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FDA警告信:德尔塔实验室有限公司

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发表于 2018-6-13 15:27:51 | 显示全部楼层 |阅读模式

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DeltaLaboratories Pty Ltd 12/19/17
德尔塔实验室有限公司
  
  
  
  
  
file:///C:/Users/admin/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png
  
  
  
  
  
  
  
10903 New  Hampshire Avenue
  Silver Spring, MD 20993
  
Via UPS                                                                                Warning Letter 320-18-21
警告信
Return Receipt Requested
December 19, 2017
2017年12月17日
Mr. Gary Leach 加里 李驰 先生
Managing Director总经理
Delta Laboratories Pty. Ltd. 德尔塔实验室有限公司
8 Warringah CL威灵格尔路 8号
Somersby, New South Wales, 2250  萨默斯比,新南威尔士州,2250
Australia澳大利亚
Dear Mr. Leach:
亲爱的李驰先生:
The U.S. Food and Drug Administration (FDA)inspected your drug manufacturing facility, Delta Laboratories Pty. Ltd. at 8Warringah CL, Somersby, from March 27–31, 2017.
美国食品药品监督管理局(FDA)在2017年3月27日至31日检查了你们的药品生产设施,位于萨默斯比威灵格尔路8号的德尔塔实验室公司。
This warning letter summarizes significant violations of current goodmanufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21CFR, parts 210 and 211.
这封警告信总结了违反CGMP条例的重大违规行为。参见21 CFR,210和211部分。
Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, yourdrug products are adulterated within the meaning of section 501(a)(2)(B) of theFederal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
因为您在制造、加工、包装或保管的方法、设施或控制措施不符合cGMP,您的药品在联邦食品、药品和化妆品法案(501(a)(2)(B) ,21 U.S.C. 351(a)(2)(B))意味着被掺假,。
We reviewed your April 13, 2017 response in detail.
我们详细地复查了您在2017年4月13日的答复。
During our inspection, our investigators observed specific violationsincluding, but not limited to, the following.
在我们的检查过程中,我们的检查人员观察到了具体的违规行为,包括但不限于以下。
1.      Your firm failed tothoroughly investigate any unexplained discrepancy or failure of a batch or anyof its components to meet any of its specifications, whether or not the batchhas already been distributed (21 CFR 211.192).
贵公司未能彻底调查批次或其任何组件的不明原因的差异或失败,以符合其标准,无论该批次是否已被放行(21 CFR 211.192)。
You failed to thoroughly investigate release and stability testingfailures concerning two batches of your (b)(4) drug products.These product failures included viscosity and appearance. During stabilitytesting, you also identified packaging defects. You did not initiateinvestigations for each of these drug quality issues. When you did investigate,you failed to adequately evaluate the manufacturing process and associatedrecords, identify root causes, and implement effective corrective actions andpreventive actions (CAPA).
您未能彻底调查两批(B)(4)药物产品的放行和稳定性检测失败。这些产品的失效包括粘度和外观。在稳定性检测期间,您还确认了包装缺陷。你没有发起对每一个药品质量问题进行调查。当你进行调查时,你没有充分评估生产工艺和相关记录,找出根本原因,并实施有效的纠正措施和预防措施(CAPA)。
For example, you found tubes swelling at the 3-month stability time point.You did not investigate this significant defect, which can be indicative ofmicrobial growth and spoilage. Notably, your packaging stabilityspecification requires “no change in packaging.”
例如,在稳定考察的3个月时间点,你发现管子胀大了。你没有调查这个显著的缺陷,它表明微生物的生长和变质了。值得注意的是,您的包装稳定性规范要求“包装无改变”。
In response to our findings, your customer recalled the remaining in-date batchof this product on November 28, 2017.
根据我们的调查结果,您的客户在2017年11月28日召回了剩余的这批产品。
For more information about handling failing, out-of-specification,out-of-trend, or other unexpected results and documentation of yourinvestigations, see FDA’s guidance document, InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production,at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf.
有关处理失败、不规范、不符合趋势或其他意外结果和调查文件的更多信息,请参阅FDA的指导文件,调查药品生产的检测结果超限(OOS)。在https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf下载。
2.      Your firm failed toestablish adequate written procedures for production and process controldesigned to assure that the drug products you manufacture have the identity,strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).
贵公司未能为生产和工艺控制制定适当的书面程序,以确保所制造的药品具有他们所声称或所拥有的特性、强度、质量和纯度(21CFR 211.100(A))。
The processes used to manufacture your (b)(4) drugproducts have not been shown to be consistent and reliable, and consequentlybatches of your drug products are likely to significantly vary in strength,quality, and purity.
用于制造(B)(4)药物产品的工艺没有被证明是一致的和可靠的,因此您的药品多批次可能在特性、质量和纯度上有显著的偏离。
For example, you lacked adequate process validation studies. Yourvalidation report summarized a retrospective analysis of a single processqualification batch, (b)(4). You manufactured and released thisbatch in 2015.Notably, testing of this batch found stability failures ofmultiple quality attributes, including appearance and viscosity. Yourvalidation report was approved on March 17, 2017, shortly before we inspectedyour facility. You lack evidence of process validation because you have notaddressed all potential sources of variation that must be controlled toconsistently yield drugs of uniform character and quality, and have notdemonstrated that the process is reproducible.
例如,你缺乏足够的工艺验证研究。您的验证报告总结回顾了一个(b)(4)单一批次工艺确认分析。您在2015生产并放行了该批产品。特别关注的是,该批次稳定性检测发现了多种质量属性失败,包括外观和粘度。在我们检查您的工厂之前,您的验证报告于2017年3月17日批准。你缺乏工艺验证的证据,因为你没有处理所有必须控制的潜在变化来源,以始终如一地产出具有统一性质和质量的药物,并且没有证明该工艺是可重复的。
Senior management stated that your firm has struggled with manufacturingthis drug product, and that you were still conducting research to gain betterproduct and process understanding. Although you acknowledged a lack ofunderstanding to assure consistent quality, you still commerciallydistributed (b)(4) drug products to consumers.
高级管理层说,贵公司一直在努力生产这种药品,而你仍然在进行研究,以获得更好的产品和工艺认知。虽然你承认缺乏认知,以确保一致的质量,但你仍然商业销售(B)(4)药品给消费者。
Each significant stage of a manufacturing process must be designed toassure that raw material inputs, in-process materials, and finished drugs meettheir quality attributes and specifications. Process validation evaluates thesoundness of design and state of control of a process throughout its lifecycle.Process qualification studies provide a determination whether an initial stateof control has been established. Successful process qualification studies are requiredprior to commercial distribution. Thereafter, ongoing vigilant oversight ofprocess performance and product quality is essential to ensure you maintain astable manufacturing operation throughout the product lifecycle.
生产工艺的每一个重要阶段都必须设计成确保原料、生产中的用料和成品药品符合其质量属性和规格。在整个生命周期中,工艺验证评价设计和工艺控制状态的正确性。工艺确认研究提供是否已建立初始控制状态的确定。在商业销售之前需要成功的工艺确认研究。此后,对工艺性能和产品质量的持续警戒监督是确保整个产品生命周期内保持稳定的制造操作的必要条件。

See FDA’s guidance document, Process Validation: GeneralPrinciples and Practices, for general principles and approaches that FDAconsiders appropriate elements of process validation, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf.
查看FDA的指南文件,工艺验证:一般原则和实践,这是作为一般原则和方法,FDA认为是适用于工艺验证的基本要素。
3.      Your firm failed tofollow an adequate written testing program designed to assess the stabilitycharacteristics of drug products and to use results of such stability testingto determine appropriate storage conditions and expiration dates (21 CFR211.166(a)).
贵公司未能遵循一个足够的书面检测程序来评估药物产品的稳定性特征,并使用这种稳定性检测结果来确定合适的储存条件和有效期(21 CFR 211.166A))。
You did not have adequate stability data to demonstratethat the chemical and physical properties of your (b)(4) drugproducts remain acceptable throughout the labeled (b)(4) expiryperiod. Two lots reviewed during our inspection failed on stability at varioustests and time points. You distributed these two lots of (b)(4) drugproducts to the U.S.
你没有足够的稳定性数据来证明你的(B)(4)药品的化学和物理性质在(B)(4)标签有效期内保持可接受的。在我们的检查期间,两个批次在各种检测和时间点上的稳定性都失败了。你把这两批(B)(4)药品销售到美国。
Batch (b)(4) failed for viscosity atmultiple time points, and you terminated the stability study for batch (b)(4) after you identifiedphase separation in all samples at the 9-monthtime point.
(B)(4)批在多个时间点黏度失败,在9个月时间点你在所有样本中都确定了相分离后,终止了(B)(4)批次的稳定性研究。
At the time of the inspection, you had nottaken appropriate action on these batches, such as notifying your customer orrecalling products from the market.
在检验时,您没有对这些批次采取适当的行动,例如通知客户或者从市场召回产品。
Inadequate Response反应不足
Your April 13, 2017, response to FDA’sinspectional observations was inadequate. You did not provide sufficientevidence that you are taking corrective actions to bring your operations intofull compliance with CGMP. In response to this letter, provide the following:
2017年4月13日你对FDA检查结果的反应是不够的。你没有提供足够的证据表明你正在采取纠正措施,使你的行动完全符合cGMP。为回应这封信,提供以下内容:
·        A summary of the actions you have taken tocomprehensively remediate your investigation process, and an improved procedure.
总结你采取综合措施来补救你的调查过程,和改进的程序。
·        Your investigations, using your revised procedures, forall drug quality related failures. A detailed summary of your review of alltest results, root causes of specification failures, affected batchesdistributed to the U.S. market, and related CAPA.
使用你的修订程序,你的调查,针对所有药品质量相关的失败。您对所有检测结果的回顾,规范失败的根本原因,销售到美国市场受影响的批次,相关CAPA的详细总结。
·        A data-driven and scientifically sound process validationprogram that appropriately identifies sources of variability, and ensuresoversight of intra-batch and inter-batch variation on an ongoing basisthroughout the product lifecycle.
数据驱动和科学健全的工艺验证程序,适当地识别变化的来源,并确保在整个产品生命周期内监督批内和批间变化。
·        Timelines for performing prospective processqualification for your drug products.
为您的药品制定工艺预确认时间表。
·        A procedure describing your stability program.
描述你的稳定计划的程序。
·        Data for (b)(4) batches successfullymanufactured as part of prospective qualification studies, to demonstrate thatthese batches are stable over the shelf life.
作为预确认研究的一部分成功制造(b)(4)批次的数据,以证明这些批次在保质期内是稳定的。
·        The disposition of (b)(4) batch (b)(4),including whether you plan to distribute it in the U.S.
(B)(4)的安排,包括你是否计划在美国销售。
·        Data to demonstrate that your (b)(4)Test–BP methodusedto test drug products marketed in the U.S.is equivalent to, or better than, thecurrent USP (b)(4)Test.
在美国市场销售的b4,用数据证实BP检测方法相当于或者优于USP检测方法。
·        A thorough assessment of your adherence to CGMPrequirements, and a CAPA plan to assure full remediation.
彻底评估你遵守CGMP的要求,以及CAPA计划,以确保全面补救。
You should comprehensively address each ofthese items in your written response.
你应该在你的书面答复中全面地解决这些问题。
Quality Unit Authority质量部门权限
Significant findings in this letterindicate that your quality unit is not fully exercising its authority and/orresponsibilities. Your firm must provide the quality unit with appropriateauthority, sufficient resources, and staff to carry out its responsibilitiesand consistently ensure drug quality.
这封信的重要发现表明,你的质量部门没有充分行使其职权和/或责任。贵公司必须向质量部门提供适当的权限、充足的资源和人员,以履行其职责,并始终如一地确保药品质量。
Responsibilities as a contractor承包商的职责
Drugs must be manufactured in conformancewith CGMP. FDA is aware that many drug manufacturers use independentcontractors, such as production facilities, testing laboratories, packagers,and labelers. FDA regards contractors as extensions of the manufacturer.
药品生产必须符合cGMP。FDA意识到许多药品生产商使用独立的承包商,例如生产设备、检测实验室、包装工和贴标机。FDA认为承包商是制造商的延伸。
You and your customer, (b)(4),have a quality agreement for the manufacture of (b)(4) drugproducts. You are responsible for the quality of drugs you produce as acontract facility, regardless of agreements in place with product owners. You are requiredto ensure that drugs are made in accordance with section 501(a)(2)(B) of theFD&C Act for safety, identity, strength, quality, and purity. SeeFDA’s guidance document, Contract Manufacturing Arrangements for Drugsuality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf.
你和你的客户,(b)(4),对于生产(B)(4)的药品有质量协议。不管与产品所有者达成协议,你对作为合同工厂生产药品的质量负责。
CGMP consultant recommended   cGMP顾问推荐
Based upon the nature of the violationsidentified at your firm, you should undertake a comprehensive and globalassessment to ensure that your systems and processes, and ultimately, the drugproducts you manufacture, conform to FDA requirements. We strongly recommendengaging a consultant, qualified as set forth in 21 CFR 211.34, to assist yourfirm in meeting CGMP requirements.
根据贵公司认定的违规行为的性质,你应该进行全面的全球评估,以确保你的系统和流程,你生产的最终药品是符合FDA的要求。我们强烈建议聘请一名合格的顾问,如21 CFR 211.34所述,以协助贵公司满足CGMP要求。
We request that the qualified consultantprovide FDA with a detailed written report describing their efforts to assistwith comprehensive remediation of your facilities, methods, controls, andquality systems to ensure they are in compliance with CGMP requirements. Youruse of a consultant does not relieve your firm's obligation to comply withCGMP. Your firm's executive management remains responsible for fully resolvingall deficiencies and ensuring ongoing CGMP compliance.
我们要求合格的顾问为FDA提供一份详细的书面报告,说明他们的努力,协助全面完善您的设施、方法、控制和质量体系,以确保它们符合CGMP要求。你的顾问的使用并不能减轻你的公司遵守CGMP的义务。贵公司的管理层负责全面解决所有缺陷并确保持续的CGMP符合性。
Conclusion结论
Violations cited in this letter are notintended as an all-inclusive list. You are responsible for investigating theseviolations, for determining the causes, for preventing the recurrence, and forpreventing other violations.
这封信中列举的违规行为并不是一个包含所有内容的列表。你负责调查这些违规行为,以确定原因,防止再次发生,并防止其他违规行为。
FDA placed your firm on Import Alert 66-40on September 28, 2017.
FDA于2017年9月28日将贵公司的进口警报设置为66-40。
Until you correct all violations completelyand we confirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as a drug manufacturer.
直到你完全纠正所有违规行为并且我们确认你遵守CGMP,FDA拒绝批准任何新的申请或补充,将你的公司列为药品制造商名单。
Failure to correct these violations mayalso result in FDA continuing to refuse admission of articles manufactured atDelta Laboratories Pty. Ltd., 8 Warringah CL, Somersby, into the United Statesunder section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under thesame authority, articles may be subject to refusal of admission, in that themethods and controls used in their manufacture do not appear to conform to CGMPwithin the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C.351(a)(2)(B).
未能纠正这些违规行为也可能导致FDA继续拒绝(8 Warringah CL, Somersby)德尔塔实验室公司制造的物品的进入美国,依据21 U.S.C. 381(a)(3).第801(a)(3)节。
After you receive this letter, respond tothis office in writing within 15 working days. Specify what you have done sinceour inspection to correct your violations and to prevent their recurrence. Ifyou cannot complete corrective actions within 15 working days, state yourreasons for delay and your schedule for completion.
收到此信后,在15个工作日内以书面形式回复本办公室。详细说明我们检查以来你做了什么来纠正你的违规行为,防止其再次发生。如果不能在15个工作日内完成纠正措施,请说明延迟原因和完成时间表。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mailyour reply to:
将您的电子答复发送到CDE-OC-OMQ-Chanss@FDA.HHS.GOV或邮件回复到:
Bill Fowler比尔福勒
Consumer Safety Officer消费者安全主任
U.S. Food and Drug Administration美国食品药品监督管理局
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993锡尔弗
USA 美国
Please identify your response with FEI3004085558.
Sincerely,
/S/
Francis Godwin弗朗西斯 戈德温
Acting Director代理主任
Office of Manufacturing Quality制造质量办公室
Office of Compliance合规办公室
Center for Drug Evaluation and Research药物评价与研究中心

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大师
发表于 2018-6-13 15:43:38 | 显示全部楼层
看到英文头就大
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药生
发表于 2018-6-13 16:14:31 | 显示全部楼层
有中文的法规翻译成英文的嘛
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药士
发表于 2018-6-13 16:20:39 | 显示全部楼层
了解一下
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药士
发表于 2018-6-13 16:33:01 | 显示全部楼层
值得重视
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大师
发表于 2018-6-13 19:46:21 | 显示全部楼层
看多了这个,就少了当初的敬畏感了
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药徒
发表于 2018-6-13 23:23:12 | 显示全部楼层
看到蝇文头就小
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发表于 2018-11-21 18:37:52 | 显示全部楼层
学习一下。。。
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发表于 2018-11-28 16:00:18 | 显示全部楼层
学习一下。。。
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