近日，FDA发布了四川某生物科技有限公司的警告信，警告信所述缺陷透露着一个个“啪啪打脸”的故事：
在检查之前通话中，该公司向FDA声称有多月未生产肝素钠粗品了，只是在进行设备测试。
FDA在检查过程中，在仓库发现有个仓库员工拿着一只纤维纸板桶离开仓库，于是询问桶里装了什么。你公司说桶里装的XX袋。但是对桶进行检查时发现有2批在FDA检查之前几天刚刚生产的肝素粗品。
FDA随后要求查看这2批肝素粗品的生产和检测记录，该公司称没有这2批肝素粗品的记录。
在检查期间，FDA检查员在行政楼3楼的QA办公室的地板上、桌子上和柜子里发现大量记录。
一个员工说这些记录是制作来支持政府基金申报的，但记录中所写的肝素粗品批次并未实际生产过。
随后的检查中，该公司又说QA办公室的所有记录实际上是真实的肝素粗品批次的。
FDA通过该公司的肝素钠粗品库存和销售记录发现该公司在2019年6月1日至2019年7月30日期间生产不止2批肝素钠粗品，但只有2批肝素钠粗品的完整批记录。
在FDA检查之前，欧美也曾发布了该公司的GMP不符合报告，包含24条GMP缺陷，其中7条为主要缺陷。
主要缺陷包括：1、污染风险；2、厂房和设施；3、设备；4、起始物料储存；5、工艺；6、物料管理，起始物料的可追溯性；7、溶剂回收。
由于欧美GMP互认，警告信答复中“在‘官方批准’之前不会再向欧洲或美国市场销售产品”。
企业最重要的就是诚信，包括之前GMP认证，也有不少企业弄虚作假。现在我国已经取消GMP认证，这也就意味着企业即将面临更加严格的飞检。洁净仪器：辽宁尘埃粒子计数器、辽宁浮游菌采样器、辽宁SX-M洁净度实时在线监测系统等都是一个医药行业不可或缺的洁净室小帮手。
警告信原文及翻译
February 13, 2020
Warning Letter 320-20-24
Dear Mr. Tuo:
The U.S. Food and Drug Administration (FDA) conducted an inspection at Yibin Lihao Biotechnical Co., Ltd, FET 3008846564, at Number 5 Binjiang Road, Luolong Industrial Central Park. Yibin, Sichuan, from July 31 to August 6, 2019.
美国FDA于2019年7月31日至8月6日检查了你们位于中国四川宜宾市南溪区罗龙工业园区滨江西路5号的宜宾市利豪生物科技有限公司生产场所。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了原料药生产严重违反CGMP的行为。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).
由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被认为是掺假药品。
We reviewed your August 26, 2019, response to our Form FDA 483 in detail.
我们已详细审核了你公司2019年8月26日对FDA 483表格的回复。
During our inspection, our investigator observed specific deviations including. but not limited to, the following.
检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：
1. Failure to prepare and use production and control records for each intermediate and APT batch.
未制订和使用各中间体和APT批次的生产和检验报告。
Your site produces crude heparin for purification into finished API. During a pre-inspectional call on July 10, 2019, your firm stated to FDA that you had not manufactured any materials for months. At the start of the FDA inspection on July 31, 2019,
your firm stated to the investigator that you were not manufacturing crude heparin and were only performing equipment testing.
你们的工厂生产肝素粗品用于最终API的精制。在检查之前2019年7月10日的电话里，你公司向FDA声称你们有多月未进行生产了。在FDA于2019年7月31日检查开始时，你公司向检查员说你们没在生产肝素粗品，只是在进行设备测试。
During a walkthrough of your warehouse, the investigator observed a warehouse employee leaving the warehouse with a fiber drum and inquired about the contents of the drum. Your firm stated that the drum contained (b)(4) bags. However. inspection of the
drum revealed two batches of crude heparin manufactured just a few days before the FDA inspection (CU190726, (b)(4), manufacturing date July 26, 2019, and CU 190727, (b)(4), manufacturing date July 27, 2019). When asked about manufacturing and testing
records pertaining to these two crude heparin batches, your firm told us that you do not have records for the two crude heparin batches.
在仓库检查时，检查员发现有个仓库员工拿着一只纤维纸板桶离开仓库，于是询问桶里装了什么。你公司说桶里装的XX袋。但是对桶进行检查时发现有2批肝素粗品是FDA检查之前几天刚刚生产的（CU190726，XX，生产日期2019年7月26日，以及CU190727，XX，生产日期2019年7月27日）。在索取这2批肝素粗品的生产和检测记录时，你公司告诉我们你们没有这2批肝素粗品的记录。
In your response, you acknowledged the failure to provide timely and complete records for crude heparin batches CU190726 and CU190727 due to deficiencies in your record keeping practices. Additionally, your response indicated that your firm is providing
training to warehouse employees and your firm would not sell to European or U.S. markets before "official approval". However, you did not adequately address how you would remediate your documentation practices, nor did you assess the impact of poor
documentation practices for distributed drugs.
在你们的回复中，你们承认因你们记录保存规范的缺陷，所以未能及时提供肝素粗品CU190726和CU190727的完整记录。另外，你们的回复说你公司正在给仓库员工进行培训，你公司在“官方批准”之前不会再向欧洲或美国市场销售产品了。但是，你们并未充分说明你们要如何弥补你们的文件规范，你们亦未评估不良文件规范对已销售药品的影响。
In response to this letter, you should provide:
在回复本函时请提交以下内容：
• A complete reconciliation of all drugs, including crude heparin, distributed from your facility. Include in the reconciliation:
• 你们公司销售的所有药品的全部数量平衡，包括肝素粗品。包括以下数据：
Batch number
批号
Batch quantity
批数量
Name of drug
药品名称
Date of release
放行日期
Date of shipment
发货日期
Destination of shipment
发货目的地
Destination market
目的市场
• 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 (CAP
A) plan that comprehensively remediates your firm's documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• 对你们生产和实验室操作所用文件系统的全面评估，以确定有哪些做法是有缺陷的。要包括一份详细的CAPA计划，全面补救你们公司的文件规范，确保你们会保存你们整个操作可追溯、清晰的、完整的、原始的、准确的同步记录。
2. Failure to establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
未建立、记录和实施有效的质量管理系统，包括管理人员主动参与和适当的生产人员配置。
During the inspection, the investigator observed your firm did not adequately control critical documentation pertinent to the traceability of crude heparin manufactured at your facility. During the walkthrough on July 31, 2019, our investigator observed
numerous records on the floor, desks, and cabinets of the Quality Assurance (QA) Office on the third floor of the office building. Some of these records included batch production records for heparin.
在检查期间，检查员发现你公司并未充分控制你工厂所生产的肝素粗品追溯性有关的关键文件。在2019年7月31日检查现场时，我们检查员在行政楼3楼的QA办公室的地板上、桌子上和柜子里发现大量记录。其中一些记录是肝素批生产记录。
During the inspection, one of your employees stated that these records were generated to support an application for govern mentfunding, but the crude heparin batches specified in the records had not actually been manufactured. However, later during the
inspection, on August 2, 2019, your firm stated that all the records in the QA Office were in fact associated with genuine crude heparin batches.
在检查期间，你们一个员工说这些记录是制作来支持政府基金申报的，但记录中所写的肝素粗品批次并未实际生产过。后来在2019年8月2日的检查期间，你公司又说QA办公室的所有记录实际上是真实的肝素粗品批次的。
Additionally, even though your Crude Heparin Sodium Inventory and Distribution Record indicated your firm manufactured (b)(4) batches of crude heparin (CU190601 to CU190730) fromJune 1, 2019, to July 30, 2019, your firm was only able to provide complete
batch records for two batches, CU190728 and CU190730.
另外，虽然你们的肝素钠粗品库存和销售记录显示你公司在2019年6月1日至2019年7月30日期间生产了XX批次肝素粗品（CU190601至CU190730），但你公司只能提供2批（CU190728 和CU190730）的完整批记录。
Traceability of crude heparin is a critical part of managing quality. You must ensure that a complete contemporaneous record of each batch of drug manufactured is retained for CGMP purposes. Your system for managing quality is inadequate and calls into
question the traceability of all drugs, including crude heparin. manufactured at your facility.
肝素粗品的可追溯性是质量管理的一个关键部分。你们必须确保所生产的每批药品的完整同步记录均得到保存，以符合GMP要求。你们的质量管理体系是不充分的，导致在你工厂所生产的所有药品，包括肝素粗品有追溯问题。
For further reference regarding heparin. see the guidance for industry Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality available online at http://www.fda.gov/downloads/Drugs/GuidanceComplianccRegulatorylnformation/Guidances/UCM291390.pdf.
关于肝素的更多参考资料，参见行业指南“药品和医疗器械用肝素：监测肝素粗品的质量”。
Your response is inadequate because it does not holistically address systemic Quality Unit (QU) deficiencies.
你们的回复是不充分的，因为它并未全面解决QU的系统性缺陷。
In response to this letter, you should provide a comprehensive assessment and remediation plan to ensure your firm will establish, document, implement, and maintain a robust system for managing quaIity involving the active participation of management
and appropriate manufacturing personnel. The assessment should also include, but not be limitedto:
在回复本函时，你们应提交一份全面评估和补救计划，以确保你公司会制订、记录、实施和保存稳健的质量管理系统，包括管理人员主动参与和适当的生产人员配置。评估还应包括但不仅限于：
• A determination of whether procedures used by your firm are robust and appropriate.
• 确定你公司所用程序是否稳健和恰当
• Provisions for oversight throughout your operations to evaluate adherence to appropriate practices.
• 对你们整个操作进行监管以评估是否遵守恰当规范的条款
• A complete and final review of each batch and its related information before the QU disposition decision.
• 在QU批处理决策之前对每个批次及其信息的完整和最终审核
• Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, andpurity of all products.
• 监管和批准调查，履行所有其它QU职责以确保所有药品的鉴定、含量、质量和纯度
Data Integrity Remediation
数据完整性补救措施
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA's guidance document Data lntegrily and Compliance with Drug CGMP for guidance on
establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/97005/download.
你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。参见FDA指南文件“数据完整性和药品GMP合格”指导建立和遵守CGMP合格数据完整性规范。
We strongly recommend that you retain a qualified consultant to assist in your remediation.
我们强烈建议你们聘请一位具备资质的顾问协助你们进行补救。
In response to this letter, you should provide the following:
在回复此函时请提交以下信息：
• A comprehensive investigation into the extent of inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Describe the scope and root causes of your data integrity
lapses in detail.
• 一份对数据记录和报告不准确性程度的全面调查。在其中详细写明你们数据完整性问题的范围和根本原因。
• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data
integrity and analyses of the risks posed by ongoing operations.
• 你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。
• A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm,
including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
• 你们公司的管理策略，包括你们全球CAPA计划详细情况。详细的纠正计划应写明你们准备如何确保你公司生成的所有数据的可靠性和完整性，包括微生物和分析数据、生产记录和提交给FDA的所有数据。
Conclusion
结论
The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility/in connection with your products. You are responsible for investigating and determining the causes of these deviations and for preventing
their recurrence or the occurrence of other deviations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止你们设施内其它偏差的发生。
FDA placed your firm on Import Alert 66-40 and 55-03 on January 15, 2020.
FDA已于2020年1月15日将你公司置于进口禁令66-40和55-03中。
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。
Failure to correct these deviations may also result in the FDA continuing to refuse admission of articles manufactured at Yibin Lihao Bio-technical Co., Ltd at Number 5 Binjiang Road, Luolong Industrial Central Park, Yibin, Sichuan, into the United States
under section 801 (a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under this authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning
of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。
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 deviations 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.
在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。
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