FDA警告信挂网，事涉世界500强企业子公司！
FDA官网挂出的警告信具体内容如下：
WARNING LETTER
CMS # 584016
October 17, 2019
Dear Mr. Scott:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, PETNET Solutions Inc., FEI 3006577728, at 350 Washington Street, Unit 268, Woburn, Massachusetts, from March 19 to April 5, 2019.
美国食品和药物管理局（FDA）于2019年3月19日至4月5日检查了Petnet Solutions Inc.的药品生产设施。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for positron emission tomography (PET) drugs. See 21 CFR, part 212.
本警告信汇总了正电子发射断层扫描（PET）药物CGMP法规的重大违规。详见美国联邦法规第21卷、第212章。
Because your methods, facilities, or controls for compounding, processing, packing, or holding do not conform to CGMP, your PET 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).
因为你们的方法、设施、生产工艺、包装或者储存的方式不符合CGMP法规，你们的PET药物根据《联邦食品、药品和化妆品法》（FD&C）第501(a)(2)(B)章节，《美国法典》第21卷第351(a)(2)(B)节被认定为违规。
We reviewed your April 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了你们于2019年4月26日对FDA 483表格的回复，并确认收到你们之后的回复。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在检查期间，我们的检查员发现的具体违规包括但不限于如下：
1. Your firm’s facilities are not adequate to ensure the prevention of contamination of equipment or product by environmental conditions that could reasonably be expected to have an adverse effect on product quality (21 CFR 212.30(a)).
贵公司的设施不足以确保防止环境条件的污染对设备或产品在质量方面可能产生的不利影响。
Facility Suitability
设施适用性
During the inspection, our investigator observed a state of disrepair and lack of cleanliness in your facility that commercially manufactures sterile injectable PET drugs. For example, rusted screws were observed holding up a light fixture in the ISO 5 area of the (b)(4) where you aseptically fill PET drug products. Furthermore, our investigator observed a hole in the top of your (b)(4) enclosure, approximately three inches in diameter, open to the surrounding room. The top of the (b)(4) surrounding the open hole was visibly dirty. Also, our investigator observed filth and damaged floor tiles in the immediately surrounding area of the room directly in front of the (b)(4).
在检查过程中，我们的调查员观察到贵公司生产无菌注射PET药品的工厂年久失修，清洁不好。例如，在无菌填充PET药品的 (b)(4) 的ISO 5区域，观察到生锈的螺钉托住了一个灯具。此外，我们的研究人员在你的 (b)(4) 外壳顶部观察到一个洞，直径大约为三英寸，打通了周围的房间。洞口周围 明显脏了。此外，我们的调查人员在房间正前方的周边区域观察到肮脏和损坏的地砖。
Your response stated that the (b)(4) is negatively pressured to protect the operator and draws air from the surrounding environment. The presence of a negatively pressured area adjacent to an ISO 5 area requires careful facility and equipment design, as well as attentiveness to ongoing control, maintenance, cleaning, and disinfection activities to ensure appropriate air quality for your aseptic filling environment.
你们对此回复，(b)(4)是负压区以保护操作员，并与周围环境通风。与ISO 5区域相邻的负压区域的存在需要仔细的设施和设备设计，并注意持续的控制、维护、清洁和消毒活动，以确保无菌灌装环境的适当空气质量。
Environmental Conditions
环境条件
Between March 2016 and March 2019, adverse trends were identified in environmental and personnel monitoring samples taken from the ISO 5 areas where you conduct aseptic manipulations. Isolates from these samples frequently included Bacillus, spp., and related bacterial sporeforming species. Also, during the (b)(4) certifications conducted by a third party between July 2017 and January 2019, sporeforming fungi were repeatedly identified in the ISO 8 area of your (b)(4) immediately adjacent to your ISO 5 area.
2016年3月至2019年3月期间，从你们进行无菌操作的ISO 5区域采集的环境和人员监测样品中发现了不利因素。这些样本中的分离物包括芽孢杆菌和相关的细菌孢子形成菌。此外，在2017年7月至2019年1月期间由第三方进行的(b)(4)检查期间，在紧邻(b)(4)ISO 5区域的(b)(4)ISO 8区域内重复检测出孢子形成真菌。
In 2017, your firm also had a sterility test failure for a batch of Fludeoxyglucose (FDG) F18 injection. You identified the microbial contaminant as the sporeforming bacteria, Brevibacillus limnophilus.
2017年，贵公司也有一批氟脱氧葡萄糖（FDG）F18注射液的没有通过无菌检测。确认了微生物污染物是孢子形成菌，即短杆菌。
Sporeforming organisms can pose a significant challenge to disinfection processes. We note you implemented a (b)(4) disinfection regimen. However, significant trends of sporeforming organisms continue in your facility. For example, in January and February 2019, your environmental monitoring identified Bacillus species in multiple surface samples for the ISO 5 Biological Safety Cabinet (BSC) you use to aseptically prepare final product vial assemblies. Over approximately three years, you failed to adequately respond to data indicating insufficient microbial control in the areas where you conduct aseptic manipulations, as well as adjacent areas.
孢子形成菌可能是消毒过程的重点清洁对象。我们注意到你们实施了一个消毒方案。然而，在你的设施中，孢子形成菌仍然存在。例如，在2019年1月和2月，你们的环境监测在用于无菌制备的ISO 5生物安全柜（BSC）的多个表面样品中监测出芽孢杆菌。在大约三年的时间里，在你进行无菌操作的区域，以及邻近区域，你没有对数据做出充分的反应，数据显示该地区的微生物控制不严。
Excursions and trends in environmental monitoring results should be monitored and promptly reviewed. Adverse trends should trigger a comprehensive evaluation of the state of control of your manufacturing operation.
应监测和及时审查环境监测结果的变化和趋势。不利的趋势应该会引起对你们生产操作控制状态的全面评估。
In your response, you stated that your facility is being remodeled. However, your risk assessment for facility remediation lacked sufficient details. Your response also did not include a plan for ensuring that your facility is adequately maintained, and environmental conditions are appropriate, to ensure product quality.
在你们的回复中，说是设施正在改建。但是，对设施修复的风险评估缺乏足够的详细信息。回复也没有包括确保您的设施得到充分维护的计划，以及确保产品质量的适当环境条件。
In response to this letter, provide:
针对本函，请提供：
· Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide an independent assessment that includes, but is not limited to:
对所有与无菌过程、设备和设施相关的污染危害进行全面的风险评估。提供独立评估，包括但不限于：
All human interactions within the ISO 5 area
Equipment placement and ergonomics
Air quality in the ISO 5 area and surrounding room
Facility layout
Personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)
Adequacy of procedures to ensure ongoing maintenance and control of your facility
ISO5区域内所有的人员活动
设备的布置和效率
ISO5区域和周围房间的空气质量
设施布局
人员流动和物质流动（用于进行和支持无菌操作的所有房间）
确保设施持续维护和控制程序的充分性
· Your results for all environmental and personnel monitoring conducted from April 2019 to present. Describe each interim measure implemented to ensure risk mitigation and provide all testing and all monitoring results obtained during remodeling. Also include facility monitoring trends and any excursions (e.g., differential pressure, humidity, non-viable particles, viable particles) during this period. List the date of production, name of product, lot number, and equipment used. Describe in detail when the overall remodeling work began and ended, and what construction was performed each day and the location.
从2019年4月至今，你们对所有环境和人员的监测结果。描述为确保风险缓解而实施的每项临时措施，并提供整改期间获得的所有测试和所有监测结果。还包括在此期间的设施监测结果和任何偏移（例如，压差、湿度、非活性颗粒、活性颗粒）。列出生产日期、产品名称、批号和使用的设备。详细描述整个改建工程何时开始和结束，以及每天进行的施工和位置。
· Your Planned Variance (PV00000182) document and Enhanced Environmental Monitoring protocols (D0013699 and D0013698) referenced in your risk assessment.
风险评估中引用了计划偏差文档（PV00000182）和增强环境监测协议（d0013699和d0013698）。
· Your facility qualifications, media fills, and most recent static and dynamic smoke studies performed for both the BSC and (b)(4) during and since completion of the facility remodeling.
在设施改造期间和改造完成后，设备资质、介质填充以及最近为BSC和(b)(4) 进行的静态和动态烟雾研究。
· Your investigations for any failed (b)(4) tests since the FDA’s March 2016 inspection of your facility.
自FDA于2016年3月对工厂进行检查以来，对任何未通过的(b)(4) 测试的调查。
2. Your firm’s laboratory failed to develop and follow adequate written procedures for testing components, in-process materials, and finished PET drug products to ensure conformance with appropriate standards, including established standards of identity, strength, quality, and purity (21 CFR 212.60(a) and (b)).
贵公司的实验室未能制定并遵循适当的书面程序来测试成分、加工材料和成品PET药物，以确保符合适当的标准，包括确定的强度、质量和纯度标准（《美国联邦法规》第21卷第212.60（a）和（b）条）。
You failed to establish adequate testing procedures for environmental monitoring for your aseptic manufacturing operations. For example, the action levels in your standard operating procedure (SOP D0012118) for environmental monitoring are not appropriate. For surface samples taken from the ISO 5 area of your (b)(4), your procedure does not require an investigation unless (b)(4) colony-forming units (CFU) are recovered from a single sample or there are (b)(4) occurrences of growth (not exceeding the single sample action limit) in a (b)(4).
你们没有为无菌生产操作建立足够的环境监测测试程序。例如，环境监测标准操作程序（sop d0012118）中的操作级别不合适。对于从 (b)(4)的ISO 5区域采集的表面样品，除非 (b)(4)菌落形成单位（CFU）是从单个样品中回收的，或者 在 (b)(4)中出现生长（不超过单个样品作用极限），否则不需要进行调查。
These action levels in your environmental monitoring SOP are not appropriate, are of particular concern when considering the repeated recoveries of sporeforming microorganisms in your ISO 5 areas.
环境监测标准操作程序中的这些是不合格的，特别值得关注在ISO 5区域中孢子形成菌的回收。
An ongoing goal for environmental control of ISO 5 areas is to remain free of microbial contamination. Action levels should be set appropriately. PET drug manufacturing requires vigilant environmental control, which requires prompt, appropriate attention to microbial recovery in ISO 5 areas.
ISO5区域环境监控的一个持续目标是保持无微生物污染。应适当设置操作。PET药物的生产需要严格的环境控制，这就需要及时、适当地注意ISO 5领域的微生物回收。
We note you committed to identify any microbial contamination in both the ISO 5 BSC and the ISO 5 area of the (b)(4) for (b)(4) after the remodeling of the facility is completed. However, you did not include a justification for limiting this identification to a (b)(4). Environmental monitoring in ISO 5 areas should include routine identification of any microorganism.
我们注意到，你们承诺在设施改造完成后，在ISO 5的BSC和ISO 5区域的（b）（4）中识别微生物污染。但是，没有包括将此标识鉴定为a (b)(4)的理由。ISO 5区域的环境监测应包括任何微生物的常规鉴定。
You also failed to follow your established sterility testing procedure (SOP D0001993) and your procedure lacks details on disinfecting and material flow. For example, your operator omitted the (b)(4) for sterility testing of (b)(4) of your PET drug product Fludeoxyglucose F-18 Injection, USP. During another sterility test, your operator omitted the (b)(4) media tube for sterility testing for (b)(4) of Amyvid, Florbetapir F-18 Injection. Additionally, on a separate occasion, your operator incubated the sterility test tubes for both the (b)(4) and (b)(4) media at the wrong temperature for sterility testing of your PET drug product F-18 Florbetapir.
你也没有遵循你建立的无菌检测程序（sop d0001993），你的程序缺乏消毒和物质流通的细节。例如，操作人员省略了用于PET药品氟脱氧葡萄糖F-18注射液（USP）的无菌检测。在另一次无菌检查中，遗漏了阿美维德F-18注射液无菌检查用的培养基管。此外，在另一个场合，在错误的温度下检测PET药物产品F-18 Florbetapir的无菌检测培养基和无菌试管。
Testing is a critical control that provides assurance that your PET drug products are sterile and therefore suitable for intended use. It is important that you follow established, appropriate procedures to ensure your sterility testing is able to detect the presence of microorganisms.
检测是一个非常重要的步骤，它保证PET药物产品是无菌的，适合预期效果。重要的是，必须遵循既定的、适当的程序，以确保无菌检测能够检测到微生物的存在。
Your response did not address whether you will have additional quality oversight for sterility testing, given the issues were attributed to operator error. Additionally, we note your procedure (SOP D0001993) for sterility testing lacks details on disinfecting and flow of testing supplies between unclassified and ISO 5 areas.
你们的回复没有说明是否会对无菌检测进行额外的质量监督，因为这些问题是由操作失误引起的。另外，我们注意到你方无菌检测程序（sop d0001993）缺乏消毒，还缺乏非无菌区域与ISO 5区域之间检测用品流动的详细信息。
In response to this letter, provide:
针对本函，请提供：
· A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
全面评估实验室实践、程序、方法、设备、文档和分析能力。在此审查的基础上，提供一个详细的计划来修正和评估实验室系统的有效性。
· Your investigations for any microorganisms recovered in ISO 5 areas or on operator gloves, as well as any trending data you have regarding detection of 1 CFU or more since January 2019. Include all organism identifications and the locations where organisms were recovered.
自2019年1月以来，对在ISO 5区域或操作员手套上发现的任何微生物的调查，以及关于检测1 CFU或更多CFU的数据。包括所有的有机体识别和有机体被回收的位置。
· Your process for qualification of the media used for sterility testing and whether the media is prepared off site or supplied by a vendor.
对无菌检测所用介质的鉴定过程，以及该介质是在场外制备还是由供应商提供。
· A comprehensive assessment of your sterility testing program, including, but not limited to, disinfection of material, material flow, and environmental monitoring.
对无菌检测程序的全面评估，包括但不限于材料消毒、物流和环境监测。
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 to evaluate your operations to assist your firm in meeting CGMP requirements.
根据我们在贵公司发现的违规行为的性质，我们强烈建议聘请一名有资格评估贵公司运营的顾问，协助贵公司满足CGMP的要求。
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.
您使用顾问并不免除贵公司遵守CGMP的义务。贵公司的执行管理层仍然负责解决所有缺陷和系统缺陷，以确保持续的CGMP合规性。
Multiple Facilities
公司设备
We note that this facility is part of a larger corporation, with PETNET facilities throughout the United States that share corporate quality oversight and procedures.
我们注意到，该设施是一家大型公司的一部分，在美国各地设有PETNET设施，共享公司质量监督和程序。
You should comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to CGMP requirements for PET drug products.
你们应该全面评估您公司的全球生产运营，以确保系统、流程和生产的产品符合CGMP对PET药品的要求。
Quality Assurance Program Audits
质量保证计划审核
In your response, you stated that you identified the need for facility improvements through “internal audits.” FDA reminds you of your responsibility to correct CGMP deficiencies found during quality assurance program audits, also referred to as “internal audits” in your correspondence with the FDA.
在你们的回复中，声明通过“内部检查”确定了设施改进的必要性。FDA提醒您，你们有责任纠正在质量保证计划检查期间发现的CGMP缺陷，在您与FDA的通信中也称为“内部检查”。
Guidance on Positron Emission Tomography (PET) Drugs
正电子发射断层扫描（pet）药物指南
See FDA’s guidance document, PET Drugs—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing.
参考FDA的指导文件，PET药物当前良好生产规范，以帮助您在生产PET药物时满足CGMP要求。还需参考FDA的指导文件，无菌加工生产的无菌药品目前的良好生产规范，以了解可能适用于PET药品生产的其他要求。
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 these violations and for preventing their recurrence or the occurrence of other violations.
这封信中列举的违规行为并不是在你的设施内的违规行为清单里只有一个。你们负责调查和确定这些违规行为的原因，并防止其再次发生或发生其他违规行为。
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
如果你们正在考虑一项可能导致工厂生产的药品供应中断的行动，FDA要求你们立即联系CDER的药品短缺人员，以便能够与FDA合作，以最有效的方式使你们的经营符合法律。根据《美国法典》第21卷第356c（b）节的规定，与药品短缺人员联系还可以让你们履行义务，报告药品生产中断。这也使FDA能够尽快考虑采取什么行动（如果有的话），以避免短缺和保护依赖你的产品的患者的健康。
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
及时纠正本函所述违规行为。如果未能及时纠正这些违规行为，可能会导致法律诉讼，而无需另行通知，包括但不限于扣押和禁令。本警告信中未解决的违规行为也可能阻止其他联邦机构授予合同。
FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.
在上述违规行为得到纠正之前，FDA还可能拒绝批准出口证书申请，以及FDA可能会拒绝批准任何新的药物申请或将贵公司列为药物制造商的补充产商。我们可能会重新检查，以确认您已完成纠正措施。
We request you email Kent Bui, Kent.Bui@fda.hhs.gov, within five days of receipt of this letter to schedule a regulatory meeting.
我们要求您在收到本函后五天内给Kent Bui发送电子邮件，以安排监管会议。
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. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
收到此信后，请在15个工作日内以书面形式回复本办公室。请说明自我们检查以来，您为纠正您的违规行为并防止其再次发生所做的工作。如果您无法在15个工作日内完成纠正措施，请说明延迟的原因和完成计划。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov and ORAPharm1_responses@fda.hhs.gov. Please identify your response with FEI: 3006577728 and CMS # 584016.
Sincerely,
/S/
Craig Swanson for Diana Amador-Toro Program Division Director/District Director U.S. Food and Drug Administration OPQO Division I / New Jersey District
Cc: Craig Sawyer, Pharm.D.
Woburn Facility Site Manager
350 Washington Street, Unit 268
Woburn, MA 01801
责任编辑 | 杰尼龟
排版设计 | 惜梦姌
新闻来源：药智网