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本帖最后由 超乎想象 于 2016-5-30 08:49 编辑
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http://mp.weixin.qq.com/s?__biz=MzA4NDA1MDEzNA==&mid=2247483820&idx=1&sn=4847c1f24c6ac15fbf362da27905cec8&scene=1&srcid=0530gQVvWB52SPY7Eg0G8Wli#wechat_redirect
Warning Letter320-16-12 ViaUPS Return ReceiptRequested May 16, 2016
Mr. Hans PeterOeltze Head of QualityAssurance BBT Biotech Gmbh Arnold-Sommerfeld-Ring28 Baesweiler,Germany 52499 Dear Mr. Oeltze: The U.S. Foodand Drug Administration (FDA) inspected your drug manufacturing facility, BBTBiotech GMBH at Arnold-Sommerfeld-Ring 28, Baesweiler, Germany, from May 4–7,2015. This warningletter summarizes significantdeviations from current good manufacturing practice (CGMP) for activepharmaceutical ingredients (API). 本警告信汇总了偏离API的CGMP的重要偏差。
Because yourmethods, facilities, or controls for manufacturing, processing, packing, orholding do not conform to CGMP, your API are adulterated within the meaning ofsection 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&CAct), 21 U.S.C. 351(a)(2)(B). 由于你们用于制造、加工、包装或储存的的方法、设施、或控制不符合CGMP，根据FDA的501(a)(2)(B)和351(a)(2)(B)章节的要求，你们的API属于掺假。 We reviewed yourMay 26, 2015, response in detail and acknowledge receipt of your subsequentresponses. During the inspection, our investigators observedspecific deviations including, but not limited to, the following. 在检查过程中，检查员发现的偏差包括但不限于下列情况： 1. Failure to follow adocumented, on-going stability testing program to monitor the stabilitycharacteristics of API and to use the results to confirm appropriate storageconditions and retest or expiry dates. 没有按照一个文件化的，正在持续的稳定性测试程序来检测API的稳定性特征，并依照此结果来确定合适的储存条件，复验期或有效期。
You did not follow your stability program, SOP No.Q-0007. According to your SOP, you must fully test at least (b)(4) batchof (b)(4) API (b)(4) for stability at definedstability intervals. Your firm could not provide any stability data to supportthe (b)(4) expiration date assigned to your (b)(4) API. 你们没有遵守你们的稳定性程序（SOP Q-0007）。根据你们的SOP，你们必须在确定的稳定性间隔期内对(b)(4) API (b)(4) 进行至少 (b)(4)批全检。你们不能提供任何稳定性数据支持你们为(b)(4) API制定的(b)(4)有效期。
For example, since January 2012, you shipped approximately (b)(4) batches of (b)(4) API to the United States for which you have no stability data to support your expiration dates. Without stability data foryour API, you could not assure that your API met specifications when used byyour customers. 例如，从2012年1月开始，你们向美国发运了约(b)(4)批的(b)(4)API，这些API都没有稳定性数据支持它们的有效期。由于没有API的稳定性数据，你们无法保证在客户使用时，你们的API能够符合质量标准。
We acknowledge your commitment to follow your SOP and perform the required stability testing on future batches. However, yourresponse was inadequate because you failed to include any retesting of the APIalready distributed. 我们接受你们遵守SOP，并且在将来的批次中执行稳定性测试的承诺。但是由于没有包括任何已经发货的API的再检验，你们的回复不够充分。
In response to this letter, provide data evaluatingwhether all API batches potentially in United States supply chain within expiryare stable for the assigned (b)(4) expiration date. 作为此次警告信的回复，你们应提供数据评估所有在美国供应链中的API批次，在指定的(b)(4)有效期内是否稳定。
2. Failure to establish andfollow a change management system evaluating all changes that could affect theproduction and control of your API, and failure to evaluate the potentialeffect changes may have on the quality of your API. 未能建立和遵守变更管理系统来评估所有的变更对你们API的生产和控制的影响。未能评估具有潜在影响的变更对于你们API质量的影响。
Your firm did not have a change management program. Youdid not require the quality unit to review or approve changes in suppliers. In2012, your firm changed your crude (b)(4) supplier from (b)(4) to (b)(4).In 2013, you added (b)(4) to your list of suppliers. You didnot provide change management documentation or any other documentation forthese supplier changes. Without adequate evaluation for critical raw materialchanges, you could not assure the acceptability of your API manufactured using materials from different suppliers. 你们公司没有一个变更控制系统。你们没有要求质量部门审核和批准供应商的变更。2012年，你们公司将(b)(4) 粗品供应商从(b)(4)变更为(b)(4)。2013年你们在供应商目录中增加了(b)(4)。针对这些供应商的变化，你们没有提供变更管理文件或者任何其他文件。由于没有对关键原料变化进行充分的评估，你们不能为API生产中使用不同供应商提供的物料的可接受性提供保证。
Your response was inadequate because you failed toprovide any information regarding the effect of supplier changes on the distributedAPI, such as the effect of changes on the impurity profile or the stability ofyour API. 由于你们未能提供供应商变化对于已发货的API影响的信息，例如对于你们API的杂质谱和稳定性的影响，所以你们的回复是不充分的。
In response to this letter, provide the following: 作为此次警告信的回复，你们应提供：
a plan to establish and follow a change management program
建立和遵守变更管理系统的计划 an evaluation of the changes on the impurity profile and stability for your API 变更对于你们的API杂质谱和稳定性的影响的评估 a risk assessmentregarding the effects of your supplier changes on the distributed API 供应商变更对已发货的API的影响的风险评估
3. Failure to adequatelyinvestigate out-of-specification (OOS) results. 未能进行充分OOS结果的调查 During the inspection, our investigators documented that lot #(b)(4) was rejected after it failed in-process control testing for the (b)(4), which is deemed a critical in-process control(including the control point and method) for your API. Although your investigation identified the supplier change as a possible root cause for the failure, you did not evaluate other lots made with crude (b)(4) fromthe same supplier. For example, you used the same crude (b)(4) fromthe new supplier in API lot #(b)(4), which you failed to evaluate beforeshipping to the United States. 检查期间，检查员记录了(b)(4)批因为(b)(4)项目在线控制失败而被拒收，该项目被认为是你们的API的一个关键在线控制（包括控制点和控制方法）。虽然你们的调查指明供应商变化可能是此次失败的一个根本原因，你们没有评估来自同一供应商的其他批次的(b)(4)粗品。例如，在向美国发货前，你们没有评估在(b)(4)API中使用的新供应商提供的相同(b)(4)粗品。
We acknowledge your commitment to follow an updated SOPrequiring a root cause analysis for in-process OOS results. However, your response was inadequate because it did not assess the effects of the failure toadequately investigate in-process OOS results or indicate how this failure mayhave affected your API quality. 我们接受你们根据已升级的SOP对在线OOS结果进行根本原因分析的承诺。但是，由于没有评估在线OOS结果调查不充分在此失败中的影响，或指明此次失败对于API质量的影响，所以你们的回复是不充分的。
In response to this letter, provide a comprehensiveassessment of all in-process OOS results for (b)(4), including rootcauses. Extend this assessment to other batches that might have been affected.Also provide a detailed evaluation of all in process attributes and parametersin terms of their roles in the process and impact on the product and in-processmaterial. 作为此次警告信的回复，你们应提供所有(b)(4)的在线OOS结果的综合评估，包括根本原因。将这一评估扩展到其他可能受到影响的批次中。同时提供一个所有工艺属性和参数在工艺过程中作用和对于产品和中间物料影响的详细评估。
4. Failure to exercisesufficient controls over computerized systems to prevent unauthorized access orchanges to data, and to provide adequate controls to prevent omission of data. 未能执行充分的计算机系统控制，防止未经授权的访问或对数据的修改，应提供充分的控制来防止数据遗漏。 Our investigator found that your (b)(4) systemused for (b)(4) and (b)(4) testinglacked access controls and audit trail capabilities. For example, all employeeshad administrator privileges and shared one user name, so actions could not beattributed or traced to specific individuals. This exposed your electronic datato manipulation and/or deletion without traceability. 检查员发现你们用于(b)(4) 和(b)(4) 检测的(b)(4)系统缺乏访问控制和审计追踪能力。例如，所有的员工都使用管理员权限并且使用同一个用户名，所以操作不能归咎或追踪到特定的人员。
Our investigator also noted that your firm copied rawdata to a CD (b)(4), and then deleted the data from the (b)(4) systemto free space on the hard drive. Files copied to the CD were selected manually;the selection process was not supervised. Without audit trail capabilities orsupervised file selection, there was no assurance that all raw data files werecopied to the CD before they were permanently deleted from the system. 检查员也注意到你们公司把原始数据拷贝到一个CD(b)(4)，然后在(b)(4)系统中删除这些数据来释放硬盘空间。拷贝到CD中的数据是手动选择的；选择的程序没有监督。由于没有审计追踪能力或监督文件的选择过程，无法保证所有的原始数据在系统中永久删除前，都被拷贝到CD中。
We acknowledge your commitment to hire a third-partyexpert to install audit trails and other controls to ensure that data cannot bedeleted from this electronic system. However, your response was inadequate.Simply preventing data deletion is not sufficient. You did not show how thesesteps will ensure that your firm retains and evaluates all data, includinglaboratory data, created as part of a CGMP record prior to release of your API. 我们接受你们雇佣第三方专家安装审计追踪和其他控制来保证数据不能在电子系统中被删除的承诺。但是，简单的防止数据被删除并不充分。你们没有提供你们公司保存和评估所有数据的步骤，包括实验室数据、在API放行前作为CGMP记录创建的记录。所以你们的回复是不充分的。
In your response to this letter, investigate yourretention and review of CGMP data and provide the results. Focus on your firm’s review and retention of laboratory raw data. In addition, provide your interim plan for reviewing and retaining data while your firm is in the process ofimplementing access controls and audit trail capabilities. 作为此次警告信的回复，你们应进行CGMP数据保存和回顾的调查并提供结论。重点是你们公司回复和保存实验室原始数据。另外，在你们公司实施进入控制和审计追踪同时，你们应提供你们审核和保存数据的中期方案。
Conclusion Deviations citedin this letter are not intended as an all-inclusive list. You are responsiblefor investigating these deviations, for determining the causes, for preventingtheir recurrence, and for preventing other deviations. If, as a resultof receiving this warning letter or for other reasons, you are considering adecision that could reduce the number of drugs produced by your manufacturingfacility, FDA requests that you contact CDER’s Drug Shortages Staff immediatelyat drugshortages@fda.hhs.gov so that we can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), andallows FDA to consider, as soon as possible, what actions, if any, may beneeded to avoid shortages and protect the health of patients who depend on yourproducts. In appropriate cases, you may be able to take corrective actionwithout interrupting supply, or to shorten any interruption, thereby avoidingor limiting drug shortages. After youreceive this letter, you have 15 business days to respond to this office inwriting. Specify what you have done since our inspection to correct yourdeviations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 business days, state your completion dateand reasons for delay. Until youcompletely correct all deviations and we confirm your compliance with CGMP, FDAmay withhold approval of any new applications or supplements listing your firmas an API manufacturer. Failure to correct these deviations may also result inFDA refusing admission of articles manufactured at BBT Biotech Gmbh,Arnold-Sommerfeld-Ring 28, Baesweiler, into the United States under section801(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 andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B). Send your replyto: Lixin (Leo) Xu,M.D., Ph.D. ComplianceOfficer U.S. Food andDrug Administration White OakBuilding 51, Rm. 4359 10903 NewHampshire Avenue Silver Spring,MD 20993 USA Please identifyyour response with FEI # 3005761912. Sincerely, /S/ Francis Godwin Acting Director Office ofManufacturing Quality Office ofCompliance Center for DrugEvaluation and Research
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发表于 2016-5-30 08:45:40
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