ViaUPS Warning Letter: 320-16-21 Return Receipt Requested June 30, 2016
Sir Andrew WittyChief Executive OfficerSmithKline Beecham LimitedGSK House980 Great West RoadBrentfordMIDDLESEXTW8 9GSUNITED KINGDOM Dear Sir Andrew:The U.S. Food and Drug Administration (FDA) inspectedyour drug manufacturing facility, SmithKline Beecham Limited at Clarendon Road,Worthing, United Kingdom from July 2–10, 2015. 美国FDA于2015年7月2-10日检查了你们位于英国的工厂。This warning letter summarizes significant deviationsfrom current good manufacturing practice (C
GMP) for active pharmaceuticalingredients (API). 本警告信总结了你们原料药在CGMP方面的严重偏差。Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your APIare 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). 由于你们的原料药生产、加工、包装或存贮所用方法、设施或控制不符合CGMP，你们的原料药根据FDCA符合掺假药的定义。We reviewed your firm’s July 31, 2015, response indetail and acknowledge receipt of subsequent responses. 我们仔细审核了你们公司于2015年7月31日及之后发来的回复。Our investigators observed specific deviationsincluding, but not limited to, the following. 我们的调查人员发现的具体偏差包括但不仅于于以下：
1. Failure to have appropriateprocedures (or practices) in place to prevent cross-contamination fromdedicated penicillin manufacturing area to non-dedicated areas. 未能制订适当的程序（或做法）来防止专用青霉生产区域与非专用区域之间的交叉污染。
A. Penicillin cross contamination 青霉素交叉污染We documented findings of penicillin in non-penicillinmanufacturing areas approximately 69 times in 2012, 72 times in 2013, 30 timesin 2014, and 16 times through July 7, 2015. Your facility and controls toprevent contamination of non-penicillin drugs with penicillin are whollyinadequate. 我们记录下非青霉素生产区域缺陷2012年69次，2013年72次，2014年30次，2015年截止7月为16次。你们用于防止非青霉素药物与青霉素药物之间污染的设施和控制整体来说是不充分的。Contamination of non-beta-lactam drugs withbeta-lactam drugs presents great risks to patient safety, including anaphylaxisand death. No safe level of penicillin contamination has been determined to bea tolerable risk. Severe allergenic response can occur in susceptiblepatients exposed to extremely low levels of penicillin and otherbeta-lactams. Due to the limitations of sampling and current analyticaltest methods, such levels are very difficult to detect. 非贝塔内酰胺药物与贝塔内酰胺药物之间的污染对患者安全有极大的风险，包括致命性过敏和致死。青霉素的污染水平是没有可接受的安全限度的。即使暴露在极低水平的青霉素和其它贝塔内酰胺药物严重的过敏反应可能会引起易感患者死亡。由于取样及现行分析方法受到限制，这样的水平是很难检出的。We acknowledge your decision to
(b)(4) untilcompletion of a product quality risk assessment. Your firm also recalledvarious lots of Bactroban® (mupirocin calcium) products because of potentialcontamination with penicillin and foreign substances such as glass, paintfragments, and fibers. 我们知道你们决定在完成产品质量风险评估之后再行生产。你们公司还召回了不同的Bactroban® (莫匹罗星钙)批次药品，因为它们具有潜在的青霉素污染以及异物污染，如玻璃、涂料碎片和纤维。In your response, you committed to revalidating yourpenicillin decontamination method. Your response is inadequate because it lacksa comprehensive reassessment of the extent of contamination throughout yourfacility, a gap analysis of previous decontamination efforts, and a copy ofyour new decontamination plan. 在你们的回复中，你们承诺会重新验证你们的青霉素除污染方法。你们的回复是不充分的，因为它缺乏对你们整个工厂污染程度的全面再评估、之前除污染努力的差距分析，以及你们新的除污染方案的复本。
B. Penicillin detection method validation 青霉素检出方法验证 Your method for detecting penicillin in non-penicillindrugs manufactured at your facility is not validated to detect the differenttypes of penicillin manufactured at your facility. In addition, you could notlocate the raw data for the method validation. Your firm has changed the methodsince the original validation. 你们在你们工厂生产的非青霉素药品中检出青霉素的方法没有经过检出在你们工厂所生产的不同类型的青霉素的验证。此外，你们不能提供方法验证的原始数据。你们公司在初始验证之后已经改变了检测方法。
C. Penicillin cleaning method validation 青霉素清洁方法验证 Your firm uses
(b)(4) to decontaminatepenicillin from all surfaces. However, the cleaning validation onlydemonstrated
(b)(4) to be effective in the removal of
(b)(4).Your firm discontinued manufacturing
(b)(4) in
(b)(4). You havenot updated your cleaning validation and have not demonstrated whether themethod originally used for
(b)(4) is also effective for the penicillindrugs you manufactured at the time of our inspection. 你们公司使用了XX方法来除去各种表面的青霉素污染。但是，清洁验证只证明了从XX上清除是有效的。你们公司中断了YY车间的XX生产。你们没有更新你们的清洁验证，没有证明是否原来用于XX的方法在我们检查时对你们所生产的青霉素药品也是有效的。In your response, you acknowledged the problems withyour current analytical method and its validation. Your response is inadequate.You did not provide supporting data or justification for your cleaningvalidation.在你们的回复中，你们告知了你们目前分析方法及其验证中所遇到的问题。你们的回复是不充分的。你们没有提供支持性数据，或者论证来支持你们的清洁验证。In response to this letter, commit to one of thefollowing two options for the building you have used to manufacture penicillin.在回复本函时，请承诺在以下两种选项中选择一种来处理你们用于生产青霉素的建筑：
- Dedicate the facility to penicillin only: We strongly urge you to dedicate the facility to penicillin-only production. If you intend to dedicate the facility to penicillin-only production, provide your timeline for implementation. Also indicate the controls you have implemented to prevent any non-penicillin drugs previously manufactured at this facility from entering the U.S. supply chain.
- 让设施专用于青霉素生产：你们强烈催促你们将设施专用于青霉素生产。如果你们愿意将其专用 于青霉素生产，请提供你们的实施时间限。还要指明你们已经实施用于防止任何之前在此工厂生产的非青霉素药品进入美国供应链。
- Fully decontaminate the facility: It is profoundly difficult to completely decontaminate a facility of beta-lactam residues. If you intend to attempt decontamination so that you can resume solely non-penicillin API production for the U.S. market, provide a comprehensive decontamination plan. Also update your methods for detection of penicillin and address all potential sources of cross-contamination of penicillin into non-penicillin drugs. Until FDA determines that your proposed decontamination plan, methods, and procedures are adequate, comprehensively implemented, and verified via an FDA inspection, you should not introduce any non-penicillin drugs into the U.S. supply chain.
- 对此设施进行全面污染清除：要完全清除设施里的贝塔内酰胺残留是非常困难的。如果你们皂片进行污染清除，从而继续只生产非青霉素原料药用于美国市场，请提供全面污染清除计划。还请更新你们用于检出青霉素的方法，解决所有可能交叉污染至非青霉素的青霉素的潜在来源。在FDA认为你们所提议的污染清除计划、方法和程序被充分全面实施，并通过FDA现场检查核对之前，你们不能再生产任何非青霉素药品进入美国供应链。
For more information, see FDA’s guidance document,
Non-PenicillinBeta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination, at
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM246958.pdf. 更多信息，参见FDA指南文件“非青霉素贝塔内酰胺药物：防止交叉污染框架”。
2. Failure to adequatelyinvestigate critical deviations and implement corrective and preventiveactions. 未能对关键偏差进行充分调查，并实施纠正和预防措施
A. Microbial contamination in (b)(4) watersystems XX水系中微生物污染 From April 20, 2014, to February 17, 2015, youinvestigated at least 25 breaches of the alert level (
(b)(4) colonyforming units) or action level (
(b)(4) colony forming units) formicrobial contamination in your water system loops in Building
(b)(4).You used water produced from this system to manufacture
(b)(4) API. Ofnote, you identified
Burkholderia cepacia, a waterborne organism knownto contribute to biofilm formation in water systems, in several of youralert-level and action-level investigations. 从2014年4月20日至2015年2月17日，你们至少针对XX建筑的水循环系统微生物污染调查了25次菌群超出警戒限或行动限。你们使用此系统制备的水来生产XX原料药。值得注意的是，你们在几次警戒限和行动限调查中鉴别出了洋葱伯克霍尔德菌，这是一种水生微生物，已知是会形成水系统中微生物膜。Your investigations failed to adequately establishroot causes. In 16 of the 25 investigations, you concluded that the root causewas sampling error but had no supporting evidence. You did not determine a rootcause in the remaining nine investigations. Our inspection also found that youwere not sanitizing the
(b)(4) water system loops
(b)(4), asrequired in your procedure
PAA219 Operation & Maintenance for (b)(4)Plant (b)(4) Water System. 你们的调查没有充分找出根本原因。在25起调查中的16起中，你们做出结论说根本原因是取样错误，但并没有支持性证据。在剩下的9起调查中，你们并没有确定根本性原因。我们的检查中还发现你们并没有对水循环系统按照你们的程序PAA219“XX车间YY水系统操作和维护程序”进行消毒。In your response, you acknowledged that your
(b)(4)water system investigations were not robust. However, you made no commitment toconduct a comprehensive investigation into the breaches and overall adversetrends. 在你们的回复中，你们说你们的XX水系统调查不够好。但是，你们承诺会对偏差和全面不良趋势实施一个全面的调查。In response to this letter, provide a summary reportof your reassessment and remediation of
(b)(4) your
(b)(4) watersystems. Also include sampling use points and sampling schedules. 在回复此函时，请提供你们对XX水系编制再评估和纠正总结报告。还请包括对使用点取样的描述及取样计划。
B. (b)(4) API batch (b)(4) without-of-specification bioburden 生物负载OOS结果的原料药XX批次 Our investigators found that three of the
(b)(4)of
(b)(4) (batch
(b)(4)) had bacterial counts (bioburden)exceeding your specification.
(b)(4) had more than
(b)(4) colonyforming units of
Sphingomonas paucimobilis per milliliter of product.
Sphingomonaspaucimobilis, an opportunistic pathogen, is one of the organisms youidentified in the water system used to manufacture this batch. Notably,
Sphingomonaspaucimobilis was also found in
(b)(4), but this
(b)(4) wasreleased based on passing microbial count testing. 我们的调查员发现3个XX批次细菌计数（生物负载）超出你们的质量标准。XX批次中少动鞘氨醇单胞菌菌落单位超标准。该菌是一种机会致病菌，是你们用于生产此批次的水系统中鉴别出的微生物之一。值得注意的是，少动鞘氨醇单胞菌也在XX中发现，但该批次根据微生物计数测试通过的结果已经放行了。Following an investigation, your firm elected toreject the
(b)(4) that failed microbiological quality control testing.However, microbial contamination by its nature rarely occurs uniformly.Therefore, rejecting the specific
(b)(4) that failed final QC testing,while releasing the remaining
(b)(4), may not prevent exposure ofcustomers to potentially objectionable contamination. 在调查之后，你们公司选择了拒收微生物质量控制测试不合格的XX批。但是，微生物污染的情况如果发生的话很少会是均匀的。因此，拒收在最终QC检测中不合格的批次，而放行其它批次，可能无法防止客户暴露于潜在的致病菌污染。In your response, you attributed the high bioburdenroot cause to an extended
(b)(4) hold time. Your response is inadequate.Your firm has no established maximum
(b)(4) hold time. You failed toinclude any supporting data to correlate your
(b)(4) holding times withincreased API bioburden. You did not extend your investigation into the
(b)(4)other
(b)(4) with similar or longer
(b)(4) hold times. 在你们的回复中，你们将高生物负载的根本原因归因于延长的XX存贮时间。你们的回复是不充分的。你们公司并没有设定最大的XX保存时长。你们公司没有包括任何支持性数据将你们的XX保存时间与原料药生物负载增加建立关联。你们没有将你们的调查扩展到XX其它有相似或更长XX保存时长的批次。In response to this letter, include a reassessment ofyour water system and how it may contribute to high API bioburden. Also provideyour corrective action and preventive action plan to prevent recurrence. 在回复此函时，请包括你们对水系编制重新评估，以及它是如何可能对原料药较高的生物负载产生影响的。还请提供你们用于防止其再次发生的纠正与预防措施计划。
C. Foreign particles found in (b)(4) API (b)(4) 在XX原料药YY中的异物 Your investigation into foreign particles found in
(b)(4)batch
(b)(4) identified:你们对XX批次中发现的外来颗粒的调查认为：
- green fibers consistent with scouring pads
- 绿色的纤维与清洁垫材质一样
- red flakes consistent with paint in the manufacturing plant
- 红色的片与生产车间所用的涂料相同
- black particulates consistent with glass particles
- 黑色的颗粒与玻璃颗粒一致
You concluded that these were “acceptable intrinsic”contaminates. 你们得出结论是这些都是“可以接受的内部”污染。Your response is inadequate. It failed to include aroot-cause evaluation of glass particles and the foreign materials found inthese drugs. You also failed to evaluate the impact of the contaminants on allother drugs manufactured with the same equipment in the same facility. 你们的回复是不充分的。回复没有包括对这些药品中发现的玻璃颗粒和外来物料的根本原因评估。你们还未能评估污染对于在相同工厂里相同设备中生产的所有其它药品的影响。In response to this letter, provide a risk assessmentfor the
(b)(4) manufacturing process and other drugs produced with thesame equipment. Include an evaluation of the physical condition of yourfacility and of your cleaning and preventive maintenance procedures for yourmanufacturing equipment. 在回复此函时，请提供XX生产工艺和在相同设备中生产的其它药品的风险评估。包括对你们工厂物理条件的评估，以及你们生产设备的清洁和预防性维护程序的评估。
Conclusion 结论 Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, fordetermining the causes, for preventing their recurrence, and for preventingother deviations. If you are considering an action that is likely tolead to a disruption in the supply of drugs produced at your facility, FDArequests that you contact CDER’s Drug Shortages Staff immediately,
atdrugshortages@fda.hhs.gov, so that FDA 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 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 dependon your products. After you receive this letter, you have 15 workingdays to respond to this office in writing. Specify what you have done tocorrect your deviations and to prevent their recurrence. If you cannot complete corrective actions within 15working days, state your completion date and reasons for delay. Until you completely correct all deviations and weconfirm your compliance with CGMP, FDA may withhold approval of any newapplications or supplements listing your firm as an API drug manufacturer.Failure to correct these deviations may also result in FDA refusing admissionof articles manufactured at SmithKline Beecham Limited, Clarendon Road,Worthing, United Kingdom, into the United States under section 801(a)(3) of theFD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may besubject to refusal of admission, in that the methods and controls used in theirmanufacture do not appear to conform to CGMP within the meaning of section501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
Send your reply to: Rafael Arroyo Compliance Officer U.S. Food and Drug Administration White Oak, Building 51, Room 4235 10903 New Hampshire Avenue Silver Spring, MD 20993 USA
Send your electronic reply toCDER-OC-OMQ-Communications@fda.hhs.gov. Please identify your response with FEI 1000166776. Sincerely,/S/ Francis Godwin Acting Director Office of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and Research
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