February 28, 2020

Warning Letter 320-20-27

Dear Mr. Kyurkchiev:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, FICOSOTA LTD., FEI 3014115921, at Madara Boulevard 48, Shumen, Shumen, from September 2 to 5, 2019.

美国FDA于2019年9月2日至5日检查了你们位于保加利亚的FICOSOTA LTD.生产场所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations forf inished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (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 product is 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。

We reviewed in detail your September 25, 2019, response to om Form FDA 483.

我们已详细审核了你公司XXXX年XX月XX日的回复，并此告知已收到后续通信。

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：

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)) 你公司未在放行之前对每批药品进行适当的实验室检测，确定其满足药品的最终质量标准，包括每种活性成分的鉴别和含量（21 CFR 211.165(a)）。

Your firm failed to perform critical quality control tests of finished drug products prior to shipment to the U.S. market. For example, our inspection found you lacked identity and strength testing for each batch of your over-the-counter (OTC) finished drug product "(b)(4)"for its labeled active pharmaceutical ingredient (API) (b)(4).

你公司未对成品在运输至美国市场之前进行关键质量控制检测。例如，你们检查发现你们OTC药品XX每个批次均缺少对其所标示API的鉴别和含量检测。

Testing of each batch for identity and strength,and all other appropriate quality attributes prior to release, is the final ina series of essential CGMP controls that ensure a drug product meets appropriate specifications.

放行前对每个批次检测其鉴别和含量，以及其它所有适当的质量属性是为确保药品符合适当的标准而执行的一系列基本CGMP控制的最终步骤。

In response to this letter, provide:

在回复本函时请提交：

•      A comprehensive 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.

•      一份对你们实验室规范、程序、方法、设备、文件和化验员能力的全面独立评估。根据该审核结果，提交一份详细的计划补救和评估你们实验室系统的有效性

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

•      一份批处置之前对你们每批药品进行分析所用已更新化学和微生物标准清单，包括检测方法

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 that are within expiry.as of the date of this letter.

一份对留样进行化学和微生物全检的行动计划和时间表，以确定所有销售至美国且本函签发时仍在效期内的药品批次的质量

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

一份对每批留样检测所得所有结果的总结。如果检测显示有药品质量不合格，则快速采取纠正措施如通知客户和召回产品

2.Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) & (2)). 你公司未检测每种组份样品的鉴别和相关项目，确保其符合所有书面的纯度、含量和质量标准。你公司亦未以适当时间间隔验证和建立你们组份供应商的检测分析可靠性(21 CFR 211.84(d)(1) and (2))。

Your firm failed to adequately test your incoming raw materials, including API and other components, for identity, purity, strength, and quality. You relied on your supplier's certificate of analysis (COA) in lieu of testing each component lot for purity, strength, and quality. However, you did not establish a supplier qualification program to assess (i.e., initially and periodically) the reliability of your suppliers'  test results for these attributes.

你公司未对进厂原料包括API和其它组份进行充分的鉴别、纯度、含量和质量检测。你们依赖你们供应商的COA，取代了你们自己对每批组份的纯度、含量和质量检测。但是你们并未建议供应商确认程序来评估（即初次和定期）你们供应商对这些属性检测结果的可靠性。

In response to this letter, provide:

在回复本函时请提交：

•      A comprehensive review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified; whether they are assigned appropriate expiration or retest dates; and whether incoming material lot controls are adequate to prevent the use of unsuitable containers, closures, and components.

•      一份对你们物料系统的全面审核，以确定是否来自每个供应商的所有容器、密闭器和组份均经过充分确认，是否给定了适当的有效期或复验期，以及进厂物料的批次控制是否足以防止使用不当的容器、密闭器和组份

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

•      你们用于检测和放行每批生产所用进厂组份的化学和微生物质量控制标准

•      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 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 (b)(4) specific identity test for each incoming component lot.

•      说明你们准备如何检测每种组份的每个批准，确保其符合所有适当的鉴别、含量、质量和纯度标准。如果你们准备接受你们供应商的所有COA结果，取代你们对每批进厂物料的含量、质量和纯度检测，则需说明你们准确如何通过初始验证和定期再验证稳固地建立你们供应商结果的可靠性。另外，在其中包括一份承诺，保证会一直对每批进厂物料执行至少一项特定鉴别项目。

•      A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer.

•      一份所有组份检测所得结果的汇总，以评估来自每个组份生产商的COA的可靠性。

3. Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are incompliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). 你公司的质量控制部门未履行其确保药品生产符合CGMP并满足既定鉴别、含量、质量和纯度标准的职责（21 CFR 211.22）。

During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug product. For example, your QU failed to ensure that:

在检查期间，我们的检查人员发现你们QU并未对你们的OTC药品生产进行充分的监管。例如，你们的QU未能确保：

•      QU responsibilities to approve and reject API and drug products were defined.

•      规定QU批准和拒收API和药品的职责

•      All testing was performed and reviewed by the QU prior to batch release.

•      在批放行之前由QU执行并审核所有检测

•      An ongoing program for monitoring process control was established to ensure stable manufacturing operations and consistent drug quality.

•      建立对工艺控制的持续监测程序，以确保稳定的生产操作和稳定的药品质量

•      Master production records and batch production records with detailed manufacturing steps and parameters were adequate and approved.

•      主生产记录和批生产记录有详细的生产步骤，参数足够详细并经过批准

•      An annual ptoduct review program was established.

•      建立年度产品回顾程序

•      Adequate procedures for out-of-specification (OOS) were established, and any unexplained discrepancies or failures of a batch or any of its components to meet any of its specifications, were thoroughly investigated.

•      建立足够的OOS程序，成品或组份与其质量标准所有未经解释的差异或不合格均经过彻底调查

In addition, your QU was not independent from production. For example, your written procedure allows your production manager to make final batch release decisions.

另外，你们的QU未与生产相互独立。例如，你们的书面程序允许你们生产经理作出最终批放行决定。

In response to this letter, provide:

在回复本函时请提交以下内容：

•      A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

•      一份全面的评估和补救计划，确保你们QU被授予权力和资源能有效运转。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 QU oversight throughout your operations to evaluate adherence to appropriate practices

QU监管你们整个操作以评估是否遵守适当的规范的条款

A complete and final review of each ·batch and its related information before the QU disposition decision .

QU监管你们整个操作以评估是否遵守适当的规范的条款

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

监管和批准调查，履行所有其它QU义务以确保所有产品的鉴别、含量、质量和纯度

•      A validation plan for ensuring a state of control throughout the product lifecycle, including a timeline for performing appropriate process performance qualification, description of your program for monitoring lot-to-lot variation to ensure an ongoing state of control, and process performance and equipment qualification protocols.

•      一份验证计划，确保在产品生命周期中保持受控状态，包括执行适当工艺性能确认的时间表，你们监测批间波动以确保持续受控状态的计划、产品性能和设备确认方案

•      A comprehensive review and remediation plan for your OOS result investigation systems. Provide a corrective action and preventive action (CAPA) plan to improve OOS handling. Your CAPA plan should include but not be limited to the following:

•      一份对你们OOS结果调查系统的全面审核和补救计划。提交一份改进OOS处理的CAPA计划。你们的CAPA计划应包括但不仅限于：

Quality unit oversight of laboratory investigations 

QU对实验室调查的监管

Identification of adverse laboratory control trends

发现不良实验室控制趋势

Resolution of causes or laboratory variations

原因或实验室波动解决方案

Initiation of thorough investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified

当未发现可得出结论的实验室原因时，对潜在生产原因启动彻底调查

Adequately scoping of each investigation and its CAPA

每起调查及其CAPA的范围界定

OOS investigation procedures with these and other remediations

OOS调查程序及其它补救措施

•      A risk assessment for any drug products in the U.S.market within expiration date for which an OOS result was obtained. Take appropriate actions, including customer notifications or recalls, if drug quality may be compromised.

•      一份有OOS结果尚在美国市场且仍在效期内的所有药品的风险评估。采取适当措施，包括当药品质量有问题时通知客户和召回药品。

4. Your firm failed to establish 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)). 你公司未建立和遵守足够的书面检测程序，设计用以评估药品的稳定性特性，以及使用稳定性测试结果确定适当的存贮条件和有效期（21 CFR 211.166(a)）。

Your stability program is inadequate because your procedure does not require a long-term stability study for your OTC drug product "(b)(4)." Although you informed our investigator that your product has a three-year expiration date, your stability program lacked chemical and microbial testing of your stability samples. During the inspection, you provided minimal data to support long-term stability of your OTC product.

你们的稳定性程序是不充分的，因为你们的程序并未要求对你们的OTC药品XX进行长期稳定性研究。虽然你们告诉我们检查员说你们的药品有3年有效期，但你们的稳定性计划中并没有稳定性样品的化学和微生物检测。在检查期间，你们提交了很少的数据来支持你们OTC药品的长期稳定性。

In response to this letter, provide:

在回复本函时请提交：

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

•      一份全面独立的评估和CAPA计划，以确保你们的稳定性程序的充分性。你们的补救程序应包括但不仅限于：

Stability indicating method

稳定性指示性方法

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

批准销售之前每种药品在其市售包装中的稳定性研究

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

每年将每种药品代表批次加入程序以确定货架期声明是否保持有效的持续计划

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

在每个时间点要检测的具体属性的详细规定

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

•      阐述你们经过补救的稳定性计划中这些和其它要素的所有程序

•      Provide stability data to support that your product will meet the quality attributes for a period of (b)(4) after containers are opened, as claimed on your product label.

•      提交稳定性数据支持你们药品标签所声明的在容器打开之后XX时间内药品仍满足质量属性要求。

•      A retrospective risk assessment of the stability of all batches of your drug product on the U.S. market within expiry. 

•      一份对你们销售至美国且仍在效期内的所有药品批次的稳定性回顾风险评估

•      A retrospective, independent review of the impact of all OOS results for all products currently in the U.S. market and within expiry as of the date of this letter.

•      一份所有OOS结果对当前在美国市场且本函签发时仍在效期内的所有药品的影响的独立回顾审核

Inadequate Response 回复不充分

In your response, you stated that you did not intend to respond to each Form FDA 483 observation since you had ceased production for the U.S. market.

在你们的回复中，你们声称无意回复FDA483表中所有缺陷，因为你们已停止生产美国产品。

Your response is inadequate because it did not provide any detail or evidence of corrective actions to bring your operations into compliance with CGMP. Specifically, your response did not address the effect these violations may have on your OTC drug product within expiry and currently in the U.S. market.

你们的回复是不充分的，因为你们并未提交任何可令你公司回复CGMP合规状态的整改措施的详细信息或证据。具体来说，你们的回复并未解决这些违规行为对你们当前仍在美国市场且在效期内的OTC药品的影响。

Remediating these CGMP violations will be necessaryif you plan to resume drug manufacturing operations for the U.S. market. We acknowledge your commitment to notify this office if you propose to resume U.S.supply. We also acknowledge your commitment to be in "full compliance with all the applicable laws and regulations before proceeding."

如果你们计划恢复销售至美国市场的药品生产操作，则必须补救这些CGMP违规行为。我们了解你们承诺如果你们准备恢复向美国供货，你们会通知本办公室。我们了解你们承诺会“在继续之前全面符合所有适用法律法规”。

Quality Systems Guidance  质量体系指南

Your firm's quality systems are inadequate. See FDA's guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

你公司的质量体系是不充分的。参见FDA指南文件“药物CGMP法规的质量体系方法”，帮助你们实施质量体系和风险管理方法，从而符合21CFR第210和211的CGMP规范要求。

Process Controls Guidance 工艺控制指南

Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. 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 https://www.fda.gov/media/71021/download.

你公司缺乏持续的工艺控制监测程序，无法确保稳定的生产操作和恒定的药品质量。参见FDA指南文件“工艺验证通则与规范”中FDA认为是工艺验证要素的方法。

CGMP Consultant Recommended CGMP顾问建议

If you resume drug manufacturing operations for the U.S. market, based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21CFR 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 and preventive actions before you pursue resolution of your firm's compliance status with FDA.

鉴于我们在你公司所发现的违规情况，如果你们要继续为美国市场生产药品，我们强烈建议你们使用一位有21 CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。我们亦建议该具备资质的顾问对你们整体运营情况进行药品CGMP合规情况全面审计，并由其在你们寻求满足FDA合规要求之前对你们CAPA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层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。

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.

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 on January 10, 2020.

FDA已于2020年1月10日将你公司置于进口禁令66-40中。

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 resultin the FDA continuing to refuse admission of articles manufactured at FICOSOTA LTD., Madara Boulevard 48, Shumen, Shumen, 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 COMP 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 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 toCDER-OC-OMO-Communications@fda.hhs.gov or mail your reply to:

Qin Xu

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 301411 5921.

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

CC: Ms. Miglena I. Bankova

Head of R&D and QC Department

FICOSOTA LTD.

Madara Boulevard 48

Shumen,Shumen,9700

Bulgaria 

【本文来源： Julia法规翻译 】