10月27日，FDA公布一封针对美国本土企业的警告信。主要的违规项包括未执行清洁验证和不遵守批记录问题，FDA认为反复出现的失效表明，管理层对药品生产的监督和控制不足。
值得注意的是，在此检查期间，为了确定数据真实性，FDA检查员在多个日志之间进行比较，确定样品色谱分析时间比实验室收到样品的时间要早5个小时；同时检查员调查了厂房门禁读卡器的记录，最终确定日志中涉及的分析员当天根本不在公司。
Warning Letter CMS # 608236
October 8, 2020
Dear Mr. Tabasso:
警告信CMS＃608236
2020年10月8日
亲爱的塔巴索先生：
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, KVK-Tech, Inc., FEI 301367632, at 100 Campus Drive, Newtown, Pennsylvania, from February 4 to March 13, 2020.
2020年2月4日至3月13日，美国食品药品监督管理局(FDA)检查了你处的药品生产设施，KVK-Tech,Inc.，FEI 301367632位于宾夕法尼亚州纽敦。
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 210 and 211).
该警告信总结了严重违反制剂CGMP规定的情况。请参阅21CFR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).
由于你用于生产、加工、包装或储存的方法、设施或控制措施不符合CGMP，因此根据FD＆C法案501(a)(2)(B)条及21 U.S.C.351(a)(2)(B) 条的规定，你药品被认为是掺假。
We reviewed your April 4, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了你们2020年4月4日对FDA 483表格的答复，并确认收到你们的后续信件。
During our inspection, our investigator observed specific violations including, but not limited to, the following.
在我们的检查过程中，调查员发现了具体的违规行为，包括但不限于以下行为。
清洁验证
1. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
1.你公司未建立并遵循适当的书面程序，来清洁和维护设备(21 CFR 211.67(b))。
You performed packaging operations for approximately (b)(4) solid oral dosage form drug products at this facility. You did not validate the processes used to clean your non-dedicated packaging equipment such as your slat counter prior to use, as required by your cleaning validation standard operating procedure SOP-0030.
在此工厂，采样对大约XX中固体口服制剂进行了包装操作。你们没有按照清洁验证标准操作程序SOP-0030的要求，在使用之前，验证用于清洁非专用包装设备(如板条数粒机)的工艺。
Inadequate removal of residues from product contact surfaces of non-dedicated manufacturing (e.g., packaging) equipment can lead to cross-contamination of drug products subsequently manufactured on that equipment.
对于非专用生产(例如包装)设备产品接触表面，不充分去除残留，可能导致随后在该设备上生产的药品产生交叉污染。
Your response stated that you did not perform cleaning validation on the slat counter because you believed the slat counter was constructed of materials similar to the (b)(4) tablet counters used at your second facility in Newtown, Pennsylvania.
你们的回答表明，你们未对板条数粒机执行清洁验证，因为你们认为板条数粒机的材料类似于宾夕法尼亚州纽敦的第二家工厂使用的XX片剂数粒机。
We acknowledge that you are now initiating cleaning validation of your slat counter, and tested swab samples for residues of (b)(4) of your drug products ((b)(4)). You also committed to performing cleaning validation for the remaining (b)(4) drug products. In addition, you stated that the cleaning validation procedure will be revised to specify that an assessment will be performed whenever modifications impacting equipment or cleaning procedures are made.
我们知晓你们现在开始对板条数粒机进行清洁验证，并测试了棉签样品中药品的残留。你们还承诺对其余XX药品进行清洁验证。此外，你们还说过将对清洁验证程序进行修订，以指定每当进行影响设备或清洁程序的修改时，都需要进行评估。
Your response is inadequate. Both the design and most difficult to clean surfaces of your (b)(4) tablet counter significantly differ from your slat counter. You did not establish the worst-case scenario for cross-contamination in your new cleaning validation studies because you lacked swab sites within the slat cavities, which can be one of the most difficult-to-clean locations and a potential site of carryover. Furthermore, your response failed to explain why you did not document your rationale to deviate from your cleaning validation SOP or specify how you would improve your overall change management system to prevent recurrence.
你们的答复不充分。XX片剂数粒机的设计和最难清洁的表面都与板条数粒机明显不同。在新的清洁验证研究中，你们没有为交叉污染建立最坏的情况，因为你们在板条腔内没有进行棉签取样，因为该位置可能是最难清洁的位点之一，有潜在残留的可能性。此外，你们的答复无法解释：对于偏离清洁验证SOP，为什么你们没有记录相应的理由；或说明如何改进总体变更管理系统，以防止再次发生。
In your response to this letter, provide the following:
针对此信，请提供：
· Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
对清洁验证程序进行了适当的改进，特别着重于纳入在药品生产工艺中确定为最差情况的条件。最差情况的识别和评估，应包括但不限于：
· Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst-case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in the cleaning solvents specified in your procedures
o drugs with characteristics that make them difficult to clean, (e.g., uncoated tablets)
o swabbing locations for areas most difficult to clean, including but not limited to slat cavities
o maximum hold times before cleaning
o具有较高毒性的
o产品具有较高活性的
o在你们程序指定的清洁溶剂中溶解度较低的药物
o具有难以清洁特性的的药物(例如未包衣的药片)
o擦拭最难清洁区域的位置，包括但不限于板条腔
o清洁前的最长放置时间
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
另外，描述在引入新的生产设备或新产品之前，变更管理系统必须采取的步骤。
· A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.
更新的SOP的摘要，以确保制定适当的程序，来验证和确认产品、工艺和设备的清洁程序。
批记录
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced. (21 CFR 211.188)
2.你们的公司未能准备批生产和控制记录，以提供与每批生产的药品的生产和控制有关的完整信息。(21 CFR 211.188)
During packaging of one lot of hydroxyzine HCl tablets, USP 50 mg, our investigator observed that the air pressure gauge reading was outside the acceptable range for your capper, although a conforming value was recorded in the batch record. In addition, our investigator observed readings on other gauges that were lower than your validated parameters.
在包装一批盐酸羟嗪USP 50 mg的过程中，尽管批记录中记录了合格值，但我们的调查员观察到压力值超出了封盖钳可接受的范围。此外，我们的调查员观察到：其它仪表的读数低于你们验证的参数。
Our investigator also noted that in the batch record for promethazine HCl tablets, USP 25 mg, your employees failed to record actual readings for the air pressure for several pieces of packaging equipment, including your slat counter, capper, and (b)(4).
我们的调查员还注意到，在盐酸异丙嗪片USP 25 mg的批记录中，你们的员工未能记录几套包装设备的实际压力读数，包括你们的板条数粒机，封盖机和XX。
In your response, you explained that during the packaging of the hydroxyzine HCl tablets your mechanic observed that the caps were not feeding into the capper properly, and he adjusted the air pressure of the capper machine below qualified limits. However, the deviation was not documented. You also stated that you found that some equipment gauges were malfunctioning and replaced them. In addition, you retrained your personnel to document the actual values in batch records.
在你们的答复中，你们解释说，在包装盐酸羟嗪片剂时，你们的机械师观察到瓶盖未正确送入封盖机，因此他将封盖机的压力调节到合格限度以下。但是，没有记录偏差。你们还指出，你们发现某些仪器的压力表出现故障，并进行了更换。此外，你们还对人员进行了再培训，以在批处理记录中记录实际值。
Your response is inadequate because you did not conduct a comprehensive review to determine the scope and impact of inaccurate data recording in production records, and did not provide a plan for improving management oversight of operations.
你们的答复是不充分的，因为你们没有进行全面的审查，来确定生产记录中不正确的数据记录的范围和影响，并且没有提供改善运营管理监督的计划。
In your response to this letter, provide the following:
针对此信，请提供：
· A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
·对整个生产和实验室运营中使用的文档系统进行全面评估，以确定哪些地方文档实践不充分。包括详细的纠正和预防措施(CAPA)计划，以全面补救公司的文件编制惯例，以确保你们在整个运营过程中保留可归因的、清晰的、完整的、原始的、准确的和同步的记录。
· 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/facility 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.
·你们的CAPA计划：对设施和设备实施例行的、警惕的运营管理监督。该计划应确保除其它事项外，迅速发现设备/设施性能问题，有效执行维修，遵守适当的预防性维护计划，及时对设备/设施基础设施进行技术升级，以及改进系统以进行持续的管理审查。
Your plan should also ensure that appropriate actions are taken throughout the company network.
你们的计划还应确保在整个公司网络中采取适当的措施。
· 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 quality unit. 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你们的程序，以确保质量部门对变更进行合理的审核和批准。你们的变更管理计划还应包括：确定变更有效性的规定。
其它观察
Other Observations
During this inspection, we found that the cleaning validation sample for oxybutynin chloride tablets, USP 5 mg lot 15749, was documented in the incoming sample logbook as received on September 24, 2019, at 10:50 PM. The chromatographic analysis for this sample was completed at approximately 5:50 PM on September 24, about five hours before the sample was received, according to your logbook.
在此检查期间，我们发现，在2019年9月24日晚上10:50样品接受日志中，记录了奥昔布宁氯化物片剂的清洁验证样品(USP 5 mg批次15749)。根据你们的日志，此样品的色谱分析于9月24日下午5:50左右完成，大约在收到样品前五个小时。
A review of the building access card reader record showed that the analyst who logged in the sample was not in the building at approximately 10:50 PM that day. Your analyst gave conflicting accounts for this discrepancy but eventually admitted to putting incorrect information in the logbook.
对厂房门禁读卡器记录的检查显示，登记样品的分析员在当天晚上10:50不在厂房中。你们的分析员针对此差异给出了相互矛盾的说明，但最终承认在日志中输入了错误的信息。
在多个工厂重复违规
Repeat Violations at Multiple Sites
FDA cited similar CGMP violations at other facilities in your company’s network. Your 110 Terry Drive site received an FDA warning letter dated February 11, 2020. These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.
对于你们公司网络中其它设施，FDA曾指出了有类似CGMP违规行为。你们的110 Terry Drive工厂页收到过FDA的警告信，日期为2020年2月11日。这些在多个工厂上反复出现的失效表明，管理层对药品生产的监督和控制不足。
Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.
你们的执行管理层有责任完全解决所有缺陷，并确保CGMP持续合规。你们应该立即全面评估公司的全球生产运营，以确保系统、工艺和生产的产品符合FDA要求。
CGMP顾问推荐
CGMP Consultant Recommended
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 if your firm intends to resume manufacturing drugs for the U.S. market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.
根据我们发现的违规行为的性质，我们强烈建议聘请符合21 CFR 211.34规定的合格顾问，来协助你们公司满足CGMP要求，前提是你们的公司打算恢复为美国市场生产药品。我们还建议合格的顾问对你们的整个运营过程进行全面审核，以确保其符合CGMP要求，并建议顾问在你们寻求公司与FDA的合规性解决方案之前，对你们的纠正和预防措施的完成情况和有效性进行评估。
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.
你聘用顾问并不能免除公司遵守CGMP的义务。你公司的执行管理层仍然负责解决所有缺陷和系统性缺陷，以确保持续符合CGMP。
暂停药品生产
Drug Production Suspended
We acknowledge your commitment to suspend manufacture of drugs at the (b)(4) facility. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility in the future. If you plan to resume manufacturing drugs, notify this office before resuming your operations.
我们知晓你们承诺在XX工厂暂停药品生产。针对此信，请澄清你们将来是否打算在该工厂恢复生产任何药物。如果你们打算恢复生产药品，请在恢复操作之前通知FDA办公室。
结论
Conclusion
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.
本信函中引用的违规行为并非旨在列出与你产品相关的所有违规行为。你有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。
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.
如果你们正在考虑可能会导致你们的工厂生产的药物供应中断的行动，则FDA要求你们立即联系CDER的药物短缺人员(drugshortages@fda.hhs.gov)，以便FDA可以与你们以最有效的方式使你们的运营符合法律规定。与药品短缺人员联系还可以使你们履行报告21 USC 356C(b)规定的药品生产中断或暂停的义务。这也使FDA可以尽快考虑可能需要采取什么措施，以避免短缺和保护依赖你们产品的患者的健康。
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.
及时纠正此信中引用的违规行为。不及时纠正这些违法行为，可能会导致采取法律行动(恕不另行通知)，包括但不限于：扣押和强制令。此警告信中未解决的违反行为也可能阻止其它联邦机构给予合同。
FDA还可能拒绝批准出口证书申请，对于新药申请或补充申请，也不会批准将你工厂列为供应商或生产商，直到上述违法行为得到纠正。我们可能会重新检查，以确认你已完成纠正措施。
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.
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.
收到这封信后，请在15个工作日内以书面形式答复FDA办公室。说明自我们检查以来，你所做的事情，以纠正你违规行为，并防止其再次发生。如果你无法在15个工作日内完成纠正措施，请说明延误原因和完成时间表。
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.
如果你认为你产品未违反FD＆C法案(或你已遵守FDA法规)，请提供你理由和任何支持信息，以供我们考虑。
参考:
FDA Warning Letters, PT. KVK-Tech, Inc., MARCS-CMS 608236. OCTOBER 08, 2020. US Food and Drug Administration (FDA). www.fda.gov.
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