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本帖最后由 超乎想象 于 2016-5-9 09:24 编辑
看到一则FDA的警告信，里面的问题真是太低级了，很难想象这是美国本土的企业水平，大跌眼镜。
（此文为康利华翻译，未经允许，请勿转载）
April 7, 2016 WARNING LETTER NO.2016-NOL-02 UNITED PARCEL SERVICE Delivery Signature Requested Chris Lemley, President & CEO Apotheca Supply, Inc. dba Apothecares 3220 Highway 31 South Building B Decatur, Alabama 35603-1731 Dear Mr. Lemley: The U.S. Food and Drug Administration (FDA) inspected yourpharmaceutical manufacturing (repackaging and relabeling) facility, ApothecaSupply, Inc. dba Apothecares, at 3220 Highway 31 South, Building B, Decatur,Alabama, from February 10-12, 2015. We identified significant deviations from current goodmanufacturing practice (CGMP) for the manufacture of active pharmaceuticalingredients (API). These deviations cause your drugs to be adulterated within themeaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act(the Act), 21 United State Code (USC) 351(a)(2)(B), because the methods used in, or the facilitiesor controls used for, their manufacture, processing, packing, or holding do notconform to, or are not operated or administered in conformity with CGMP. We reviewed your February 23, 2015, response in detail; and,note it lacks sufficient corrective actions. We also acknowledge receiptof your subsequent correspondence.
Our investigator observedspecific deviations during the inspection, including, but not limited to, the following: 调查员在检查时发现的特定的偏差 ,包括但不限于:
1.Your quality unit failedto review and approve all quality related documents; and, the mainresponsibilities of your quality unit were not described in writing. 你的质量部门未能审核和批准所有质量相关文件;质量部门的主要职责没有书面描述.
During our inspection, wefound your quality unit did not approve your written standard operatingprocedures (SOPs) for numerous critical processes, such as quality unitresponsibilities, expiration date extension, material quarantine, productdistribution, equipment cleaning, product return, complaint handling, productrecalls, supplier qualification, raw material testing, and annual productreviews. We also found your quality unit did not review and approvequality-related documents, batch records, certificates of analysis, and theextension of API expiration dates. Specific examples include: 在检查中,我们发现你们的质量部门不批准一些关键程序的SOP,例如质量部门职责, 失效日期延长, 物料隔离, 产品物流分布, 设备清洁, 产品返回, 投诉处理, 产品召回, 供应商授权, 原料检验, 和产品质量年度回顾. 我们也发现你们质量部门不审核和批准与质量相关的文件, 批记录, COA和延长后的API失效日期. 特定的例子包括:
a. Your quality unit didnot routinely release or reject all API. We found that your firm’s officemanager releases your drugs from quarantine to distribution, even though thisperson is neither identified as a member of your quality unit nor hasdocumented CGMP training. 你们质量部门不对API进行常规的放行和拒绝 . 我们发现你们公司办公室经理负责放行药品到流通部门, 尽管这个人既不属于质量部门,也没有文件显示接受过CGMP培训.
b. Your quality unit didnot routinely complete annual product quality reviews for yourrepacking operations as required in your SOP Procedural Review. This deficiency is similar to deficiencieswe found during our June 2009 and January 2010 inspections. 你们质量部门没有按照你们的SOP《产品回顾》对你们再包装操作完成年度产品质量回顾。这个缺陷和我们再2009年6月和2010年1月发现的缺陷类似。
c. Your quality unit didnot approve your master production record instructions for the APIcyclobenzaprine HCL, estradiol, levofloxacin hemihydrate, and sildenafilcitrate. 你们质量部门不批准盐酸环苯扎林，雌二醇，左旋氧氟沙星，和枸橼酸西地那非API的主生产批记录 。
d. Your quality unit didnot review and approve certificates of analysis (CoA) for repackagedAPI. You generated CoAs by (b)(4). We identified CoAgenerated by your firm containing inaccurately (b)(4) assay specifications and results. 你们的质量部门不审核和批准再包装API的COA 。你们生成了 (b)(4)的COA。我们发现你们公司生成的COA中包含不准确的 (b)(4)含量测定质量标准和结果。
e. You generatedinaccurate CoA that extended the expiration date of APIs. Specifically,you extended the expiration dates of coenzyme Q10 USP, carprofen USP,bupivacaine HCL USP, ursodiol EP, and itraconazole EP. You authorized theextension of these expiration dates with signature approvals from employees notidentified as members of the quality unit and with no documented CGMPtraining. 你们生成的包含了不准确的API的失效日期的COA 。特别是，你们延长了辅酶Q10 USP，卡洛芬USP，盐酸布比卡因的USP、EP、EP熊去氧胆酸，伊曲康唑EP的失效日期。你们授权签字批准延长这些失效日期的员工既不是质量部门的成员,也没有文件显示接受过CGMP培训。
In your response, datedMarch 23, 2015, you submitted SOP Responsibilities ofthe Quality Assurance Unit, which states your quality assurance unit is responsiblefor the review and approval of all quality-related documents. Yourresponse is inadequate because you did not provide a risk assessment evaluatingthe potential effect of your deviations on the quality of API you previouslyrepackaged and released. 你们在2015年3月23日的回复中 ，提交了《质量保证部门的职责》的SOP，其中声称你们的质量部门负责审核和批准所有与质量项目按的文件。你们的回复不充分，因为你们没有进行一个风险分析来评估你们在之前API再包装和放行质量方面的偏差可能的影响。
In response to thisletter, conduct a risk assessment and provide us with a summary of the risksyour deviations posed to the quality of your API. Include in your riskassessment all API within expiry that were repackaged and distributed withinthe United States. Evaluate the product batch records and CoAs not approved by yourquality unit and address them in your risk assessment. Ensure each CoA yougenerated contains accurate information. Also, provide adequatejustification for your risk assessment. 作为此警告信的回应，你们应进行风险评估并向我们提供你们API质量偏差的风险总结。应包括在失效日期内的所有在美国范围内再包装和流通的API批次。评估所有未被质量部门批准的批记录和COA，并在风险评估中说明。保证你们生成的每一COA都包含准确的信息。并且，提供你们合适的风险评估判断结果。
Provide your plan forensuring continuous compliance with your annual product quality reviewprocedure. It is your responsibility to adhere to procedures establishedat your facility and commitments made in your correspondence to the FDA. 提供你们保证持续符合你们年度质量回顾的计划。你们有责任在你们的机构建立程序，并在你们的回复中向FDA做出承诺。
Additionally, provide anorganizational chart that specifies the personnel authorized to release API andprovide evidence that quality unit personnel are adequately trained in currentgood manufacturing practice. 另外，提供一个组织机构图，标明授权放行API的人员并提供证据证明质量人员 接受了充分的CGMP培训。
2.Your firm failed to havestability data to support the extension of expiration dates. 你们公司的稳定性数据不支持延长的失效日期 。
You extended API manufacturers’expiration dates by as much as two years and listed the new expiration dates inyour CoAs for APIs repackaged at your facility. You tested APIs to verifythat the results complied with the manufacturers’ specifications. However,you did not perform stability testing to ensure that APIs met allspecifications for the expiration dates you listed on your CoAs. You haveno scientific justification for extending the expiration dates. Forexample, our investigator found unsupported extension of expiration dates forthe following APIs: 你们延长了API的 生产商失效日期至两年，并在你们公司的API再包装的COA列出新的失效日期。你们检验API断定结果符合生产商质量标准。但是，你们没有进行稳定性试验保证在你们COA中列出的失效日期前符合所有的质量标准。你们延长失效日期没有科学的理由。例如，我们的检查员发现以下API不支持延长的失效日期：
API | Lot # | Manufacturer’s expiration date | Apotheca’s expiration date | Coenzyme Q10 USP | (b)(4) | (b)(4) | September 2016 | Carprofen USP | (b)(4) | (b)(4) | September 2016 | Bupivacaine HCL USP | (b)(4) | (b)(4) | March 2016 (retest date) | Ursodiol EP powder | (b)(4) | (b)(4) | August 2016 | Itraconazole EP | (b)(4) | (b)(4) | September 2016 |
This deviation is similarto one found during our January 2010 inspection of your facility. In yourresponse, you state you have stopped the practice of extending themanufacturer’s API expiration dates. In response to this letter, provide adescription of your process for ensuring this practice will not recur; and,provide your plan to ensure your CoAs are accurate and complete. 此偏差和我们在2010年1月对你们公司的检查中发现偏差类似。在回复中，你们声称你们已经停止延长生产商API失效日期的操作。作为此次警告信的回复，请提供你们保证此操作不再发生的程序的描述；并且，提供你们保证你们COA准确和完整的计划
3.Your firm failed toensure the cleanliness of your facility and equipment. 你们公司未能保证厂房和设备的清洁 。
Your firm weighs andrepackages bulk powder APIs including hormones, tricyclics, muscle relaxants,NSAIDS (non-steroidal anti-inflammatory drugs), antifungals and quinolones innon-dedicated suites using non-dedicated equipment. During the inspection,the investigator found expired cleaning products that your cleaning procedureor operators identified as cleaning agents for the suite andequipment. These include (b)(4) detergent (b)(4)(expiration 10/13), (b)(4) (expiration 10/12), and (b)(4) Sterile (b)(4)(expiration05/2010). In addition, your operators used cleaning agents that are notdocumented in your cleaning procedure. Specifically, (b)(4) are used to clean surfaces of the non-dedicatedsuites. Neither of these cleaning agents are listed in your cleaningprocedure. 你们公司使用非专用的组件和非专用的设备称量和再包装散装API粉末包括激素类、肌松药、非甾体类抗炎药（非甾体类抗炎药），抗真菌药物、喹诺酮类药物。在本次检查中，检查员发现过期的清洁产品，你们的清洁程序和操作人员确认是用于组件和设备清洁剂。这些包括 (b)(4)清洁剂 (b)(4)（失效期2013年10月）， (b)(4)（失效期2012年10月），和 无菌(b)(4)（失效期2010年5月）。此外，你们操作人员使用的清洁剂在你们的清洁程序上没有文件规定。特别是，(b)(4)用来清洁非专用的组件。以上清洁剂都没有列入你们的清洁规程中。
Moreover, you have notperformed cleaning validation studies to determine the effectiveness of yourcurrent cleaning agents to remove residual powders following repackagingoperations in order to prevent cross contamination. 更严重的是，你们没有进行清洁验证研究来确定你们当前使用的清洁剂去除再包装操作过程中的粉末残留的有效性，避免交叉污染。
This CGMP deficiency issimilar to one we found during our January 2010 inspection. In yourresponse, you state you are developing a cleaning validation program toevaluate the effectiveness of your cleaning process. In response to thisletter, provide your cleaning validation protocol, the timeline for itsexecution, and your justification of its effectiveness for the various drugsyou repackage and cleaning procedures you use. Provide your process forensuring that no unapproved cleaning agents will be used in your facility. 此CGMP缺陷与我们在2010年1月检查中发现的的缺陷类似。在你们的回复中，你们声称你们开发了一个清洁验证程序来评估清洁程序的有效性。作为此次警告信的回应，请提供你们清洁验证的方案，执行的时间表，和你们使用的对于不同药物再包装和清洁程序的有效性判断的结论。请提供你们的程序保证在你们的工厂中使用非挥发性的清洁剂。
To ensure your APIs meetthe quality and purity characteristics they purport, or are represented topossess, please reference the FDA-issued ICH guidance entitled Q7A Good ManufacturingPractice Guidance for Active Pharmaceutical Ingredients available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf. 为保证你们的API符合你们预期的质量和纯度特征，或能代表工艺，请参考FDA发布的ICH指南Q7A
The deviations cited in this letter are not intended to be anall-inclusive list of deviations that exist at your facility. You areresponsible for investigating and determining the causes of the deviationsidentified above and for preventing their recurrence and the occurrence ofother deviations. If, as a result of receiving this letter or for other reasons,you are considering a decision that could reduce the number of APIs produced byyour facility, FDA requests you contact CDER’s Drug Shortages Staff immediatelyatdrugshortages@fda.hhs.gov so we can work with you on the most effective way to bring youroperations into compliance with the law. Contacting the Drug ShortagesStaff also allows you to meet any obligations you may have to reportdiscontinuances in the manufacture of your drug under 21 USC 356C(a)(1); and,allows 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. You should take prompt action to correct the violations cited inthis letter. Failure to promptly correct these violations may resultin legal action without further notice including, without limitation, seizureand injunction. Other federal agencies may take this warning letterinto account when considering the award of contracts. Additionally,FDA may withhold approval of requests for exportcertificates, or approval of pending drug applications listing yourfacility, until the above violations are corrected. FDA mayre-inspect to verify corrective actions have been completed. Within 15 working days of receipt of this letter, please notifythis office in writing of the specific steps you have taken to correct andprevent the recurrence of deviations, and provide copies of supportingdocumentation. If you cannot complete corrective actions within 15 workingdays, state the reason for the delay and the date by which you will havecompleted the corrections. Additionally, if you no longerdistribute the APIs at issue, provide the date(s) and reason(s) you ceasedproduction. Please identify your response with FEI No. 3006406317.
Please address all correspondence to Rebecca A. Asente, Compliance Officer, atthe address above. If you have questions regarding the contents of thisletter, please contact Ms. Asente at (504) 846-6104. Sincerely, /S/ Ruth P. Dixon District Director New Orleans District
原文来源：http://mp.weixin.qq.com/s?__biz=MzA4NDA1MDEzNA==&mid=2247483722&idx=1&sn=dab8250c7dc4560d95b7ac5869ef69b0&scene=1&srcid=0509Sg0Gy8huzeckIuB09vsk#wechat_redirect
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发表于 2016-5-9 09:16:59
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