据药智传媒记者获悉淮安纵横生物科技有限公司在1月9日收到了FDA的警告信，信中指出淮安纵横存在未能在出厂前对产品进行检测；未能检验以确认产品的每一种成分；未能建立并遵循稳定性测试确定有效期等问题。今日，FDA官网挂出了警告信全文。

FDA官网挂出的警告信具体内容如下：

Warning Letter 320-20-16

January 9, 2020

Dear Mr. Li:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Huaian Zongheng Bio-Tech Co., Ltd., FEI 3007628845, at No. 615 North Xiangyu Road, Huaian, from July 1 to 5, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

 美国食品药品监督管理局（FDA）于2019年7月1日至5日检查了淮安纵横生物科技有限公司。本警告函汇总了成品药CGMP法规的重大违规。详见美国联邦法规第21卷，第210和211章。

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).

因为你们的方法、设施、生产工艺、包装或者储存的方式不符合CGMP法规，你们的药品根据《联邦食品、药品和化妆品法》（FD&C）第501(a)(2)(B)章节，《美国法典》第21卷第351(a)(2)(B)节被认定为违规。

We reviewed your July 25, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 我们详细审查了你们于2019年7月25日对FDA 483文件的回复，并确认收到你们之后的回复。

During our inspection, our investigator observed specific violations including, but not limited to, the following.

在检查期间，我们的检查员发现的具体违规包括但不限于如下。

1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

淮安纵横未能在出厂前对每批药品的最终规格（包括每种活性成分的特性和强度）进行符合要求的实验室测定。

Your firm contract manufactures over-the-counter (OTC) (b)(4) drug products, including versions specifically marketed for children. You released your drug products without adequate testing, including identity and strength testing for each active ingredient. For example, you did not test drug products (b)(4) for their labeled active ingredient, (b)(4), prior to release.

淮安纵横生产的某种非处方药品，包括专门为儿童生产的版本。在没有充分每种活性成分的特性和强度测试的情况下销售了药物产品。

Complete testing of each batch before release is essential to determine if the drug products you manufacture meet appropriate specifications.

在出厂前对每一批药品进行完整的测试，对于确定生产的药品是否符合标准是很重要的。

In your response, you provided third-party testing results for assay of (b)(4) contained in (b)(4) drug product lot of (b)(4) and (b)(4) drug product lot of (b)(4). You also provided the revised finished product specifications for both drug products to add the requirements for (b)(4) assay testing prior to release in the future.

在淮安纵横的回复中，提供了某些药品批次的第三方检测结果，还提供了修订后的两种药品的成品规格，以增加相应药品在未来发布前的化验测试要求。

Your response is inadequate. Your testing was limited to assay, and you failed to specify and perform at least one test to verify the identity of (b)(4) in (b)(4) batch of drug product you manufacture containing the active ingredient. Further, you failed to test all of your retain samples of drug products containing (b)(4) within expiry to determine whether they meet established specifications for identity and assay. Your response is also inadequate because you did not include sufficient information about your testing procedures, methods, or a detailed description of the tests you will conduct (e.g., identity, strength, and purity).

淮安纵横的回复是不充分的。提供的测试仅限于分析，未能指定并执行至少一项测试以验证生产的的药品批次中含有活性成分的标识。此外，未能在有效期内测试所有保留的含有该成分的药品样品，以确定它们是否符合既定的鉴定和分析标准。也没有提供关于测试程序、方法的足够信息，或者将要进行的测试的详细描述（例如特性、强度和纯度）。

In response to this letter, provide the following:

针对本函，请提供以下内容：

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.

    o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States within expiry as of the date of this letter

    o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls 

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

• Your procedure to ensure that any test methods performed by a contract testing laboratory on your behalf are properly validated before use.

•化学和微生物标准表，包括测试方法，用于在出厂前分析每批药品。

• 一份行动计划和时间表，用于对保留样品进行全面的化学和微生物测试，以确定自本函日期起有效期内出售给美国的所有批次药品的质量。

• 记录测试结果的摘要并保留每个批次的样品。如果检测发现药品质量不合格，应迅速采取应急措施，如通知顾客和产品召回。

•对实验室操作、程序、方法、设备、文件和分析能力进行全面、独立的评估。在此审查的基础上，提供一个详细的计划来完善和评估实验室系统的有效性。

•确保第三方测试实验室执行的任何测试方法在使用前得到正确的验证。

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

淮安纵横没有至少一次检验以确认药品的每一种成分。

You failed to test incoming components used to manufacture your drug products to determine their identity. For example, your firm did not ensure that at least one specific identity test was conducted for each lot of active ingredients (b)(4).

没有在生产前对活性成分进行测试。

In your response, you stated that you revised the specifications for incoming active ingredients (e.g., (b)(4)) to include an identification test. You also provided an example of the revised specification sheet for (b)(4), in addition to an example of a third-party laboratory test report for the (b)(4) content in (b)(4) lot of (b)(4) raw material.

在淮安纵横的回复中，声明修改了掺入活性成分的标准，以包括鉴定试验。除了某些批次某种原料中某种成分含量的第三方实验室测试报告示例外，还提供了该成分修订规范表的示例。

Your response is inadequate. You failed to specify and perform at least one test to verify the identity of all of the components you use to manufacture your drug products. Further, you failed to test your retain samples of active ingredients used in the manufacture of drug products to determine whether they meet established specifications for identity.

对此，淮安纵横的回复是不充分的。因为未能指定并执行至少一个测试来验证用于制造药物产品的所有成分。此外，没有测试保留用于药品生产的活性成分样本，以确定它们是否符合标准。

In response to this letter, provide the following:

针对本函，请提供以下内容：

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

    o An action plan and timelines for conducting full. chemical and microbiological testing of API retain samples to determine the quality of all batches of active ingredients used in the manufacture of drug products distributed to the United States within expiry.

    o A summary of all results obtained from testing API retain samples from each batch. If such testing reveals substandard quality drug substances, take rapid corrective actions, such as notifying customers and product recalls

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier's Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier's results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.

• A summary of your program for qualifying and overseeing contract facilities that test the drugs you manufacture.

•化学和微生物质量控制标准，用于测试和放行每批进入生产中使用的原料。

• 一份行动计划和时间安排，以便全面测试。原料药的化学和微生物测试保留样品，以确定在有效期内用于生产出售到美国所有批次药品的活性成分质量。 

• 记录测试结果的摘要并保留每个批次的样品。如果检测发现药品质量不合格，应迅速采取应急措施，如通知顾客和产品召回。

•说明如何测试每批原料药是否符合所有特性、强度、质量和纯度标准。如果打算接受供应商的分析证书（COA）中的结果，而不是测试每个批次的原料药，请说明将如何通过初始验证和定期重新验证来可靠地确定供应商结果的可靠性。此外，还应承诺始终对每批进厂原料进行至少一次特定的成分测试。

•所有原料药测试结果的总结，以评估各原料药供应商的COA可靠性。包括描述COA验证程序的标准操作程序（SOP）。

•用于鉴定和监督测试生产的药物的第三方实验室的计划摘要。

3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

淮安纵横没有建立并遵循适当的书面测试计划，该计划旨在评估药品的稳定性特征，并使用稳定性测试的结果来确定适当的储存条件和有效期。

Your firm did not have an adequate stability testing program to demonstrate that the chemical and (b)(4) properties of your drug products remain acceptable throughout their labeled expiry period. Your firm does not have adequate stability data to support the assigned expiration date of up to 36 months.

淮安纵横没有足够的稳定性测试程序来证明该公司生产的药品的化学性质和某种性质在标示的有效期内是安全的。没有足够的稳定性数据支持标示的36个月有效期。

In your response, you committed to revising your stability procedures to include extending your accelerated stability studies from three months to six months with new drug samples, requiring 36 months of real-time stability for drug products, and conducting stability studies at the appropriate humidity and temperatures with respective monitoring. You also purchased an (b)(4).

在回复中，淮安纵横承诺完善稳定性程序，包括将新药物样品的稳定性研究从3个月延长到6个月，要求药物产品的稳定性为36个月，并在适当的湿度和温度下进行稳定性研究，并进行相应的监测。

Your response is inadequate. While you state in your response you have real time stability data for one identical drug product formula for another market, you did not provide the supporting data for this assertion. Additionally, for other drug product formulas you failed to provide data to demonstrate that the chemical and (b)(4) properties of your drug products will remain acceptable throughout their labeled expiry period of up to 36 months.

这些回复是不充分的。虽然在回复中声明，另一个市场的同一种药物产品配方有稳定性数据，但没有提供此支持数据。此外，没有提供其他药物产品配方的数据证明其药物产品的化学和活性成分特性在其标记的有效期（最长36个月）内保持安全有效。

In response to this letter, provide the following:

针对本函，请提供以下内容：

• A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy ·of your stability program. Your remediated program should include, but not be limited to:

    o Stability indicating methods

    o Stability studies for each drug product in its marketed container-closure system before distribution is permitted

    o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid

    o Detailed definition of the specific attributes to be tested at each station (timepoint)

• All procedures that describe these and other elements of your remediated stability program.

•全面、独立的评估、应急措施和预防措施（CAPA）计划，以确保稳定性计划的充分性。淮安纵横的补救计划应包括但不限于：

o稳定性指示方法

o允许销售前，对每种药品在其上市容器封闭系统中的稳定性进行研究

o一个正在进行的计划，每年向该计划中添加每种产品的代表性批次，以确定保质期索赔是否有效

o在每个时间点测试的具体属性的详细定义

•描述以上和完善稳定性计划的其他改变的所有过程。

4. 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)).

淮安纵横没有为生产过程制定足够的书面程序，以确保公司生产的药品具有其声称或代表拥有的特性、强度、质量和纯度。

Your firm failed to adequately validate the manufacturing processes for your drug products. You performed process validation for only one of your drug products; however, you manufacture numerous drug products with different formulations and with multiple active pharmaceutical ingredients. During the inspection you provided your rationale for this practice, stating that each active ingredient was similar in its chemical propet;ties and that during actual manufacturing you tested the formulation and the drug products had met specification. However, one of the active ingredients in your formulations is (b)(4), which you failed to test in finished product batches as detailed above.

也没有充分验证公司药品的生产工艺。淮安纵横只对一种药物产品进行了工艺验证，但是，公司使用不同的配方和多种有效药物成分制造了许多药物产品。在检查期间，公司为这一做法提供了一些理由，说明每个活性成分的化学性质相似、在实际生产过程中测试的配方和药物产品已符合标准。然而，淮安纵横的配方中的某种活性成分，未能在上述成品批次中进行测试。

In your response, you committed to reperforming process validation for one drug product. Your response is inadequate. You did not provide sufficient process performance qualification (PPQ) protocols or studies for each formulation of your drug products.

在淮安纵横的回复中，承诺对一种药物产品进行再成型工艺验证。但是这种回复并不充分。因为没有为每种药物制剂提供足够的工艺性能鉴定（PPQ）方案或研究。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established.

过程验证评估设计的可靠性和整个过程周期的控制状态。制造过程的每个重要阶段都必须进行适当的设计，并确保生产过程中材料和成品药品的质量。工艺评定研究确定是否已建立控制的初始状态。

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. See FDA's guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at http://www.fda.gov/media/71021/download.

在销售之前，必须进行工艺鉴定研究。此后，有必要对过程性能和产品质量进行持续性监督，以确保产品在整个有效周期内保持稳定。

In response to this letter, provide the following:

针对本函，请提供以下内容：

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. ·

• A timeline for performing appropriate PPQ for each of your marketed drug products.

• Your process performance protocol(s) and written procedures for qualification of equipment and facilities.

•确认计划的详细摘要，以确保在产品整个有效周期内的控制状态，以及相关程序。请描述过程性能鉴定程序，以及对批内和批间变化的持续监控，以确保持续的控制状态。·

•为每种已上市药品执行适当的PPQ时间表。

•工艺性能协议、设备和设施鉴定的书面程序。

5. Your firm failed to use equipment in the manufacture, processing, packing or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended used and for its cleaning and maintenance (21 CFR 211.63).

淮安纵横没有在药品的生产、加工、包装或保管过程中使用设计适当、尺寸适当、位置适宜的设备，以便于其预期用途的操作和清洁维护。

You have not established that your (b)(4) is adequately designed, controlled, maintained, and monitored to ensure it consistently produces (b)(4) that is suitable for use in your drug products. For example, neither your (b)(4) qualification nor your routine monitoring of the (b)(4) includes testing the (b)(4) for (b)(4).

（由于涉及商业机密，不知具体内容）

In your response, you stated that you revised the monitoring and testing frequency of your (b)(4) for (b)(4) to twice a month, and you provided the test report from a third-party laboratory who performs these tests on your behalf.

淮安纵横声明将监控和测试频率修改为每月两次，并提供了第三方实验室的测试报告。

Your response is inadequate. You failed to provide data to demonstrate that your (b)(4) system is capable of producing (b)(4) in a reproducible manner that consistently meets the (b)(4) USP monograph and appropriate microbial specifications. Further, you failed to conduct a risk assessment to determine the potential impacts of substandard (b)(4) on the drug products that you manufacture.

这样是不充分的。因为没有提供数据证明该系统能够以可重复的方式生产某种药品，且始终符合USP专论和微生物标准。也没有进行风险评估，以确定不合格成分对生产的药品的潜在影响。

In response to this letter, provide the following:

针对本函，请提供以下内容：

• A comprehensive, independent assessment of your (b)(4) design, control, and maintenance.

• Then, a comprehensive remediation plan for the design, control, and maintenance of the (b)(4).

o Followed by a (b)(4) validation report to evaluate whether the remediated system design consistently produces (b)(4) adhering to (b)(4), USP monograph specifications and appropriate microbial limits. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits.

• A tabular summary of the chemical and microbial monitoring results that you have collected from testing your (b)(4) for the past two years. Also include within the table the following:

    o specifications for the tested attribute

    o date of sampling

    o point of use (POU) from which the sample was collected

In addition, provide a description of the location of each POU and how it is used in drug manufacturing, along with a description of the (b)(4) during (b)(4) testing.

• A detailed risk assessment addressing the potential effects of the observed (b)(4) failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.

•对**的设计、控制和维护进行全面、独立的评估。

•然后，设计、控制和维护**的综合补救计划。

o随后提交**验证报告，以评估经补救的系统设计是否符合USP专论规范和适当的微生物限度。还应对系统设计、持续控制和维护程序的改进总结。

•管理持续控制、维护和监测的程序，确保补救系统始终符合USP专论规范和适当的微生物限度。

•过去两年中，从测试某种药品中收集的化学和微生物监测结果的表格摘要。表中还包括以下内容：

o测试属性的规范

o取样日期

o从中收集样品的使用点（POU）

此外，提供每个POU的位置和如何在药物制造中使用的说明。

•一份详细的风险评估报告，说明所观察到的某种成分失效对目前在美国销售的所有批次药品质量的潜在影响。指定针对风险评估将采取的操作，如客户通知和产品召回。

Concerns Regarding Glycerin关于甘油的问题

The drug products you manufacture contain glycerin as an ingredient. The use of glycerin contaminated with diethylene glycol (DEG) has resulted in various lethal poisoning incidents in humans worldwide. See FDA's guidance document, Testing of Glycerin for Diethylene Glycol, to help you meet CGMP requirements when distributing glycerin for use in drug products, including testing for DEG and recommendations for supply chain integrity, at https://www.fda.gov/media/71029/download.

淮安纵横生产的药品含有甘油成分。使用被二甘醇（DEG）污染的甘油已经在世界范围内造成了各种致命的中毒事件。请参阅FDA的指导文件“甘油二甘醇测试”，以帮助在销售药品时满足CGMP要求，包括二甘醇测试和供应链完整性建议。

Responsibilities as a Contractor作为承包商的责任

You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA's guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

无论是否与产品所有者达成协议，淮安纵横都应对作为合同设施生产的药品质量负责。必须确保药品的生产符合FD&C法案的安全性、特性、强度、质量和纯度。

CGMP Consultant RecommendedCGMP顾问推荐

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. 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FDA在淮安纵横发现的违规行为，FDA强烈建议淮安纵横聘请一名顾问，协助公司满足CGMP的要求。FDA还建议合格的顾问对公司的CGMP合规性的整个操作进行全面审计，并在公司寻求解决与FDA的合规状况之前，评估应急措施和预防措施的完成情况和有效性。

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.

使用顾问并不免除公司遵守CGMP的义务。公司的执行管理层仍然负责解决所有缺陷和系统缺陷，以确保遵守CGMP要求。

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 these violations and for preventing their recurrence or the occurrence of other violations.

这封信中所列举的违规行为并不是对你们公司存在的违规行为的全面陈述。你们负责调查和确定这些违规行为的原因，并防止其再次发生或发生其他违规行为。

FDA placed your firm on Import Alert 66-40 on November 8, 2019.

FDA于2019年11月8日将淮安纵横置于进口警戒66-40。

Until you correct all violations 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.

在你们完全纠正所有违规行为，并且我们确认符合CGMP规定之前，FDA可能会拒绝批准任何新的药物申请或将贵公司列为药物制造商的补充产商。

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Huaian Zongheng Bio-Tech Co., Ltd., at No. 615 North Xiangyu Road, Huaian into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority 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).

如果不纠正这些违规行为，FDA可能会拒绝淮安纵横生物科技有限公司生产的药品进入美国。

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 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.

Send your electronic reply to CDER-OC-OMO-Communications@fda.hhs.gov or mail your reply to:

Philip Kreiter

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4235

10903 New Hampshire A venue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3007628845.

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

责任编辑：杰尼龟

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