翻译：JULIA 来源：Julia法规翻译
Warning Letter 320-18-72 August 27, 2018
Mr. Shenglin Gao
General Manager, Longood Medicine (Beijing) Co., Ltd.
No. 13, Yunteng Road, Miyun Economic Development Area, Beijing 101500,China
Dear Mr. Gao:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Longood Medicine (Beijing) Co., Ltd. at No. 13, Yunteng Road, Beijing, from September 25 to 29, 2017.
美国FDA于2017年9月25-29日检查了你们位于中国北京市密云县经济技术开发区云腾路13号的蓝戈医药用品（北京）有限公司生产场所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了制剂生产严重违反CGMP的行为。参见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), 21U.S.C. 351(a)(2)(B).
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的制剂根据FDCA的501(a)(2)(B)以及21U.S.C. 351(a)(2)(B)被认为是掺假药品。
Your firm also manufactures unapproved new drug products in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a).
你公司亦生产了未经批准的新药，违反了FDAC第505(a)部分21 U.S.C. 355(a)。
We reviewed your October 13, 2017,r esponse in detail and acknowledge receipt of subsequent correspondence.
我们详细审核了你们于2017年10月13日发来的回复并且告知已收悉后续通信。
During our inspection, our investigator observed specific violations 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：
CGMP Violations CGMP违规
1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, including drug products manufactured, processed, packed or heldunder contract by another company. Your firm failed to establish a quality unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).
你公司未能建立足够的质量部门，使其具备批准或拒收所有组份、制剂容器密闭器、中间体、包材、标签和制剂成品，包括委托给另一公司生产、加工、包装或保存的药品的职责和权力。你公司未能建立质量部门，使其具备权力审核生产记录以确保不会有错误发生，或者在发生错误时会经会全面调查（21 CFR 211.22(a)）。
Contractor Oversight 合同生产商监管
You failed to ensure that your third-party contractor uses a validated terminal sterilization process, consistent with the requirements of 21 CFR 211.113(b), to sterilize your drug product, Chlora-Cleanze Proprep applicators, purported as sterile and labeled for “use prior to surgery.”
你未能确保你们的第三方生产商使用经过验证的终端灭菌工艺对你们产品Chlora-Cleanze Proprep涂装器进行灭菌，使其符合21 CFR 211.113(b)要求。该产品理应为无菌，并标示为“外科手术前使用”。
You released Chlora-Cleanze Proprep applicators without assurance of their sterility. For example, you were unable to provide adequate records demonstrating that your contractor terminally sterilized Chlora-Cleanze Proprep applicators lot 20170601, distributed to the United States. You also failed to provide evidence that your quality unit reviewed all appropriate records prior to releasing the lot.
你们放行了Chlora-Cleanze Proprep涂装器却未确保其无菌性。例如，你们未能提交足够的记录证明你们合同生产商对销往美国的Chlora-Cleanze Proprep涂装器批号20170601进行了最终灭菌。你们亦未提交证据证明你们质量部门在放行该批次之前审核了所有适当的记录。
In your response, you acknowledged that your terminal sterilization contractor provided incomplete records for Chlora-Cleanze Proprep applicators (lot 20170601). Your response is inadequate.You failed to describe how your firm determined the lot was acceptable for release without complete documentation from your contractor. In addition, you failed to provide evidence from your contractor demonstrating this lot was terminally sterilized.
在你们的回复中，你们说你们的最终灭菌合同生产商提供了Chlora-Cleanze Proprep涂装器（批号20170601）不完整记录。你们的回复是不充分的。你们未能说明你们公司是如何确定在没拿到合同商完整记录时该批次可以放行的。此外，你们未能提供从你们合同商处获得的证据来证明该批准经过了终端灭菌。
Your response also provided terminal sterilization validation documentation for a different (b)(4) product ((b)(4)) to support the sterilization of Chlora-Cleanze Proprep applicators. Your response is inadequate in that it lacks sufficient validation data to support sterilization efficacy. You did not provide scientific rationale demonstrating validation studies for the (b)(4) sterilization process are representative of the sterilization process for Chlora-Cleanze Proprep applicators. (b)(4) drug product has a different formulation, includinga different active ingredient. You failed to address whether you will validatethe terminal sterilization process for the Chlora-Cleanze Proprep applicators.
你们的回复还提交了不同XX产品XX的最终灭菌验证文件用以支持Chlora-Cleanze Proprep涂装器的灭菌。你们的回复是不充分的，它缺乏足够的验证数据支持灭菌有效性。你们未提交科学合理论证证明XX灭菌工艺的验证研究可代表Chlora-Cleanze Proprep涂装器的灭菌工艺。XX药品有着不同的配方，包括不同的活性成分。你们未能说明你们是否要验证Chlora-Cleanze Proprep涂装器的终端灭菌工艺。
In your response to this letter, provide:在回复此函时请提交：
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Your qualification procedures for assessing the suitability and competence of potential contractors before outsourcing, and for ongoing monitoring and review of the performance of the contract facility to identifying and implement any needed improvements;
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你们在外包之前评估潜在合同商适用性和资质，以及持续监测和审核合同场所表现以发现和执行任何所需的改进的确认程序；
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A detailed plan for ensuring that the process your contractor uses to terminally sterilize all products, including Chlora-Cleanze Proprep applicators, is adequately validated;
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确保你们合同商用于对所有产品，包括Chlora-Cleanze Proprep涂装器进行终端灭菌的工艺经过充分验证的详细计划；
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Complete sterilization records from your contractor for Chlora-Cleanze Proprep applicators, lot 20170601. If you do not have sufficient evidence that the lot in question or any lot intended for the U.S. market was adequately sterilized, indicate the corrective actions you will take, such as customer notifications and product recalls.
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从你们合同商处获得的20170601 批号Chlora-Cleanze Proprep涂装器完整灭菌记录。如果你们没有足够的证据证明该批次或其它准备销往美国市场批次有充分灭菌的证据，则请说明你们将采取的纠正措施，如通知客户和召回产品。
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A corrective action and preventive action (CAPA) plan to fully remediate your review and release procedures for finished drug products. Your procedures should require that third-party contractors provide sufficient production and control records to demonstrate compliance with established, approved written procedures and specifications before a lot is released or distributed by your quality unit.
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一份全面弥补你们成品审核和放行程序的CAPA计划。你们的程序应要求第三方合同商提交足够的生产和检测记录，以证明一个批次在质量部门放行或允许销售之前符合既定的、经过批准的书面程序和质量标准。
Uncontrolled Documents 不受控文件
Our investigators found numerous uncontrolled and unofficial production and laboratory records associated with Chlora-Cleanze Proprep applicators (lot 20170601) during the inspection. These include duplicate records which contain incomplete fields and strike-throughs.
我们的调查人员在检查期间发现大量与Chlora-Cleanze Proprep涂装器有关的不受控的非正式生产和化验室文件，其中包括有填写不完整和删除的重复记录。
In your response, you state that you will examine your document control procedures and provide training to management. Your response is inadequate. Training should include all employees involved in the manufacturing process. Additionally, you failed to indicate whether the uncontrolled and unofficial production and laboratory records for lot 20170601 were reviewed prior to release of the lot. Further, you did not perform a full retrospective review to determine the extent of the production and laboratory record deficiencies, and commit to a CAPA plan to comprehensively identify and address root causes.
在你们的回复中，你们声称你们将检查你们的文件控制程序，并为管理人员进行培训。你们的回复是不充分的。培训应包括生产工艺涉及的所有员工。另外，你们未能说明在放20170601批之前你们是否对该批准未受控和非正式的生产和化验室记录进行了审核。还有，你们亦未进行全面的回顾性审核以确定生产和化验室记录缺失的程度，并承诺制订CAPA计划来全面识别和解决根本原因。
In your response to this letter, provide:在回复此函时，请提交：
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A comprehensive, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are deficient. Include a detailed CAPA plan that systemically remediates deficient documentation practices, and ensures you retain complete and accurate records.
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对你们生产和化验室操作所用文件体系的全面独立评估，以确定哪些文件做法有缺陷。包括一份详细的CAPA计划，系统性地弥补有缺陷的文件做法，并确保你们保存了完整准确的记录。
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A comprehensive CAPA for your training program to ensure all staff at your facility are fully trained in CGMP. Provide a fully remediated training program for your entire operation. Place special emphasis on assuring that all staff involved in any CGMP function are trained and competent in acceptable recordkeeping practices, such as retaining all records, completing records contemporaneously, documenting any error in records, and ensuring that all procedures are approved by quality unit.
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一份对你们培训程序的全面CAPA，确保你们工厂的所有员工进行全面CGMP培训。提交一份经过全面弥补的整体运营培训程序，特别要强调确保所有涉及CGMP职责的员工均经过培训，并有资质执行可接受的记录保存规范，如保存所有记录、同步完成记录、记下记录中的所有错误，以及确保所有程序均经过质量部门批准。
2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)). 你公司未能建立足够的书面生产和工艺控制程序，用以确保你们生产的药品具备其应有的鉴别、剂量、质量和纯度（21 CFR 211.100(a)）。
Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for your Chlora-Cleanze Proprep applicators. You told our investigator that you had validated your process for manufacturing another drug product, and that the process was similar to your Chlora-Cleanze Proprep manufacturing process. You did not provide validation of the Chlora-Cleanze Proprep manufacturing process.
你公司没有足够的持续计划用以监测工艺控制，从而确保你们的Chlora-Cleanze Proprep涂装器具备稳定的生产操作和持续的药品质量。你们告诉我们的调查人员你们已经验证了你们生产另一药品的工艺，该工艺类似于你们的Chlora-Cleanze Proprep生产工艺。你们并未提供你们Chlora-Cleanze Proprep生产工艺的验证。
Your response states that you conduct in-process testing of batches (b)(4) to filling operations. You also state that you will conduct stability testing on Chlora-Cleanze Proprep applicators. Your response is inadequate. In the absence of process validation, testing alone is insufficient to determine whether your processes are of sound design and operating in a state of control throughout a product’s lifecycle.
你们的回复声称你们对灌装操作批次进行了中控检测。你们声称将对Chlora-Cleanze Proprep涂装器进行稳定性检测。你们的回复是不充分的。没有工艺验证，仅是检测并不足以确定你们的工艺是否设计合理并在其产品生命周期中在受控状态操作。
In response to this letter, detail your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for your Chlora-Cleanze Proprep applicator manufacturing process, and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control for all of your products. Also include your PPQ protocol.
在回复此函时，请提交你们详细的验证计划，以确保产品整个生命周期的受控状态，包括有执行你们的Chlora-Cleanze Proprep涂装器产品生产工艺的适当的工艺性能确认（PPQ）的时间表，并描述你们警惕监测批间波动的程序以确保你们所有产品的持续受控状态。另外还应包括你们的PPQ方案。
When significant variability is observed in one or more stages of pharmaceutical production, it is essential that executive management support and implement effective actions to address the source(s) of the variation and provide for a continued state of control. See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, athttps://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070336.pdf.
当在药品生产的一个或多个阶段发现严重波动时，高级管理人员有必要支持并实施有效措施来解决波动来源，并提供持续的受控状态。参见FDA指南。
CGMP Consultant Recommended CGMP顾问建议
Based upon the nature of the CGMP 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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and evaluate the completion and effectiveness of any corrective actions and preventive actions you have implemented. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
基于我们在你们公司所发现的CGMP违规情况，我们强烈建议你们聘请具备21CFR211.34所述资质的顾问，协助你们公司符合CGMP要求。我们还建议由该顾问对你们整体操作进行全面CGMP合规审计，并评估你们所实施的所有CAPA的完整性和有效性。你们使用顾问并不能解除你们公司符合CGMP的义务。你们公司的高级管理人员仍负有义务全面解决所有缺陷并确保持续CGMP符合性。
Unapproved New Drug Violations未经批准新药违规
As formulated and labeled, Biotronix Healthcare Chlora-Cleanze Proprep-I Applicators (Chlora-Cleanze Proprep) are unapproved new drugs. Examples of claims observed on your product label for Chlora-Cleanze Proprep that establish the intended uses of the product include, but may not be limited to, the following:
根据其配方和标示，Healthcare Chlora-Cleanze Proprep-IApplicators (Chlora-Cleanze Proprep)属未批准的新药。你们Chlora-Cleanze Proprep产品标签上的声明中说明其既定用途的内容包括但不仅限于以下：
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“Chlorhexidine gluconate 2% w/v…Antiseptic”
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葡萄糖酸氯己定2% w/v……消毒剂
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“Isopropyl Alcohol 70% w/v…Antiseptic”
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异丙醇70% w/v……消毒剂
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“Antiseptic Solution”
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消毒剂溶液
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“Use prior to surgery to prepare patient’s skin. Helps in the reduction of potentially harmful bacteria”
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外科手术前使用，用于患者皮肤消毒。帮助减少可能的有害菌。
Based on the above claims, Chlora-Cleanze Proprep is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, this product is intended as a patient pre-operative skin preparation.
基于上述声明，Chlora-Cleanze Proprep按FDCA第201(g)(1)(B)部分21U.S.C. 321(g)(1)(B)定义为“药品”，因为其用于诊断、治愈、缓解、治疗或预防疾病，和/或依FDCA第201(g)(1)(C)部分21U.S.C. 321(g)(1)(C)，因为其用于影响人体结构或功能。尤其是此产品用作患者手术前皮肤准备。
Drug products, such as Chlora-Cleanze Proprep intended for OTC use as preoperative skin preparations,are being evaluated as part of the OTC Drug Review. See the Tentative Final Monographs for First Aid Antiseptics, Healthcare and Consumer Antiseptics for Over-the-Counter Use, 43 FR 1210 (January 6, 1978) and amended at 56 FR 33644(July 22, 1991), 59 FR 31402 (June 17, 1994), 78 FR 76446 (December 17, 2013),80 FR 25166 (May 5, 2015) and 81 FR 42911 (June 29, 2016). Pending a finalrule, the agency does not intend to pursue regulatory action against products marketed in conformance with the conditions proposed in the tentative finalmonographs and each general condition in 21 CFR 330.1. Such marketing, however,is subject to the risk that a final rule may require reformulation and/or relabeling or FDA approval through the “new drug” procedures of the FD&CAct (section 505).
药品如Chlora-Cleanze Proprep用作OTC用途，用以术前皮肤准备，需经过OTC药品审核。参见43FR1210（1978年1月6日）OTC用途急救消毒剂、保健用消毒剂临时定稿各论，及其修正56 FR 33644（1991年7月2日）、59FR31402（1994年6月17日）、78FR76446（2013年12月17日）、80FR25166（2015年5月5日）和81FR42911（2016年6月29日）。由于该规定并未定稿，FDA无意对针对所销售的产品不符合21CFR330.1中规定的各条款和临时各论采取法规措施。但是此类销售可能需要遵守该规定中对重新配方和/或重新标签的要求，或通过FDCA的新药程序（505部分）获得FDA批准。
However, the formulation for Chlora-Cleanze Proprep is not consistent with the applicable tentative final monographs for pre-operative skin preparations. The active ingredient,chlorohexidine gluconate (CHG), is not covered under the OTC Drug Review for topical antimicrobial use in humans. See 59 FR 31402 at 31412-31413. Therefore, any topical antimicrobial product that contains CHG as an active ingredient requires an FDA-approved application for marketing. Based on our review, Chlora-Cleanze Proprep does not have such an approval.
但是，Chlora-Cleanze Proprep的配方与适用的术前皮肤准备的临时各论要求并不一致。活性成分葡萄糖酸氯己定（CHG）并不在人用局部抗微生物OTC药品审核的范围内。参见59 FR 31402 at 31412-31413。因此所有含CHG作为活性成分的局部抗微生物药品均需要FDA上市申报批准。根据我们的审核，Chlora-Cleanze Proprep并不具备此批准。
Thus, as formulated and labeled,Chlora-Cleanze Proprep does not conform with the tentative final monographs described above. This product is a new drug within the meaning of section201(p) of the FD&C Act, 21 U.S.C. 321(p). As a new drug, Chlora-CleanzeProprep may not be legally marketed in the United States absent approval of an application filed in accordance with section 505 of the FD&C Act, 21 U.S.C.355(a). Chlora-Cleanze Proprep is not the subject of an FDA-approved application, and therefore, the current marketing of this product violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
因此，Chlora-Cleanze Proprep按其配方和标签，并不符合上述临时各论。此产品归属FDCA第201(p)部分所规定的新药范畴。作为一种新药，如果未依据FDCA第505部分21 U.S.C. 355(a)要求提交申报并获得批准，Chlora-Cleanze Proprep可能无法在美国合法上市。21 U.S.C. 355(a)并不具备FDA药品批文，因此当前销售此产品违反了FDCA第505(a)部分21U.S.C. 355(a)。将此产品引入州际贸易是FDCA第301(d)部分21U.S.C. 331(d)所禁止的。
Conclusion 结论
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing the recurrence, and for preventing other violations.
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，防止其它偏差的发生。
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approvalof any new 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 violations may also result in FDA refusing admission of articles manufactured at Longood Medicine (Beijing) Co., Ltd., No. 13, Yunteng Road, Beijing, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same 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 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.
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。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
Mr. Rory Geyer
Compliance Officer
U. S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your response withFEI 3011090864.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation andResearch