未遵守既定的程序及OOS未彻底调查，FDA发出警告信。
WARNING LETTER
Brigham and Women’s Hospital Inc.
MARCS-CMS 623476 — APRIL 11, 2022
April 11, 2022
Dear Dr. Eppen:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Brigham and Women’s Hospital Inc., FEI 3012030543, located at 75 Francis Street, Boston, MA from August 5 to September 16, 2021.
美国食品和药物管理局(FDA)于2021年8月5日至9月16日检查了贵公司位于马萨诸塞州波士顿弗朗西斯街75号的药品生产设施Brigham and Women 's Hospital Inc, FEI 3012030543。
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for positron emission tomography (PET) drugs. See Title 21 Code of Federal Regulations (CFR), part 212 (21 CFR part 212).
本警告信总结了正电子发射断层扫描(PET)药物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212部分(21 CFR第212部分)。
Because your methods, facilities, or controls for manufacturing, 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).
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PET药品属于《联邦食品、药品和化妆品法案》(FD&C法案)501(a)(2)(B)、21 U.S.C. 351(a)(2)(B)》规定的掺假药品。
We reviewed your October 12, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
FDA详细审查了企业于2021年10月12日对FDA 483表格的回复，并确认收到了后续的信函。
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 facilities are not adequate to ensure the prevention of contamination of equipment or product by substances, personnel, or environmental conditions that could reasonably be expected to have an adverse effect on product quality. Procedures to ensure that all equipment is clean, suitable for its intended purposes, properly installed, maintained, and capable of repeatedly producing valid results, are not adequately followed. (21 CFR 212.30(a) and (b)).
1. 企业的设施不足以确保防止可能对产品质量产生不利影响的物料、人员或环境条件对设备或产品的污染。没有充分遵守确保所有设备清洁、适合其预期用途、正确安装、维护和能够反复产生有效结果的程序。(21 CFR 212.30(a)及(b))。
You manufacture PET drug products for parenteral administration in a facility that is not adequately designed or controlled for aseptic processing. In addition, you did not ensure that your equipment is suitable for aseptic operations.
在未充分设计或控制无菌处理的设施中生产用于肠外给药的PET药品。此外，也没有确保设备适用于无菌操作。
Facility Suitability
设施的适用性
You failed to provide adequate facilities for the prevention of contamination.
企业没有提供足够的设施来防止污染。
From about July 1, 2020 through October 1, 2020, your facility experienced a series of water infiltrations in and around your Technical Corridor. The water infiltrations occurred in this uncontrolled and unclassified area, which is located behind, and above equipment used in the PET aseptic production operation, including your hot cells, biological safety cabinet, and laminar flow hood. During the inspection, investigators also observed an overhead water supply pipe actively leaking onto the floor within your raw material storage area. Furthermore, your environmental monitoring (EM) program revealed several fungal species in your facility’s ISO 5 classified environments, such as your hot cell used for the manufacturing of drug product [18F]-Fludeoxyglucose for Injection. In your investigation, you attributed the fungal recoveries in the ISO 5 classified environment to the water infiltrations. Your investigation states that the water infiltrations were due to multiple failures associated with the mechanical suite above your manufacturing area and with the roof penetrations leading into the plenum spaces above your cleanroom areas. Notably, the EM data indicates that the water infiltration problem preceded the date of detection and manifested as a loss of environmental control in your aseptic production facility. The failure to appropriately design and maintain the facility led to a lack of control and subjected drug products to the risk of contamination.
从2020年7月1日到2020年10月1日，贵厂技术夹层内外发生了一系列渗水事件。渗水发生在这个不受控制和未分类的区域，位于PET无菌生产操作设备的后面和上面，包括企业的热室、生物安全柜和层流净化罩。在检查过程中，调查人员还观察到一个高架供水管道泄漏到企业的原材料储存区域的地板上。此外，企业的环境监测(EM)程序显示工厂的ISO 5分类环境中有几种真菌，例如用于生产药品[18F]-注射用氟脱氧葡萄糖。在企业的调查中，将真菌在ISO 5分类环境中的恢复归因于水的渗透。企业的调查表明，渗水是由于生产区上方的机械套件以及通向洁净室区域上方的通风空间的屋顶贯穿件的多个故障造成的。值得注意的是，EM数据显示渗水问题早于检测日期，表现为企业无菌生产设施环境控制的缺失。未能适当地设计和维护设施，导致缺乏控制，并使药品受到污染的风险。
Equipment
设备
From June 29, 2020 to November 25, 2020, your EM program repeatedly recovered microorganisms, including several fungal organisms, from your facility’s ISO 5 areas. Air monitoring in critical areas should normally yield no microbiological contamination. Your EM program also recovered many of the same organisms in the adjacent ISO 7 areas. During this time, you manufactured drug products including (b)(4) batches of [18F]-Fludeoxyglucose for Injection and (b)(4) sub-batches of [13N]-Ammonia for Injection. You acknowledged in your response that you failed to apply the appropriate minimum contact time for a sporicidal disinfectant used within the ISO 5 area of your biological safety cabinets and hot cells. Additionally, we observed an operator insert their upper torso and head into your biological safety cabinet while performing the cleaning and disinfection process. Furthermore, you failed to ensure all operators completed their media fill qualifications within your established requalification periods, which is a repeat issue from your 2019 inspection. Finally, you failed to adequately follow your procedures to investigate each ISO 5 EM result exceeding action level to determine product impact, identify root causes, and to implement effective corrective actions and preventive actions (CAPA).
从2020年6月29日到2020年11月25日，企业的EM项目多次从工厂的ISO 5区域回收微生物，包括几种真菌生物。关键区域的空气监测通常不会产生微生物污染。企业的EM程序还在临近的ISO 7区域发现了许多相同的生物体。在此期间，企业生产的药品包括xx批[18F]-注射用氟脱氧葡萄糖和xx批[13N]-注射用氨。企业在答复中承认，未能在生物安全柜和热室的ISO 5区域内对使用的杀菌消毒剂应用适当的最小接触时间。此外，我们还观察到一位操作人员在清洗和消毒过程中将上半身和头部伸入到生物安全柜中。此外，未能确保所有操作员在企业规定的再确认期内完成模拟灌装实验，这是2019年检查的重复问题。最后，未能充分遵循企业的程序调查每一个超过行动限的ISO 5 EM结果，以确定产品影响，确定根本原因，并实施有效的纠正措施和预防措施(CAPA)。
In your response, you stated that your engineering department conducted responsive emergency remediations for each water infiltration, and that your facility was returned to a state of control in November 2020. However, you halted any further remediations in favor of a “comprehensive” repair project to be completed in February 2022. Your response also indicates that you will continue PET drug manufacturing while remediating your facility. You did not discuss your plans to proactively assess your facility and the Technical Corridor for its adequacy to manufacture PET drugs, including the prevention of contamination. Your response is inadequate because you did not include a sufficient plan for ensuring that your facility is robustly designed and maintained. Furthermore, you did not explain what additional steps you would take to prevent contamination while you continue manufacturing during remediations. Your response also failed to sufficiently address your ISO 5 decontamination program to improve its robustness such as assessing the potential for increasing disinfection frequency, ensuring more comprehensive application of disinfectants to all surfaces in critical environments and surrounding environments, and other steps that would ensure more effective disinfection.
回复中，企业表示工程部对每一次渗水进行了响应性紧急补救，设施于2020年11月恢复到可控状态。然而，企业停止了任何进一步的整改措施，以支持将于2022年2月完成的“全面”修复项目。企业的回复还表明，将继续生产PET药品，同时修复企业的设施。没有讨论企业计划主动评估设施和技术夹层是否足以生产PET药品，包括防止污染。企业的回复是不充分的，因为没有提供充分的计划来确保设施得到可靠的设计和维护。此外，没有说明在整改期间继续生产时，企业将采取哪些额外的措施来防止污染。企业的回复也未能充分说明ISO 5防止污染计划，以提高其可靠性，例如评估增加消毒频率的潜力，确保在关键环境和周围环境中更全面地将消毒剂应用于所有表面，以及其他确保更有效消毒的措施。
Your response also acknowledged the need to investigate each quality related event. As a correction, you revised your Quality Management Systems SOP to reinforce investigation and reporting of all quality related events as required by your Environmental Control SOP and your Interpretation/Investigation of Positive Media Results SOP. Your response is inadequate because you did not describe why you failed to follow your established procedures nor indicate how you intend to assure that your written procedures will be consistently followed in the future.
企业的回复也承认有必要调查每一个与质量相关的事件。作为更正，企业修订了质量管理体系SOP，按照企业的环境控制SOP和阳性培养基结果解释/调查SOP的要求，加强对所有质量相关事件的调查和报告。企业的回复是不充分的，因为没有描述为什么企业没有遵循既定程序，也没有说明未来如何确保始终遵守书面程序。
PET drug products have short expiry periods. Consequently, PET drug products are released and administered before the results of batch specific sterility testing and EM are known. Your ongoing EM program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.
PET药品的有效期很短。因此，PET药品在批次特定无菌检测和EM结果已知之前就已经放行和使用。企业正在进行的EM程序对于及时检测和应对生产环境中潜在的产品污染危害至关重要。在无菌生产设施中失去环境控制最终会对患者造成严重危害。
In response to this letter, provide the following:
针对本函，请提供以下内容：
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:
对企业的无菌工艺、设备和设施的所有污染危害进行全面的风险评估，包括但不限于:
o All human interactions within ISO 5 areas
O人员与ISO 5区域的所有互动
o Equipment placement and ergonomics
o设备安置和人体工程学
o Air quality in ISO 5 areas and the surrounding areas
o ISO 5区域及其辅助区域的空气质量
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）
o Facility management systems and environmental controls (e.g., temperature, humidity, air handling, interactions of areas of differing classifications)
o设施管理系统和环境控制(例如温度、湿度、空气处理、不同分类区域的相互作用)
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, control, and maintenance.
一份详细的整改计划及时间表，以解决污染危害源独立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
Your plans and results evaluating whether an adequate state of control was maintained for PET drug production during your facility remediation activities.
企业的整改计划和结果评估期间是否对PET药品生产保持了适当的控制状态。
A list of all environmental monitoring results outside alert and action limits for ISO 5 and ISO 7 areas since November 2020.
自2020年11月以来ISO 5和ISO 7区域所有超出警报和行动限制的环境监测结果清单。
Your 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, timely upgrades to equipment and facilities, adherence to appropriate preventive maintenance schedules, effective execution of repairs, and improved systems for ongoing management review.
企业的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，及时升级设备和设施，遵守适当的预防性维护时间表，有效地执行维修，并改进持续管理审查的系统。
Your procedures for conducting routine facility walkthroughs, at appropriate frequencies, to assess the state of repair of your facility in order to mitigate contamination hazards.
制定适当的维护设施的程序，以评估设施的维修状态，以减少污染危害。
Evaluation whether cleaning and disinfecting methods (e.g., agents, procedures, frequency) used in all classified areas are effective.
评估在所有分类区域使用的清洁和消毒方法(如药剂、程序、频率)是否有效。
Your facility qualifications, media fills, and most recent static and dynamic smoke studies performed for both the biological safety cabinet and laminar flow hood during and since completion of the facility remediation.
企业的设施资质，介质灌装，以及在设施修复完成期间和之后对生物安全柜和层流罩进行的最新静态和动态烟雾研究。
Complete investigations into all batches with potential microbial contamination. The investigations should detail your findings regarding the root causes of the contamination.
完成所有潜在微生物污染批次的调查。调查应该详细说明污染的根本原因。
Appropriate microbiological raw material, in-process, and batch release specifications (i.e., sterility, endotoxin, total counts, appropriate identification of in-process bioburden flora) for each of your drug products.
为每种药物产品制定适当的微生物原料、中间产品和批次放行规范（即无菌、内毒素、总计数、中间产品生物负荷菌群的适当标识）。
Your plan to ensure your staff will adhere to your established procedures.
确保员工遵守既定程序的计划。
2. Your firm failed to conduct adequate investigations and take appropriate corrective action when a failure of a production batch or any component of the batch failed to meet any of its specifications. (21 CFR 212.20(d)).
2. 当生产批次或该批次的任何原辅料不符合其任何质量标准时，贵公司未能进行充分的调查并采取适当的纠正措施。(21 CFR 212.20 (d))。
You failed to conduct adequate investigations into multiple out-of-specification (OOS) endotoxin results, including implementing appropriate and effective CAPAs.
未能对多个OOS内毒素结果进行充分调查，包括实施适当和有效的CAPA。
For example, analysis of drug product [13N]-Ammonia for Injection, batch 13NNH3210511-A revealed an OOS result for endotoxins, and the batch was released without an adequate investigation. An initial OOS test result was invalidated due to a system suitability failure. A second analysis, which met system suitability criteria, obtained an OOS result of 30.7 EU/mL (exceeding your (b)(4) EU/mL specification). You resampled from the final product vial and conducted another test, which met the specification. You repeated the analysis, which also yielded a passing result. You released the batch and subsequent sub-batches based on the passing results.
例如，对批号13NNH3210511-A的药品[13N]-注射用氨进行分析后，发现内毒素OOS结果，该批次未经充分调查就放行。由于系统性失败，初始OOS测试结果无效。第二次分析符合系统适用性标准，得到30.7 EU/mL的OOS结果(超过企业的xx EU/mL标准)。企业从最终产品瓶重新取样，并进行了另一项符合标准的测试。进行重复分析，也得到了一个合格的结果。企业根据合格的结果放行了该批以及后续的批次。
You invalidated the OOS result without conducting an adequate investigation for potential sources of contamination, and concluded that “concerns with (b)(4) were confirmed using a new bottle of (b)(4)”. Your investigation failed to include testing of the initial reagent bottle of (b)(4) to support your assumed cause of the OOS. Your investigation also did not clearly identify errors by the laboratory in the handling of the (b)(4) as the cause of the OOS. Your investigation also identified neither corrective nor preventive actions. Despite a failure to clearly establish a laboratory cause, you did not extend your investigation into potential manufacturing causes. The investigation failed to evaluate the potential sources of endotoxin contamination from the upstream process including contamination from manufacturing equipment, raw materials, processing conditions, or the working environment.
企业在没有对潜在污染源进行充分调查的情况下宣布OOS结果无效，并得出结论:“使用新xx瓶确认了xx的问题”。企业的调查没有包括xx初始试剂瓶的测试，以支持企业假设的OOS原因。企业的调查也没有明确地指出实验室在处理xx时的错误是OOS的原因。企业的调查也没有发现纠正和预防措施。尽管未能清楚地确定实验室原因，企业没有将调查扩展到潜在的生产原因。调查未能评估来自上游工艺的潜在内毒素污染源，包括来自制造设备、原材料、加工条件或工作环境的污染。
In your response, you revised your Quality Management System SOP to include concepts from FDA’s Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production and standardized your reporting format. However, your response is inadequate because you did not provide a retrospective evaluation of OOS endotoxin testing results. It is also unclear whether you revised your Pyrogen Testing SOP to reflect revisions to your Quality Management System SOP, as your Pyrogen Testing SOP still allows the testing of OOS endotoxin results until (b)(4) passing results are obtained without limiting the number of retests that can be conducted.
回复中，企业修订了质量管理体系SOP，纳入了FDA《行业指南》、《药品生产OOS检测结果调查》中的概念，并把报告格式进行标准化。然而，企业的回复是不充分的，因为没有提供OOS内毒素检测结果的回顾性评估。也不清楚企业是否修改了热原检测SOP以反映对质量管理体系SOP的修订，因为企业的热原检测SOP仍然允许OOS内毒素结果的检测，直到获得xx合格结果，而不限制可进行的复检次数。
For more information about pyrogen and endotoxin testing, see FDA’s Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers https://www.fda.gov/media/83477/download.
有关热原和内毒素检测的更多信息，请参阅FDA的行业热原和内毒素检测指南:问答https://www.fda.gov/media/83477/download。
In response to this letter, provide the following:
针对本函，请提供：
A retrospective review of all invalidated OOS (including in-process and release/stability testing) results for PET drug products and a report summarizing the findings of the analysis, including the following for each OOS:
对PET药品所有无效OOS(包括生产和放行/稳定性测试)结果的回顾性审核，以及汇总分析结果的报告，每个OOS包括以下内容:
o Determine whether the scientific justification and evidence related 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 rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o对于最终确定实验室根本原因的调查，应提供理由并确保发现易受相同或类似根本原因影响的所有其他实验室方法进行整改。
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，提供一份对生产的彻底审查(例如，批生产记录、生产步骤的充分性、设备/设施的适用性、原材料的变异性、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 review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:
一份对企业OOS结果调查系统的综合审查和整改计划。CAPA应包括但不限于以下内容:
o Quality unit oversight of laboratory investigations
o质量部门对实验室调查的监督
o Identification of adverse laboratory control trends
o识别实验室控制的不利趋势
o Resolution of causes of laboratory variation
o解决实验室差错的原因
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o当无法最终确定实验室原因时，启动对潜在生产原因的彻底调查
o Adequately scoping of each investigation and its CAPA
o充分确定每个调查的范围及其CAPA
o Revised OOS investigation procedures with these and other remediations
o修订后的OOS调查规程，包括这些及其它整改措施
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, at https://www.fda.gov/media/71026/download.
请参阅FDA的指导文件，PET药品-当前良好生产规范，以帮助企业在生产PET药品时满足CGMP要求，请访问https://www.fda.gov/media/71013/download。该指导文件还参考了FDA的指导文件《无菌工艺生产的无菌药品-现行良好生产规范》，以了解可能适用于PET药品生产的其他概念和期望，请访问https://www.fda.gov/media/71026/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 to evaluate your operations 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，我们强烈建议聘请一名有资质的顾问来评估企业的操作，以协助贵公司满足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 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.
在这封信中引用的违规行为并非与企业的产品相关的工厂违规行为的所有清单。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履行企业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的产品的患者的健康。
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.
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什么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，FDA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。
If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.
如果企业认为产品没有违反FD&C法案(或遵守了FDA法规)，请提供理由和任何支持信息，以供FDA考虑。
Send your electronic reply to ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter # 623476 and include FEI: 3012030543.
If you have questions regarding the content of this letter, please contact CDR Liatte Closs, Compliance Officer, at liatte.closs@fda.hhs.gov.
Sincerely,
/S/
Craig Swanson
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations Division I
New Jersey District
CC: Peter Holton, Director of Operations BICOR
Brigham and Women’s Hospital Inc.
75 Francis Street
Boston, MA 02115
Email: pholton@partners.org
