FDA警告信：土耳其Deva Holding AS 20190806

罗伊鲱

Warning Letter 320-19-33             August 6, 2019

Mr. Philipp Daniel Haas， Chairman and Chief Executive Officer

Deva Holding AS – Cerkezkoy Subesi

Halkali Merkez Mahallesi, Basin Ekspres Cd. No: 1, Kucukcekmece,34303, Istanbul Turkey

Dear Mr. Haas:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Deva Holding AS – Cerkezkoy Subesiat Organize Fatih Bulvar Fatih Bulvar 32 Cerkezkoy, Tekirdag, 59500, Turkey, from February 4, 2019 to February 15, 2019.

美国FDA于2019年2月4日至15日检查了你们位于土耳其的Deva Holding AS – CerkezkoySubesi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。

We reviewed your March 6, 2019 response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2019年3月6日的回复，并此告知已收到后续通信。

During our inspection, our investigators 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：

• Your firm failed to perform operations related to the manufacture, processing, and packing of penicillin in facilities separate from those used for other drug products for human use (21 CFR 211.42(d)).你公司未在与其它人用药品分开的设施内生产、加工和包装青霉素（21 CFR 211.42(d)）。
  
  

You manufacture drugs on two campuses: Cerkezkoy 1 (CK1) and Cerkezkoy 2 (CK2) which are approximately ¼ mile apart. CK1 manufactures various products, including penicillin, (b)(4), and non-beta-lactam drug products. You manufacture (b)(4)capsules for the U.S. market in the (b)(4) Building and penicillin drug products in an adjacent building on the CK2 campus.

你们在2个厂区生产药品：Cerkezkoy 1 (CK1) 和 Cerkezkoy 2 (CK2)，相距约四分之一英里（约0.4km）。CK1生产不同药品，包括青霉素XX，和非β内酰胺药品。你们在CK2厂区XX建筑内生产销往美国的XX胶囊，在相邻建筑内生产青霉素药品。

• Penicillin cross contamination  青霉素交叉污染
  
  

The presence of penicillin (b)(4) was detected throughout the CK2 campus outside the penicillin manufacturing areas in the campus approximately 103 times in 2017, 44  times in 2018, and 9 times in 2019 through June 2019. Of these incidents, penicillin was detected 2 times in the material acceptance ramp and 5 times in the personnel entrance area in the (b)(4) Building where the non-beta-lactam drug product, (b)(4)capsules, is made for the U.S. market. Penicillin was also detected in common areas, including dining areas, that are accessible to employees working in both the penicillin and non-penicillin manufacturing areas.

在2017年，整个CK2厂区青霉素生产区域以外有检出青霉素XX约103次，2018年44次，2019年截止6月为9次。在这些事件中，在销往美国的XX非β内酰胺胶囊生产所在XX建筑内的物料接收平台检出青霉素2次，人员入口检出5次。在常规区域包括就餐区亦有检出青霉素，员工通过该区域可去往青霉素和非青霉素生产工作区域。

Your facility and controls to prevent contamination of non-penicillin drugs with penicillin are inadequate. Contamination ofnon-beta-lactam drugs with beta-lactam drugs presents great risk to patient safety, including potential anaphylaxis and death. No safe level of penicillin contamination has been determined to be a tolerable risk. Severe allergenic responses can occur in susceptible patients exposed to extremely low levels of penicillin and other beta-lactams.

你们的设施和防止非青药品与青霉素药品的控制是不充分的。非β内酰胺药品与β内酰胺药品污染对患者安全构成极大风险，包括潜在过敏反应和致死。青霉素污染没有认为可接受风险的安全水平。易过敏患者暴露于极低水平青霉素和其它β内酰胺产品就可能产生严重过敏反应。

In your March 6, 2019 response, you summarized your corrective actions, including the testing of retain samples from all commercial batches of (b)(4) capsules for penicillin contamination, using a newly-validated method, in which all batches had the result of “Not Detected”. Your response also documented additional penicillin monitoring of the (b)(4) Building that was performed following the inspection in which no penicillin residue was detected.

在你们2019年3月6日的回复中，你们总结了你们的整改措施，包括检测所有XX胶囊商业批次的留样中的青霉素污染情况，使用了新验证过的方法，所有批准结果均为“未检出”。你们的回复中亦说明了在检查之后对未检出青霉素残留的XX建筑进行的更多青霉素监测。

Your firm’s response is inadequate because your test method’s limit of detection was inadequate, and your response lacks a comprehensive reassessment of the extent of contamination throughout your facility and a plan for decontamination. In addition, the beta-lactam monitoring study that was performed in the (b)(4) Building was inadequate because (1) it was a one-time study; (2) it only included 7 sampling locations; and (3) no sampling sites were located within the production area for the (b)(4) capsules.

你公司的回复是不充分的，因为你们的检验方法的检测限是不够的，你们的回复缺少对你们整个设施内污染程度的重新全面评估，以及灭活计划。此外，在XX建筑内执行的β内酰胺药品监测研究是不充分的，因为（1）该研究为一次性研究，（2）仅包括了7个取样点，（3）在XX胶囊生产区域内没有设置取样点。

• Inadequate penicillin monitoring 青霉素监测不充分
  
  

Your routine, (b)(4) monitoring of penicillin in non-penicillin areas of your facility, conducted from January 2017 to June 2019, was inadequate because it did not include any monitoring locations within the production area where (b)(4) capsules are manufactured. We note that you started monitoring for penicillin in the (b)(4) production area after your firm was placed on Import Alert 66-40 in July 2019.

你们2017年1月至2019年6月日常对你们设施内非青霉素区域的青霉素XX监测是不充分的，因为其中在XX胶囊生产区域内没有任何监测点。我们注意到你们自2019年7月你公司被置于进口禁令66-40之后才开始在XX生产区域进行青霉素监测。

• Penicillin cleaning method validation 青霉素清洁方法验证
  
  

Your firm uses (b)(4) solutions to decontaminate penicillin from surfaces. However, you lacked effectiveness data to show that the decontaminant solutions used throughout CK1 and CK2 are an effective decontaminant agent in your common areas, including dining areas accessible to all employees. On February 12, 2019, an employee, who performed a dissolution testing demonstration, was observed to have a stain on her clothing that was tested and determined to be (b)(4) after she returned from a break in the common dining area in the CK1 campus. It is unacceptable to have common areas where employees exposed to beta-lactam drugs are not isolated and separated from other employees manufacturing non-beta-lactam drugs.

<span 你公司使用了XX溶液进行表面青霉素灭活。但是你们缺乏有效性数据来证明CK1和CK2所用灭活溶液在你们一般区域是有效的，包括所有员工可进出的就餐区域。2019年2月12日，一名员工在CK1厂区公用就餐区域休息之后返回，做溶出度检测，发现在其衣服上有污渍，经过检测确定是XX。员工在未隔离并与其它生产非β内酰胺药品的员工分开的公用区域暴露于β内酰胺药品是不可接受的。

Your March 6, 2019 response included additional cleaning validation studies for the (b)(4) solutions; however, there is no explanation as to why the original cleaning process, which utilized the same concentrations of (b)(4) solution, was insufficient to eliminate penicillin cross contamination which is evidenced by the findings discussed inpart A.

你们2019年3月6日的回复包括了对XX溶液的更多清洁验证研究，但是没有解释为何原始的清洁工艺使用了相同浓度的XX溶液却不足以清除青霉素交叉污染，A部分所讨论的缺陷证明了该事。

We acknowledge your decision to recall all batches of (b)(4) capsules from the U.S. market due to the potential for penicillin cross contamination.

我们知晓你们因潜在青霉素交叉污染决定召回美国市场的所有批次XX胶囊。

In response to this letter, provide the following:

在回复此函时请提交以下内容

• A plan to fully decontaminate the non-beta-lactam portion of the facility. It is profoundly difficult to completely decontaminatea facility of beta-lactam residues. If you intend to attempt decontamination so that you can resume solely non-penicillin production for the U.S market, provide a comprehensive decontamination plan.
• 一份对部分设施进行全面灭活的计划。要完全灭活β内酰胺残留设施是很困难的。如果你们有意尝试灭活然后继续只生产美国市场的非青产品，请提交全面灭活计划。
• A list of all decontaminant solutions used in your facility, including validation data to support that the decontaminant solutions can break the beta-lactam ring of the beta-lactam drug products manufactured
• 一份在你们设施内所用的所有灭活溶液清单，包括支持这些灭活溶液可断开所生产的β内酰胺药品的β内酰胺环的验证数据
• A program for future monitoring of beta-lactam residue throughout the facility
• 一份进一步监测整个设施内β内酰胺残留的计划
• A revised control plan for identified routes of beta-lactam contamination
• 一份修订后的识别β内酰胺污染途径的控制计划
  
  

For more information, see FDA’s guidance document, Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination, at https://www.fda.gov/media/79971/download.

更多信息参见FDA指南文件“非青β内酰胺药品：防止交叉污染的CGMP框架”。

• Your firm failed to test non-penicillin drug products for the presence of penicillin when a reasonable possibility existed that the non-penicillin drug product had been exposed to cross-contamination with penicillin (21 CFR 211.176).  当存在合理可能性非青药品曾暴露于青霉素交叉污染中时，你公司未检查非青药品中青霉素（21 CFR 211.176）。
  
  

You did not test your non-penicillin drug product, (b)(4) capsules, for the presence of penicillin despite the known possibility of cross-contamination with penicillin.

尽管已知有青霉素交叉污染可能，但你们未检测你们非青药品XX胶囊中青霉素。

In response to the findings of the inspection, you stated in your March 6, 2019 response that retain samples from all batches of (b)(4) capsules distributed to the U.S. market were tested for penicillin contamination using a newly-validated analytical method, and all batches reported a result of “not detected”. However, your method for detecting penicillin in non-penicillin drugs manufactured at your facility is notsufficiently sensitive to detect very low levels of contamination. The limit of detection (LOD) for your method was reported to be (b)(4) mg/mL which isequivalent to (b)(4) parts per billion (ppb). (b)(4) ppb is notan acceptable LOD. Please see FDA’s published analytical method which has a LOD of 0.2 ppb at https://www.ncbi.nlm.nih.gov/pubmed/29766324.

在回复检查缺陷时，你们在2019年3月6日回复中声称所有销往美国的XX胶囊批次留样使用了新验证后的分析方法检验其中青霉素污染情况，所有批次结果均报告为“未检出”。但是你们用于检验在你们设施中所生产的非青药品中青霉素的检验方法并不够灵敏，不能检出非常低水平的污染。你们方法的检测限（LOD）报告为XXmg/ml，等同于XXppb。XXppb是不可接受的LOD。请参见FDA发布的分析方法，其LOD为0.2ppb。

<span In response to this letter, provide a commitment to either validate and implement FDA’s analytical method for the analysis ofpenicillin in non-penicillin drug products to achieve a LOD of 0.2 ppb or validate an analytical method with a LOD that is equivalent or better than 0.2ppb.

在回复此函时，请提交一份承诺，承诺将验证和实施FDA的非青药品中青霉素分析方法达到LOD0.2ppb，或验证一个LOD等同或优于0.2ppb的分析方法。

CGMP Consultant Recommended CGMP顾问建议

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualifiedas 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.

根据我们在你公司发现的缺陷情况，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。我们亦建议由该具备资质的顾问对你们整个操作进行一次全面CGMP合规审计，在你们寻求公司符合FDA要求之前，由该顾问评估你们CAPA的有效性和完成情况。

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

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。

If you are considering an action that is likely tolead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov,so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。

FDA placed your firm on Import Alert 66-40 on July1, 2019.

FDA已于2019年7月1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 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 continuing to refuse admission of articles manufactured at Deva Holding AS – Cerkezkoy Subesi, Organize Fatih Bulvar Fatih Bulvar 32 Cerkezkoy,Tekirdag, 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。

<span 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。

ive

将验证和实施FDA的非青药品中青霉素分析方法达到LOD0.2ppb，或验证一个LOD等同或优于0.2ppb的分析方法。

这个方法在哪里可以找到

清晨的太阳

进来参观一下，顺便看看情况