无菌操作不符合cGMP，FDA发出警警告信。
WARNING LETTER
Cangene BioPharma, LLC dba Emergent BioSolutions
MARCS-CMS 630316 — AUGUST 10, 2022
August 10, 2022
Dear Mr. Kramer:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cangene BioPharma, LLC dba Emergent BioSolutions, FEI 1000512361, at 1111 South Paca Street, Baltimore, MD 21230, from February 7 to 11, 2022, and from February 14 to 18, 2022.
美国食品和药物管理局(FDA)于2022年2月7日至11日和2022年2月14日至18日检查了贵司位于马里兰州巴尔的摩南Paca街1111号的药品生产工厂Cangene BioPharma, LLC dba Emergent BioSolutions, FEI 1000512361。
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，企业的药品根据《联邦食品、药品和化妆品法案》(FD&C法案)第501(a)(2)(B)条21 U.S.C. 351(a)(2)(B)属于掺假药品。
We reviewed your March 10, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
FDA详细审查了企业于2022年3月10日对FDA 483表格的回复，并确认收到了企业随后的回信。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在我们的检查过程中，我们的调查人员发现了具体的违规行为，包括但不限于以下几点。
1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and you failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and (b)).
1. 未能做到间隔适当时间，清洁、维护设备和器具，根据药品特性进行消毒和/或灭菌，防止出故障与污染，以免改变药品的安全性、成分、规格、质量或纯度而超出官方或其它既定要求。未制定并遵循设备清洁和维护的书面规程。(21 CFR 211.67(a) 和 (b))。
Your system for ensuring suitable design and adequate control of equipment was deficient. Your firm failed to use suitable equipment for aseptic manufacturing, which led to particulate contamination of your sterile drug products.
企业用于确保适当设计和充分控制设备的系统有缺陷。贵公司没有使用合适的设备进行无菌生产，这导致了无菌药品的颗粒污染。
Multiple customer complaint investigations related to the presence of foreign particulates (i.e., metal particulates) in your drug products determined that the root cause was associated with the (b)(4) and (b)(4) tray units, both equipment that are present in your manufacturing environment and used in your aseptic processing operations. One of the investigations documented that seven vials were found to have metal particulates and an additional vial was found to have silicone particulates. The investigation also deemed the metal and other particulates to be “intrinsic” to the manufacturing process and stated that no further action was required. Your investigation added that the metal particulates likely entered the vials through manipulation of your tray units.
与企业药品中存在外来颗粒(即金属颗粒)相关的多个客户投诉调查确定，根本原因与xx和xx托盘单元有关，这两种设备都存在于企业的生产环境中，并用于无菌加工操作。其中一项调查显示，7个小瓶中发现了金属颗粒，另外一个小瓶中发现了硅酮颗粒。调查还认为这种金属和其他微粒是生产过程的“固有”颗粒，并表示不需要采取进一步行动。企业的调查补充说，金属颗粒可能是通过操作托盘单元进入小瓶的。
You examined approximately (b)(4) tray units and found that most (b)(4) needed to be further evaluated due to apparent damage. Further evaluation of your tray units confirmed they were inadequate for use in sterile drug production and should have been removed as part of preventive maintenance.
企业大约检查了xx托盘，发现由于明显损坏，大部分xx需要进一步评估。对托盘单元的进一步评估证实它们不适合用于无菌药品生产，应该作为预防性维护的一部分予以移除。
Your procedure for maintenance of (b)(4) tray units was inadequate. Your procedure, “SOP 9087, Inspection, Cleaning, and Storage Procedures for Trays and (b)(4)” indicated that tray units should be visually inspected prior to use in the manufacturing process, however, it lacked specificity regarding how you document your activities for the inspection, identification, segregation, evaluation, and repair and/or retirement of defective tray units. Our investigator also noted that you lacked documentation and adequate reconcilability for the visual inspection of tray units.
企业对xx托盘的维护程序不充分。企业的程序“SOP 9087，托盘和(b)(4)的检查、清洁和存放程序”表明，托盘单元在生产过程中使用前应进行目视检查，但是，它缺乏关于如何记录有缺陷的托盘单元的检查、识别、隔离、评估和修复和/或报废活动的具体说明。FDA的调查人员还注意到企业缺乏对托盘单元进行目视检查的文件和充分的协调性。
In your response, you state you will initiate improved inspection of all tray units, and any confirmed unacceptable trays will be submitted for repair and/or replacement. You also commit to revise your SOP 9087, “Inspection, Cleaning, and Storage Procedures for Trays and (b)(4),” to include examples of conditions that require maintenance assessment for repair or replacement (e.g., excessive scratching, old age, and worn appearance).
在企业的回复中，表示将对所有托盘单元进行改进检查，任何确认不合格的托盘将提交维修和/或更换。企业还承诺修改SOP 9087，“托盘的检查、清洁和存储程序”和(b)(4)，以包括维修或更换时需要进行维护评估的条件示例(例如，过度划痕、老化和磨损外观)。
Your response is inadequate. You did not provide substantive evidence that your tray units are suitable for their intended purpose. Your response also lacks a systemic review of the preventive maintenance program used by your facility, including but not limited to replacement frequencies. Furthermore, you did not provide documentation of the actions taken on the defective tray units you evaluated. Also, you did not provide sufficient details regarding how your firm will ensure tray units are effectively identified and tracked (i.e., with unique identification number) to ensure suitability prior to use in production.
企业的答复不充分。没有提供实质性的证据证明企业的托盘单元适合其预期用途。企业的回复也缺乏对设施使用的预防性维护程序的系统审查，包括但不限于更换频率。此外，企业没有提供对评估的有缺陷托盘所采取的措施的文件。另外，企业没有提供足够的细节，说明贵公司将如何确保托盘单元被有效地识别和追踪(即，具有唯一的识别号)，以确保在生产使用前的适用性。
Your response also fails to address how you will ensure adequate investigation of intrinsic and extrinsic visible particulate contamination issues. You do not commit to accurately define and categorize intrinsic and extrinsic particulates in your operation, and to properly evaluate visible particulate contamination in your parenteral products. It is important that intrinsic visible particulate contamination is appropriately evaluated and investigated. In addition, extrinsic or foreign particulate contamination should occur very infrequently and be thoroughly investigated.
企业的回复也未能说明将如何确保对内在和外在可见颗粒污染问题进行充分的调查。没有承诺准确定义和分类企业操作中的内在和外在颗粒，并没有正确评估企业肠道产品中的可见颗粒污染。对固有可见颗粒污染进行适当的评估和调查是很重要的。此外，外部或外来颗粒污染应很少发生，并应进行彻底调查。
In response to this letter, provide:
针对本函，请提供：
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)计划对设施和设备实施日常的、警惕的运营管理监督。除其他事项外，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/设施进行技术升级，并改进持续管理审查的系统。
A CAPA plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
基于回顾性评估的CAPA计划，包括对企业的清洁过程和做法的适当整改措施，以及完成时间。提供设备清洗生命周期管理过程中漏洞的详细汇总。描述企业的清洁计划的改进，包括清洁效率的提高;改进所有产品和设备清洁执行的持续验证;以及所有其他需要整改的地方。
A comprehensive, independent review and remediation plan for the design, control, and maintenance of the (b)(4) units used in your manufacturing process.
一份对企业生产过程中使用的xx部件的设计、控制和维护的综合独立的审查和整改计划。
Your revised procedure(s) which include the identification of all (b)(4) tray units, and the process of tracking and tracing for maintenance and determining suitability for use.
企业修订的程序包括所有xx托盘单元的识别，以及维护和确定是否适合使用的追踪过程。
An independent review of your classification and investigation of particulate contamination in your products. The review should comprehensively assess your program, including but not limited to ensuring appropriate classifications of particulates (e.g., inherent, intrinsic, extrinsic), and appropriate investigations and CAPA.
一份对企业产品中颗粒污染的分类和调查的独立审查。评审应全面评估企业的程序，包括但不限于确保适当的微粒分类(例如，固有的、内在的、外在的)，以及适当的调查和CAPA。
A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to, evaluating:
一份全面的评估和整改计划，以确保你们的质量部门(QU)获得有效运作的权力和资源。评估还应包括但不限于:
o whether procedures used by your firm are robust and appropriate
o 贵公司使用的程序是否稳健和适当
o sufficiency of provisions used for QU oversight throughout your operations to evaluate adherence to appropriate practices
o评估企业QU是否能充分监督生产过程
o whether an effective and complete final review of each batch and its related information is conducted before the QU disposition decision
o在QU做出处置决定之前，是否对每个批次及其相关信息进行有效和完整的最终审核
o implementation of oversight and approval of investigations, as well as discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
o执行监督和批准调查，以及履行所有其他QU职责，以确保所有产品的鉴别、规格、质量和纯度标准
Also, describe how top management at your company supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
同时，描述贵公司的最高管理层是如何支持质量保证和可靠的运营的，包括但不限于及时提供资源，主动解决新出现的生产/质量问题，并确保持续的受控状态。
2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
2.未能建立和遵守适当的书面程序，以防止无菌的药品受到微生物污染，包括所有无菌和灭菌工艺的验证程序[ 21 CFR 211.113(b)。
Your aseptic filling line operations required extensive (b)(4) interventions during the manufacturing process. Our investigators observed numerous instances of poor aseptic technique by your operators while performing (b)(4) interventions during production runs. Examples of these poor aseptic techniques include, but are not limited to:
企业的无菌灌装线操作在生产过程中需要大量的xx干预。我们的调查人员在生产过程中进行xx干预时，观察到操作人员在不良无菌技术方面存在诸多问题。这些无菌技术缺陷的例子包括但不限于:
An operator was leaning into the aseptic filling cabinet which caused blockage of the unidirectional airflow over open glass vials. Notably, there was no subsequent clearance of the vials on the line exposed to potential contamination hazard.
一名操作人员斜身进入无菌灌装柜中，导致开口玻璃小瓶上的单向气流受阻。值得注意的是，生产线上暴露于潜在污染危害的小瓶随后没有得到清理。
An operator left the filling cabinet door open for an excessive period.
操作人员打开灌装柜门的时间过长。
Poor practices by operators when manipulating vial tray containers and the (b)(4) used for charging these trays.
操作员在操作小瓶托盘容器和托盘装料（b）（4）时的不良做法。
In addition, sterile (b)(4) used for (b)(4) interventions inside the filling line cabinet were stored outside the cabinet, adjacent to the swing door. The inadequate storage location of the (b)(4) increases the potential for their contamination.
另外，灌装线柜内用于(b)(4)干预的无菌(b)(4)存放在柜外，靠近弹簧门。(b)(4)的贮存地点不适当，增加了其受污染的可能性。
Your SOP 9002, “Personnel Conduct in the Sterile Core”, Section 6.3 (Material Handling), under subsection 6.3.2 states that personnel should “(b)(4)”. Also, sub-section 6.3.8 mentions that “(b)(4)...”. Your procedure is deficient in that it did not strictly instruct personnel to not disrupt the path of unidirectional air flow during sterile manufacturing process.
企业的SOP 9002，“无菌核心中的人员行为”，章节6.3(材料处理)，在第6.3.2小节中规定人员应该“(b)(4)”。此外，第6.3.8节提到“(b)(4)……”。企业的程序有缺陷，因为它没有严格指导人员在无菌生产过程中不要破坏单向气流的路径。
To safeguard sterility of the drug product in aseptic processing operations, you must establish robust operational design and procedures, and personnel must employ strict discipline. The poor aseptic techniques observed during the inspection could cause potential breaches in sterility assurance.
在无菌工艺操作中，为确保药品的无菌性，必须建立稳健的操作设计和程序，人员必须遵守严格的纪律。检查过程中发现的无菌技术缺陷可能会导致无菌保证的潜在漏洞。
You state you have made improvements to your program for monitoring aseptic processing personnel behavior and classroom training on aseptic behaviors.
企业表示已经改进了无菌工艺人员行为监控和无菌行为培训的程序。
Your response is inadequate. You do not indicate whether you have conducted a risk assessment that encompasses all batches within expiry and reviewed available videos associated with the batches to identify any poor aseptic practices and associated risks to your marketed drug products. Additionally, you do not provide the procedure for the aseptic processing behavior monitoring program that describes how you will document and evaluate observation(s) to determine if identified aseptic deviations may have impacted drug sterility.
企业的答复不充分。企业没有说明是否进行了包含所有有效期内批次的风险评估，并审查了与这些批次相关的现有视频，以识别企业已上市药品的不良无菌操作和相关风险。另外，企业没有提供无菌工艺行为监测计划的程序，该程序描述了企业将如何记录和评估观察结果，以确定已识别无菌偏差是否会影响药物的无菌性。
In response to this letter, provide:
针对本函，请提供：
Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of QU oversight (e.g., audit) during aseptic processing and its support operations.
企业确保生产过程中适当的无菌操作和洁净室行为的计划。包括确保对所有生产批次进行常规和有效监督的步骤。还应描述无菌工艺及其支持操作中QU监督(如审核)的频率。
A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
一份彻底的回顾性审查和风险评估，评估无菌技术缺陷和洁净室行为可能对药品的质量和无菌性的影响。
A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
一份关于无菌工艺、设备和设施的所有污染危害的全面风险评估，包括但不限于:
o all human interactions within the ISO 5 area
o ISO 5级区内的所有人员互动
o equipment placement and ergonomics
o 设备安置和人体工程学
o air quality in the ISO 5 area and surrounding room
o ISO 5区及其辅助区的空气质量
o facility layout
o 设施布局
o personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)
o 人流和物流（用于执行和辅助无菌操作的所有区域）
A detailed remediation plan with timelines to address the findings of the independent contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.
一份详细的整改计划及时间表，以解决污染危害源风险评估所发现的问题。请描述对无菌加工操作设计和控制所做出的具体切实改进。
Repeat Violations at Facility
设施重复违规行为
Similar deviations were cited in a previous inspection, conducted from April 12 to 16, 2021, and discussed during the regulatory meeting held on October 6, 2021. You responded by proposing specific remediations to address these observations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
此前在2021年4月12日至16日进行的检查中也发现了类似的缺陷，并在2021年10月6日召开的监管会议上进行了讨论。企业提出了具体的整改措施来解决这些问题。屡次失败表明，对药品生产的行政管理监督和控制是不够的。
Ineffective Quality System
质量体系缺陷
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective operations oversight to ensure reliable operations, we found that your QU was not fully exercising its authority or responsibilities. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and products manufactured by your firm conform to FDA requirements.
这封信中的重大发现表明贵公司没有按照CGMP的要求运行有效的质量体系。除了缺乏有效的运营监督以确保可靠运营外，FDA还发现企业的QU没有充分行使其权力或责任。企业应立即全面评估贵公司的全球生产业务，以确保贵公司生产的系统、工艺和产品符合FDA要求。
CGMP Consultant Recommended
CGMP顾问推荐
Based upon the nature of the violations, 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.
基于这些违规行为的性质，FDA强烈建议企业聘请符合21 CFR 211.34要求的顾问来帮助贵公司满足CGMP要求。使用顾问并不能减轻你们公司遵守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。
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.
在这封信中引用的违规行为并非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。
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.
如果企业正在考虑一项可能导致贵工厂生产的药品供应中断的行动，FDA要求企业立即联系CDER的药品短缺工作人员，地址是drugshortages@fda.hhs.gov，以便FDA可以与企业合作，以最有效的方式使企业的操作符合法律。根据21 U.S.C. 356C(b)，联系药品短缺工作人员也允许企业履行可能需要报告药品生产中断的任何义务。这也允许FDA尽快考虑采取什么行动（如有），可能需要避免短缺和保护依赖企业产品的患者的健康。
Correct any violations promptly. Failure to address this matter promptly and adequately 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。如果未能及时且充分地解决该问题，可能会在不另行通知的情况下导致监管或法律行动，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.
这封信告知企业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。说明企业已经采取了何种措施来解决任何违规，并防止其再次发生。在回复这封信时，企业可以提供额外的信息供FDA考虑，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，说明延迟的原因和完成计划。
Send your electronic reply to ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter CMS # 630316 and include FEI: 1000512361
请将电子回复发送到ORAPHARM1_RESPONSES@fda.hhs.gov。企业的书面通知应参考警告信CMS # 630316，FEI: 1000512361
If you have questions regarding the content of this letter, please contact Jose Hernandez-Guzman, Compliance Officer at jose.hernandez-guzman@fda.hhs.gov or 631-787-3002 x1017.
如果对这封信的内容有任何疑问，请联系合规官何塞·埃尔南德斯-古兹曼(Jose Hernandez-Guzman): jose.hernandez-guzman@fda.hhs.gov或631-787-3002 x1017。
/S/
Nerizza Guerin
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations Division I
New Jersey District
