which impacts the ability of the system to maintain microbiological control, was recorded at (b)(4) in the system storage tank. (b)(4) measurements were below the limit of (b)(4) for (b)(4) out of (b)(4) days in January 2018. These occurrences were not documented in the validation report as deviations and reviewed before you deemed the water system validated.
•在系统验证过程中,水系统的性能参数出现偏差。例如,影响系统维持微生物控制能力的(b)(4)浓度记录在系统储罐中的(b)(4)。2018年1月xx天xx天的xx天xx天的测量值低于xx天xx天的极限。这些情况没有作为偏差记录在验证报告中,也没有在企业认为水系统验证之前进行评审。
• The water system validation study did not provide scientific data supporting the type and frequency of chemical sanitization performed in addition to the routine (b)(4) sanitization. Your protocol also lacked provisions for evaluating these parameters of your water system sanitization program. Your current practice is to conduct chemical sanitization (b)(4).
•除常规 (b)(4)消毒外,水系统验证研究未提供支持化学消毒类型和频率的科学数据。企业的方案还缺少评估水系统消毒程序的这些参数的规定。企业目前的做法是进行化学消毒 (b)(4)。
• The protocol allowed for reduced sampling and testing if results were considered acceptable but you did not define what an acceptable standard would be. Although you had results as high as (b)(4) at your (b)(4), you still reduced sampling and testing to a (b)(4) frequency.
•如果结果被认为是可接受的,协议允许减少采样和测试,但企业没有定义可接受的标准是什么。尽管企业xx的结果高达xx,但企业仍然将抽样和测试降低到xx的频率。
You have not shown that your water system can consistently produce water suitable for drug manufacturing and meets, at a minimum, the USP purified water monograph and appropriate microbial limits.
企业没有证明水系统能够持续生产适合药品生产的水,并且至少满足USP纯化水专论和适当的微生物限度。
It is essential that you design your water system to ensure consistently high purity water that is suitable for its intended use. High bioburden or objectionable microbes in the water used as an ingredient in your drugs may pose significant risk to consumers.
至关重要的是,企业设计的水系统,以确保持续高纯度的水适合其预期用途。作为药品成分的水中含有高生物负荷或有害微生物,可能对消费者构成重大风险。
In your response, you committed to reassessing your water system followed by revalidation. You also committed to conducting a gap assessment of your validation program and performing comprehensive CGMP and quality systems training for all personnel.
在企业的回复中,承诺重新评估水系统,然后进行重新验证。企业还承诺对验证程序进行差距分析,并对所有人员进行全面的CGMP和质量体系培训。
In response to this letter provide:

在回复本函时,请提供:

• A comprehensive independent assessment of your water system design, control, and maintenance, and corresponding corrective actions and preventative actions (CAPA).
•对水系统设计、控制和维护以及相应的纠正措施和预防措施(CAPA)进行全面独立的评估。
• A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design or new system consistently produces water adhering to (b)(4) Water, USP monograph specifications and appropriate microbial limits (total counts, objectionable microbes).
•全面的整改计划,安装和运行合适的水系统。包括一个稳健的持续控制、维护和监控程序,以确保经过整改的系统设计或新系统持续生产符合xx水、USP各论规范和适当的微生物限度(总数量、有害微生物)的水。
• Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
•关于后者,确保水的微生物总数限值适合贵公司生产的产品的预期用途。
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).

2. 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)。

Your water system was subject to microbiological contamination and numerous deviations from operating parameters since validation. Many of these deviations were either not investigated or did not result in implementation of CAPA.
自验证以来,企业的水系统受到微生物污染,运行参数发生了许多偏差。这些偏差要么没有被调查,要么没有实施CAPA。
• No investigations were conducted in response to identification of Burkholderia contaminans in seven samples taken from your water system ports (b)(4), and (b)(4), between January 1, 2020, and June 30, 2020. Burkholderia contaminans was not identified as an objectionable organism in your procedures or your (b)(4) water specifications. The presence of objectionable microorganisms in your (b)(4) water system can adversely affect the quality of your drug products.
•在2020年1月1日至2020年6月30日期间,从企业水系xx口xx口和xx口采集的7个样本中发现了伯克霍尔德氏菌,但未进行调查。在企业的程序或xx水规范中,伯克霍氏菌并没有被确定为一种有害生物。在企业xx水系统中存在的有害微生物会对药品的质量产生不利影响。
• You opened a CAPA during the validation of your water system due to findings of Burkholderia cepacia in three samples collected at ports (b)(4) and (b)(4). These ports supply water for manufacturing. The CAPA investigation identified a possible root cause of a “(b)(4)” from the (b)(4) supply port to the (b)(4) sample port and your firm proposed (b)(4). However, the CAPA was closed approximately a year and a half later without addition of the filter or explanation why corrective action was not taken. You subsequently identified Burkholderia contaminans at port (b)(4) multiple times in 2020.
•由于在xx和xx口岸收集的三个样品中发现了冠状伯克霍氏菌,企业在水系统验证期间开启了CAPA。这些港口为制造业供水。CAPA调查确认了从xx供应端口到xx样品端口和贵公司提出xx的一个可能的根本原因。然而,CAPA在大约一年半后关闭,没有增加过滤器或解释为什么没有采取纠正措施。随后,企业于2020年多次在xx口岸发现伯克霍尔德氏菌。
• During the validation of your water system, a third-party service technician observed staining inside the water tank and noted you were investigating the cause. You lacked documentation of the cause or CAPA addressing the service technician’s finding.
•在水系统验证期间,第三方服务技术人员观察到水箱内部有污渍,并注意到企业正在调查原因。企业缺乏有关原因的文件或针对服务技术员发现的CAPA。
• Deviations in the (b)(4) sanitization process were not logged in accordance with your deviation procedure. We found a pattern of failure to conduct investigations or implement CAPA following deviations in the operating parameters during ozone sanitization when the minimum level of (b)(4) was not met in the storage tank, (b)(4), and loop supply.
•未按照企业的偏差程序记录(b)(4)消毒过程中的偏差。我们发现,在臭氧消毒过程中,当储罐(b)(4)和回路供应中未达到最低水平(b)(4)时,运行参数出现偏差后,无法进行调查或实施CAPA。
In your response, you committed to hire a third-party expert and to perform training on investigations. You also committed to performing a review of all CAPA, out-of-specification (OOS), out-of-trend (OOT), and invalidated quality control data initiated from January 1, 2019, to present. You also revised your purified water specifications to include Burkholderia cepacia complex (BCC) as an objectionable organism as of January 11, 2021.
在企业的回复中,承诺聘请第三方专家并进行调查培训。企业还承诺对自2019年1月1日起至今的所有CAPA、OOS、OOT和无效质量控制数据进行审核。企业还修订了纯化水规程,在2021年1月11日将洋葱伯克霍尔德菌复合体(BCC)列为一种有害生物。
Your response is inadequate because you failed to accurately categorize some OOS and OOT results, deviations, and unexpected discrepancies.
企业的回复是不充分的,因为企业未能准确地对一些OOS和OOT结果、偏差和意外差异进行分类。
In response to this letter, provide:

针对本函,请提供:

• A retrospective, independent review of all invalidated OOS (including in-process, release, and stability testing) results for US products irrespective of whether the batch was ultimately distributed in the US and a report summarizing the findings of the analysis, including the following for each OOS:
•一份回顾性独立审查,针对美国市场上产品的所有被无效的OOS结果(包括中控和放行/稳定性检验),以及一份关于每个OOS的分析的总结报告,包括以下内容:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o 确定与被无效OOS结果相关的科学论证和证据是否能结论性地证明实验室错误是根本原因。
o For investigations that conclusively establish laboratory root cause, provide the rationale, and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o 对于可得出结论归因为实验室根本原因的调查,请提供依据并确保易受相同或相似根本原因影响的所有其它实验室方法被识别且进行整改。
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
o 对于不能得出结论或未发现实验室根本原因的所有OOS,请包括一份彻底的生产审查(例如,批生产记录、生产步骤的充分性、设备/设施的适用性、原料的变异性、工艺能力、偏差历史、投诉历史、批失败历史)。请总结每个调查的潜在生产根本原因,以及任何生产操作的改进。
• A comprehensive retrospective review of all GMP documentation associated with distributed finished drug product batches that remain within expiry and the equipment and systems used in their manufacture to ensure all OOS results, OOT results, deviations, and unexpected discrepancies were categorized and appropriately investigated.
•全面回顾性审查与过期的成品药批次相关的所有GMP文件及其生产中使用的设备和系统,以确保对所有OOS结果、OOT结果、偏差和意外差异进行分类和适当调查。
• Explain whether you have reconsidered the sequence of the water system components in your current design. You currently have (b)(4) system although the latter represents the best means of microbial reduction.
•说明企业是否重新考虑了当前设计中水系统组件的顺序。目前有 (b)(4)系统,尽管后者是减少微生物的最佳方法。
• A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
•详细的风险评估,解决观察到的水系统故障对目前在美国销售或到期的所有药品批次质量的潜在影响。指定响应风险评估将采取的行动,如客户通知和产品召回。
• A detailed description of all CAPA that have been identified to address this violation, with timeframes for CAPA activities.
•详细描述已确定的针对此违规的所有CAPA,以及CAPA活动的时间框架。
3. 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)).

3.未能建立实验室控制,包括制订科学可靠和适宜的质量标准、标准、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))

Before beginning distribution, you did not adequately study antimicrobial effectiveness in your finished drugs products to evaluate the ability of the preservative system to inhibit the growth of certain objectionable organisms including BCC.
在开始分发之前,企业没有充分研究药品的抗菌效果,以评估防腐系统抑制某些不良生物(包括BCC)生长的能力。
For example, (b)(4) studies for 0.12% chlorhexidine gluconate oral rinse (Paroex) using Burkholderia cepacia were not performed until July 2020. Notably, BCC was found to proliferate to excessive levels in your product over its shelf life for several batches including too numerous to count (TNTC) levels. Numerous lots of this product were recalled from the market because of excessive microbiological contamination. Paroex is produced by a contract manufacturer under your ANDA 076434.
例如,直到2020年7月才对0.12%洗必泰葡萄糖酸酯漱口液(Paroex)进行了使用冠状伯克霍氏菌的研究。值得注意的是,在企业产品的货架期限内,发现有几个批次的BCC扩散到过量水平,包括数量众多(TNTC)水平。由于微生物污染严重,大量该产品被从市场上召回。parex是由合同制造商根据企业的ANDA 076434生产的。
In your response, you committed to assessing your procedure titled “U.S. Regulatory Information Concerning SAI Products” to determine its adequacy in establishing and maintaining product-specific information and meeting regulatory requirements.
在企业的回复中,承诺评估名为“U.S.“关于SAI产品的监管信息”,以确定其在建立和维护特定产品信息并满足监管要求方面的充分性。
You committed to adding BCC to microbiological tests for products manufactured at and for your firm. You also committed to developing and implementing a procedure to establish steps to follow when a new microorganism is identified in the manufacturing facility to ensure the adequacy of controls, including addressing potentially objectionable microorganisms.
企业承诺将BCC添加到罐公司生产的产品的微生物检测中。企业还承诺制定和实施一套程序,以确定在生产设施中发现新微生物时应遵循的步骤,以确保控制的充分性,包括处理潜在的有害微生物。
In response to this letter, describe how your product and process development programs will build quality into your products, including conducting appropriate studies to support each new product.

针对这封信,请描述企业的产品和工艺开发计划将如何提高产品质量,包括进行适当的研究以支持每种新产品。

4. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

4.未设置完善的质量管理部门,并具有批准和拒绝所有原辅料、药品容器、密封系统、中间体、包装材料、标签及药品的职责与权力。 (21 CFR 211.22(a))

You did not adequately exercise your responsibility to ensure all drug products manufactured by and for your firm possessed appropriate quality attributes, antimicrobial properties, or preservative systems to ensure their microbiological quality and safety. For example, your non-sterile aqueous-based drug product specifications did not include Burkholderia cepacia.
企业没有充分履行责任,确保贵公司生产和为贵公司生产的所有药品具有适当的质量属性、抗菌性能或防腐系统,以确保其微生物质量和安全性。例如,企业的非无菌水基药物产品规格中不包括洋葱伯克霍尔德菌。
Your drugs are often used in hospitals or clinical settings in which patients may have a higher vulnerability to infection with Burkholderia cepacia and other objectionable organisms. Detecting numbers and types of objectionable microorganisms in your drug products is critical to making appropriate batch disposition decisions.
企业的药品经常用于医院或临床环境,在这些环境中,患者可能更容易感染冠状伯克霍尔德菌和其他有害微生物。检测药品中有害微生物的数量和类型对于做出适当的批次处理决定至关重要。
The agreement between your firm and your contract manufacturer ((b)(4)) specifically identified your responsibilities with respect to the manufacture of your drug products. Your responsibilities include the provision of support regarding technical and regulatory issues to (b)(4) for the products’ manufacture. You are also responsible for overseeing the CGMP compliance of your contract manufacturer through mechanisms including the review of procedures and records associated with the manufacture of your products.
贵公司与合同制造商( (b)(4))之间的协议明确规定了贵公司在药品生产方面的责任。企业的责任包括为 (b)(4)的产品制造提供技术和法规方面的支持。企业还负责通过包括审查与企业的产品制造相关的程序和记录在内的机制,监督企业的合同制造商的CGMP合规性。
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
药品生产必须符合CGMP要求。FDA意识到许多药品制造商使用独立的承包商,如生产设施,检测实验室,包装商和标签商。FDA认为承包商是制造商的延伸。
We acknowledge that you initially recalled batches of Paroex bearing an expiration date from June 30, 2022, to September 30, 2022, because of the presence of objectionable microbiological contamination or substantial risk of contamination. We also acknowledge your expansion of the recall to include all potentially affected lots of Paroex following further discussions with FDA. We also acknowledge your subsequent recalls of Hydral Dry Mouth Relief, Butler Clear Dip, and Perioshield Oral Health Rinse, medical devices, because of potential contamination with objectionable organisms.
我们承认,企业最初召回了一批有效期为2022年6月30日至2022年9月30日的parex,因为存在有害微生物污染或严重的污染风险。我们也承认,在与FDA进一步讨论后,企业将召回范围扩大到所有可能受影响的parex批次。我们也承认企业随后召回的Hydral口干缓解剂、Butler清浸剂和Perioshield口腔健康冲洗剂等医疗设备,因为它们可能受到有害生物的污染。
You are responsible for the quality of your drugs regardless of whether you manufacture them, or a contract facility manufactures them for you on your behalf. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity.
企业对药品的质量负责,无论企业是否生产药品,或者合同工厂代表企业生产药品。企业必须确保药品是按照FD&C法案第501(a)(2)(B)条生产的,以确保安全性、鉴别、规格、质量和纯度。
In response to this letter, provide your updated procedures that ensure all activities performed by you and your contract manufacturers are adequate and approved by your quality unit.
在回复本函时,请提供企业更新的程序,以确保企业和企业的合同制造商进行的所有活动都是充分的,并得到企业质量部门的批准。
Medical Device Quality System Violations

医疗器械质量体系违规行为

5. Your firm failed to adequately validate a process whose results cannot be fully verified by subsequent inspection and test through established procedures (21 CFR 820.75(a)).

5. 贵公司未能充分验证工艺,该工艺的结果无法通过既定程序的后续检查和测试完全验证(21 CFR 820.75(a))。

Refer above to the discussion of 21 CFR 211.100(a) and (b) violations.
参考以上关于21 CFR 211.100(a)和(b)违反的讨论。
6. Your failed to adequately establish procedures for corrective and preventive action to include the documentation of such activities (21 CFR 820.100(a) & (b)).

6. 企业未能充分建立纠正和预防措施的程序,包括此类活动的文件(21 CFR 820.100(a) & (b))。

Refer above to the discussion of 21 CFR 211.192 violations.

参考以上关于21条CFR 211.192违规的讨论。

7. Failure to adequately establish schedules for the adjustment, cleaning, and other maintenance of equipment (21 CFR 820.70(g)).

7. 未能充分制定设备变更、清洁和其他维护的时间表(21 CFR 820.70(g))。

Specifically, the (b)(4) Sanitization system of the (b)(4) water system was not part of a maintenance schedule. The system included three gauges that measure the (b)(4) in the system to verify that the sanitization process and the storage tank control are acceptable. There was no documentation that gauges ((b)(4)) had been calibrated.

具体来说,xx水系统的xx卫生处理系统不是维护计划的一部分。系统包括三个测量系统中xx的仪表,以验证卫生处理过程和储罐控制是可接受的。没有对xx量具进行校准的文件。

8. Failure to adequately establish procedures for design input (21 CFR 820.30(c)).

8. 未能充分建立设计输入程序(21 CFR 820.30(c))。

Specifically, the design for Hydral Spray failed to include Burkholderia cepacia as a challenge in (b)(4) although Burkholderia cepacia was included in the (b)(4) challenge for other products to include the (b)(4) toothpaste in June 2017. The risk management file of the Hydral Spray was not updated to include these objectionable organisms and any controls necessary to mitigate the risks as part of Hydral spray design verification and validation. The risk management file was updated on January 18, 2021, after the start of the FDA inspection.

具体来说,Hydral Spray的设计没有将cepacia Burkholderia作为xx中的挑战项,尽管2017年6月其他产品在xx中包含了cepacia Burkholderia的挑战项。作为Hydral Spray设计验证和验证的一部分,没有更新Hydral Spray的风险管理文件,以包括这些有害生物和任何必要的控制以降低风险。风险管理文件于2021年1月18日更新,在FDA开始检查之后。

Quality Systems

质量体系

Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/media/71535/download, Q9 Quality Risk Management at https://www.fda.gov/media/71543/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download.
贵公司的质量体系不完善。有关建立和维护符合cgmp的质量体系的指导,请参阅FDA指南:Q8(R2)药物开发在https://www.fda.gov/media/71535/download, Q9质量风险管理在https://www.fda.gov/media/71543/download, Q10药物质量体系在https://www.fda.gov/media/71553/download。
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.
基于我们在贵公司发现的违规性质,我们强烈建议聘请一名符合21 CFR 211.34规定的资质顾问,协助贵公司满足CGMP要求。企业使用顾问并不减轻贵公司遵守CGMP的义务。贵公司的执行管理层仍有责任解决所有缺陷,以确保持续的CGMP符合性。
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/DrugSafety/ucm559508.htm.
有关cepacia伯克霍尔德菌复合物的重要性和非无菌水性药品的其他不良污染的进一步信息,请参见FDA 2021年7月7日发布的咨询通知,网址为https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm。
Drug Production Suspended

暂停药品生产

We acknowledge your commitment to suspend production of drugs at this facility.

我们确认了企业承诺暂停该工厂的药品生产。

If you plan to resume manufacturing drugs, notify this office before resuming your operations.

如贵公司计划恢复生产药品,请在恢复生产前通知本办公室。

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 and in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
本函中所列举的违规行为并非贵工厂和企业产品中存在的所有违规行为。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. Additionally, should FDA determine that you have Quality System regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been corrected.
请及时纠正任何违规行为。未能及时和充分地解决此问题可能导致在没有进一步通知的情况下采取监管或法律行动,包括但不限于扣押和禁令。未解决的违规行为也可能阻止其他联邦机构授予合同。此外,如果FDA确定企业存在违反III类器械上市前批准申请合理相关的质量体系法规,在违规行为得到纠正之前,此类器械将不会获得批准。
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. Also, should FDA determine that your devices do not meet the requirements of the Act, requests for Certificates to Foreign Governments (CFG) may not be granted.
未能解决违规也可能导致FDA扣留出口证书的发放。FDA可能会拒绝批准将贵公司列为药品制造商的新申请或补充申请,直到完全解决任何违规问题并确认贵公司符合CGMP。我们可能会重新检查,以确认企已完成纠正措施,以解决任何违规行为。此外,如果FDA确定您的设备不符合法案的要求,则可能不会批准向外国政府提交证书(CFG)的请求。
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 since our inspection to correct your 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.
这封信通知企业我们的发现,并为企业提供了一个解决上述缺陷的机会。收到本函后,请于15个工作日内以书面方式回复本办公室。说明自我们检查以来,企业为纠正违规行为和防止违规行为再次发生所做的工作。在回复本函时,企业可以提供额外的信息供我们考虑,因为我们将继续评估企业的活动和做法。如果企业不能在15个工作日内完成纠正措施,请说明延误的原因和完成的时间表。
Your written notification should refer to the Warning Letter Number above (614058). Please address your reply via email to: oradevices2firmresponse@fda.hhs.gov
Attention: Rafael Padilla. Compliance Officer
U.S. Food and Drug Administration
Office of Medical Devices and Radiological Health Operations Div. 2 Central
If you have questions regarding the contents of this letter, please contact Rafael Padilla at (312) 596-4212.
Sincerely,
/S/
Blake Bevill, M.S.
Program Division Director
Office of Medical Devices and Radiological Health Operations Div. 2 Central
Sincerely,
/S/
Jeffrey Meng
Acting Program Division Director
Division of Pharmaceutical Quality Operations Division III
发布于 2022-09-20 08:30:06 © 著作权归作者所有
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