Warning Letter320-19-33 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.
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。
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