FDA警告信：你们的OOS结果和水系统监测不合格调查系统是不充分的……

翻译：JULIA  来源：Julia法规翻译

August 1, 2019 Case # 577583 WARNING LETTER

Dear Mr. Ambrose:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, TG United, Inc., FEI: 3005350897, at 16275 Aviation Loop Drive, from December 17, 2018, to February 15, 2019.

美国 FDA 于 2018 年 12 月 17 日至 2019 年 2 月 15 日检查了你们位于佛州的 TG United, Inc. 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 与 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，你们的药品根据 FDCA 的 501(a)(2)(B) 以及 21 U.S.C. 351(a)(2)(B) 被认为是掺假药品。

Your firm manufactures HISTEX PD Drops,Triprolidine HCl, Diphenhydramine HCl, ED Chlorped Jr., Rynex PSE, Rynex PE, Ed Chlorped D, Poly-Hist PD Drops, Capron DM Liquid, and Rynex DM that are unapproved new drugs in violation of section 505(a) of the FD&C Act, 21U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

你公司生产的 HISTEX PD Drops, Triprolidine HCl, Diphenhydramine HCl, EDChlorped Jr., Rynex PSE, Rynex PE, Ed Chlorped D, Poly-Hist PD Drops, Capron DMLiquid 和 Rynex DM 依据 FDCA 第 505(a) 条款 21U.S.C. 355(a) 为未批准新药。在州际贸易中引入和运输此类药品违反了 FDCA 第 301(d) 条款 21 U.S.C. 331(d) 。

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Rynex PSE, Rynex PE, andRynex DM are labeled to contain brompheniramine maleate; HISTEX PD Drops andTriprolidine HCl are labeled to contain triprolidine; ED Chlorped Jr. and EdChlorped D are labeled to contain chlorpheniramine maleate; Capron DM Liquid is labeled to contain pyrilamine maleate; Diphenhydramine HCl is labeled to contain diphenhydramine HCl; and Poly Hist PD Drops is labeled to containthonzylamine HCl.

Rynex PSE ， Rynex PE 和 Rynex DM 标示含马来酸溴苯那敏， HISTEX PD Drops 和 Triprolidine HCl 标示含曲普利定， ED Chlorped Jr. 和 Ed Chlorped D 标示含扑尔敏， Capron DM Liquid 标示含马来酸吡拉明， Diphenhydramine HCl 标示含盐酸苯海拉明， Poly Hist PD Drops 标示含盐酸甲氧基胺。

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We reviewed your March 8, 2019, response in detail.

我们已详细审核了你公司 2019 年 3 月 8 日的回复。

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：

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR211.192). 你公司未能调查所有未经解释的差异，或已销售或未销售药品批次或其成分不符合其质量标准的情况（ 21 CFR 211.192 ）。

Your system to investigate out-of-specification (OOS) results and water system monitoring failures is inadequate. You failed to initiate investigations, sufficiently investigate, and/or finalize such investigations in a timely manner.

你们的 OOS 结果和水系统监测不合格调查系统是不充分的。你们未启动调查，执行充分调查和 / 或及时完成此类调查。

Failure to Conduct Investigations 未能执行调查

You lacked investigations into failures of your water system to meet chemical purity specifications, including a determination of root causes and corrective actions to prevent recurrence.

你们缺乏对你们水系统不符合化学纯度标准的调查，包括确定根本原因和纠正措施以防止其重复发生。

Inadequate Investigations 调查不充分

In addition, you failed to finalize manufacturing process investigations, including incidents related to OOS results generated from stability, finished product, and raw material testing. For investigations opened between June 20, 2017, and September 25, 2018, 14 outof 39 investigations remained open at the time of the inspection. Your firm continued manufacturing while significant investigations remained open with no clear assessment of impact or identification of appropriate follow-up actions.

另外你们未能完成生产工艺调查，包括与稳定性、制剂和原料检测中发生的 OOS 结果有关的事件。对于 2017 年 6 月 20 日至 2018 年 9 月 25 日之间启动的调查， 39 件中有 14 件在检查时仍未关闭。你公司在重大调查未关闭时继续生产，对影响性没有明确的评估，亦未制订适当的跟踪措施。

In your response, you stated that your quality unit will complete the investigations within 30 days. Your response is inadequate because it does not sufficiently address the investigations that remained open, initiating an investigation in a timely manner, and improvements to your investigation program.

在你们的回复中，你们声称你们质量部门将在 30 天内完成调查。你们的回复是不充分的，因为其中并未充分解决调查仍未关闭的问题，及时启动调查，以及对你们调查程序的改进。

In response to this letter, provide:

在回复此函时请提交

• A retrospective review of all invalidated OOS results (stability, commercial batch release) and invalidated water system monitoring failures associated with products distributed to the U.S. market and within expiry/retest date. Assess whether the scientific justification and evidence was conclusive. For investigations that conclusively establish laboratory root cause, determine adequacy of the corrective action and preventive action (CAPA) plan, and ensure that other laboratory methods potentially vulnerable to the same root cause are identified for remediation.

• 对与销售至美国且仍在有效期内药品有关的所有宣布无效的 OOS 结果和宣布无效的水系统监测不合格的回顾审核（稳定性、商业批次放行）。评估科学论证和证据是否支持得出结论。对于可得出结论而说明的实验室根本原因的调查案例，确定 CAPA 计划的充分性，确保已找出其它可能受到相同根本原因影响的实验室方法并进行补救。

For any OOS result or water system monitoring failure with 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, raw materials, process capability, deviation history, batch failure history, and water systems). Summarize each CAPA plan, identifying the potential manufacturing root causes for each such investigation, and process improvements where appropriate. Your CAPA plan should also include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, quality unit oversight, and a process for evaluating CAPA effectiveness.

对于任何 OOS 结果或水系统监测不合格且不能得出结论或在实验室未发现根本原因的情况，提供一份对生产的彻底回顾（例如，批生产记录、生产步骤的充分性、原料、工艺能力、偏差历史、批不合格历史以及水系统）。总结所有 CAPA 计划，找出每个此类调查中可能的生产根本原因，适当时写明工艺改进。你们的 CAPA 计划亦应包括但不仅限于调查能力、根本原因分析、书面程序、质量部门监管以及评估 CAPA 有效性的流程。

• For each product, tabulate the annual total number of OOS results, and the annual number of OOS results that were invalidated, for raw materials, in-process material, released finished product, and real-time product stability testing from 2017 to the present. Include all OOS results investigated per 21CFR 211.192, even if invalidated due to laboratory error.

• 对于每个品种，采用表格方式列出原料、中间体、已放行成品和实时药品稳定性测试的年度 OOS 结果，年度内宣布无效的 OOS 总个数。包括所有根据 21CFR211.192 进行调查的 OOS 结果，包括由于实验室误差宣布无效的 OOS

Specify how you assign a date to an OOS result (e.g., the time the initial OOS result is identified; when the initial laboratory investigation is initiated or closed; or when the final investigation is closed). Include a copy of your procedure for this process.

说明你们如何为 OOS 结果给定日期（例如发现初始 OOS 结果的时间，何时启动或关闭初始实验室调查，以及何时关闭最终调查）。在其中包括一份你们对此流程的程序副本。

• A table listing all OOS results from 2017 to the present of products distributed to the U.S. market, including the following information:

• 一份表格，列出自 2017 年以来销售至美国市场药品的所有 OOS 结果，包括以下信息

o date OOS result occurred

o OOS 结果发生日期

o identifying code

o 编号

o description of OOS result

o OOS 结果描述

o description of root cause

o 根据原因描述

o whether the OOS result was accepted, or invalidated as a laboratory error

o OOS 结果是否被接受，还是作为实验室错误被宣布无效

o disposition of any impacted batch(es)

o 所有受影响批次的处置

o distribution dateof any impacted batch(es)

o 所有受影响批次的销售日期

2. 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 use and for its cleaning and maintenance (21 CFR 211.63). 你公司未能使用具备适当设计、足够尺寸以恰当放置以便于操作其既定用途和清洁以及维护的设备执行药品生产、加工、处理、包装或存贮（ 21 CFR 211.63 ）。

You have not established that your (b)(4) water systems are adequately designed, controlled, maintained, and monitored to ensure they consistently produce water that meets the USP monograph for (b)(4) water and appropriate microbial limits. Water from your systems is used as a component in your drug products and used for cleaning your manufactur ingequipment and utensils.

你们未证明你们的 XX 水系统经过充分设计、控制、维护和监测，以确保其持续生产出符合 USP 各论 XX 水和适当微生物限度的水。你们系统生产出的水被用作你们药品的成分，并用于清洁你们的生产设备和工器具。

In addition, you lacked adequate sampling and testing of the water produced by your water system used within your liquids facility. During the review of your water systems’ data from 2018, our investigator noted multiple water test results for total organic carbon (TOC) and one testing result for resistivity that did not meet established limits. Also, your firm did not perform studies to ensure the (b)(4) sanitization is effective against microorganisms.

此外，你们对你们水系统生产所生产用于你们液体车间的水缺少足够的取样和检测。在审核你们水系统 2018 年以来数据时，我们检查人员注意到多个水检验 TOC 结果和一个电导检测结果不符合既定限度。你们公司亦未执行研究来确保 XX 消毒对微生物是有效的。

Your response indicated that you updated the procedure governing the maintenance of the (b)(4) water system. Your response is inadequate because it lacked details on how you ensure that (b)(4) water system will consistently produce water that is suitable for its intendeduse. You also failed to address the impact on distributed and future drug products.

你们的回复说你们更新了 XX 水系统维护管理程序。你们的回复是不充分的，因为其中缺少你们要如何确保 XX 水系统能持续生成适合其用途的水。你们亦未说明对已销售和未来药品的影响。

This is a repeat violation from your 2017 inspection. In response to this letter provide:

这是 2017 年现场检查的重复缺陷。在回复此函时请提交：

• A comprehensive , independent assessment of your water system design and maintenance.

• 对你们水系统设计和维护的全面独立评估

• A summary of the protocol(s) designed to evaluate whether your (b)(4) water system is adequate for its intended use.

• 一份设计用以评估你们 XX 水系统是否足够你们既定用途的方案总结

• A summary of the implementation of the protocol(s) referenced above.

• 一份上述方案的执行总结

• A summary o f the improvements made to your system design and ongoing routine control and maintenance program.

• 一份对你们系统设计改进，以及持续日常控制和维护程序总结

• 你公司未能以适当时间间隔清洁、维护和消毒和 / 或灭菌（适当时针对药品特性）设备和工器具，以防止发生可能改变药品安全性、鉴别、剂量、质量或纯度使其超出官方或其它既定要求的故障或污染（ 21 CFR 211.67(a) 。）

You failed to demonstrate that your cleaning practices are adequate to remove residue from shared equipment used to manufacture your OTC drug products. Your determination of the adequacy of your cleaning process is limited to TOC rinse sample testing of equipment. Your firm did not conduct any testing to demonstrate that your transfer hoses and your utensils used in the manufacture of multiple drug products were adequately cleaned.

你们未能证明你们的清洁做法足以清除你们 OTC 药品生产共用设备中的残留。你们确定你们清洁工艺充分性时仅限于设备 TOC 淋洗样品检测。你公司并未执行任何检测用以证明你们用于生产多个药品的转移软管和你们的工器具经过了充分清洁。

In your response, you provided an outline of your cleaning validation strategy and timeframes for completion. However, your response is inadequate because you provided no interim plans to ensure that your cleaning practices are adequate and reproducible in removing residue from shared equipment.

在你们的回复中，你们提交了一份你们清洁验证策略和完成时间框架的大纲。但是你们的回复是不充分的，因为你们未提交临时计划以确保你们的清洁做法足以清除共用设备中的残留并可重复。

This is a repeat violation from your 2012, 2014,and 2017 inspections. In response to this letter, provide the following:

这是你们在 2012 、 2014 和 2017 年检查中的重复缺陷。在回复此函时请提交以下资料：

• A comprehensive plan to evaluate cleaning procedures and practices and any associated validation studies for each piece of manufacturing equipment used to manufacture more than one product.

• 一份对清洁程序和做法，以及用于生产不止一个产品的各台生产设备的所有相关验证研究的全面评估计划

• A summary of updates to your cleaning procedures incorporating conditions identified as worst case. This should include, but not be limited to, the identification and evaluation of:

• 一份对你们清洁程序进行更新的总结，加入识别为最差情形的条件。其中应包括但不仅限于对以下情况的识别和评估：

• Drugs of the highest toxicity

• 最高毒性药品

• Drugs of the lowest solubility in their cleaning solvents

• 在其清洁溶剂中具有最低溶解度的药品

• Drugs with characteristics that make them difficult to clean

• 具有难以清洁特性的药品

• Swabbing locations for areas that are most difficult to clean

• 最难清洁区域的擦拭取样点

• A summary of improvements made to ensure an appropriate program is in placefor validation and ongoing verification of cleaning procedures for products (including introduction of new products) and equipment.

• 一份改进总结，以确保具备适当产品（包括引入新产品）和设备清洁验证和持续确认程序

4. Your firm failed to 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)). 你公司未能遵守足够的书面检测程序，用以评估药品的稳定性特性，并使用稳定性检测结果来确定适当的存贮条件和有效期（ 21 CFR 211.166(a) ）。

Your stability program is not adequate to demonstrate the quality of your OTC drug products through expiry. Reliable stability data is critical for ensuring that products maintain their identity, strength, quality, purity, and safety throughout their shelf lives. For example, your firm has not completed test method validation for test methods to assess impurities, including degradants, for finished drug products manufactured at your facility through expiry. Specifically, our investigator requested to review validation of the test methods for impurities. Your management provided our investigator with a cart full of raw data that had not been reviewed and approved by your quality unit.

你们的稳定性计划不足以证明你们 OTC 药品在有效期内的质量。可靠的稳定性数据对于确保产品在其货架期内保持其鉴别、剂量、质量、纯度和安全性是至关重要的。例如，你公司未完成分析方法验证以评估在你工厂生产的成品中杂质，包括降解产物。你们的管理人员向我们检查员提供了满满一小车的原始数据，均未经过质量部门审核和批准。

In your response, you stated that thetest method validation protocols are in place, testing is ongoing, and anaddendum report will be written. Your response is inadequate because you havenot demonstrated that your test methods used to support the stability ofcurrently marketed products are validated.

在你们的回复中，你们声称已制订了检验方法验证方案，正在检测，会写一份补充报告。你们的回复是不充分的，因为你们并未证明你们用于支持当前上市产品稳定性的检验方法经过了验证。

This is a repeat violation from your2010, 2012, 2014, and 2017 inspections. In response to this letter, provide:

这是你公司 2010 、 2012 、 2014 和 2017 年检查中的重复缺陷。在回复此函时请提交：

• A table listing all drug products distributed to the U.S. market since 2016, including the following information:

• 一份表格，列出所有自 2016 年销至美国的所有药品，包括以下信息

o The name of the drug product

o 药品名称

o The stability-indicating test method name and unique identifier

o 稳定性指示性检验方法名称和唯一识别号

o Whether the test method for each formulation of your drug is validated, and if so, when

o 你们药品每个配方的检测方法是否经过验证，如果验证了，何时

o The batch number(s) and time point(s) where product was analyzed for stability using the test

o 产品进行稳定性分析的批号和时间点

o If any testing timepoints were missed per your firm’s stability program

o 是否根据你公司稳定性计划有缺失任何检测时间点

• A comprehensive , independent assessment and CAPA plan to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to:

• 一份全面独立评估和 CAPA 计划，以确保你们稳定性计划的充分性。你们 CAPA 计划应包括但不仅限于

• A remediated SOP describing your stability program

• 一份经过补救的 SOP ，描述你们的稳定性计划

o Stability-indicating test methods for each formulation of your drug products

o 你们药品的每种配方的稳定性指示性检测方法

o An ongoing stability program in which representative batches of each formulation of your OTC products are added each year to the program to determine if the shelf life claim remains valid

o 一份持续稳定性计划，在其中应有你们 OTC 药品每种配方的代表性批次每年加入计划中，以确定货架期声明是否保持有效

o Specific attributes to be tested at each time interval, including impurities

o 在每个时间点要检测的具体属性，包括杂质

Repeat Violationsat Facility 工厂重复违规

FDA cited similar CGMP violations from 2010, 2012, 2014, and 2017 inspections. Such CGMP violations resulted in a July 2011 Untitled Letter to your firm followed by a December 2012 Regulatory Meeting.

FDA 在 2010 、 2012 、 2014 和 2017 年检查中均发现有类似 CGMP 缺陷。此类 CGMP 缺陷导致 FDA 于 2011 年 7 月向你公司签发了无标题函，然后在 2012 年 12 月举行了监管会议。

In response to each of those inspections and compliance actions taken against your firm, you proposed specific remediations to fully address the violations. Failure to remediate such violations, among many others cited on the Form FDA 483, Inspectional Observations, demonstrate that executive management oversight and control over the manufacture of drugs is inadequate. This repeated failure to correct bringsin to question your firm’s ability to manufacture drugs according to CGMP.

作为这些检查的回复，以及对你公司采取的合规措施的响应，你们提议了具体的补救措施来全面解决违规问题。未能补救这些违规情况，其中包括 FDA483 表中的检查缺陷，证明高级管理层对药品生产的监管和控制是不充分的。重复失控使得你公司按 CGMP 生产药品的能力产生问题。

CGMP Consultant Recommended CGMP 顾问建议

Based upon the nature of the violations, we strongly recommend engaging a consultant qualified as set forthin 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP.

根据你们违规情况，我们强烈建议你们使用一位有 21CFR 211.34 所述资质的顾问来协助你们公司符合 CGMP 要求。你们使用顾问并不能解除你们公司符合 CGMP 的义务。

Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续 CGMP 符合性。

Unapproved New Drug Charges 未批准新药指控（略）

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 their 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，防止你们设施内其它偏差的发生。

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.

请即刻纠正本函中所述违规行为，否则可能会导致不经通知的强制法律措施，包括无限扣押货物。本警告信中违规行为不解决亦可能阻碍联邦当局给予其他合同。

Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We mayalso refuse your requests for export certificates

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。

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.

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。

Your written notification should refer to Case # 577583. Please electronically submit your reply on company letterhead to Jose R. Lopez, Compliance Officer, at [email protected]. In addition, please submit a signed copy of your response to [email protected] and [email protected] .

你们的书面通知请引用案件编号#577583，将回复以公司台头信纸电子发送至 [email protected]

If you have questions regarding the contents ofthis letter, you may contact Mr. Lopez via (787) 729-8603 or [email protected] .

Sincerely,

/S/

Monica R. Maxwell

Program Division Director

Office of Pharmaceutical Quality Operations,Division II