近日，FDA官网爆出美国Sage制药有限公司产品经检查每毫升含菌量达57000CFU，并在其中检出致病菌——洋葱伯克氏菌。美国FDA批评他们对微生物检验方法和方法验证的不足和取样和设施的缺陷，并在在线清洁（CIP）系统内发现生成了生物膜具体缺陷如下：
1. Your firm failed to establish anddocument the accuracy, sensitivity, specificity, and reproducibility of itstest methods (21 CFR 211.165(e)).
你公司未能制订和记录其检测方法的准确度、灵敏度、专属性和重复性(21 CFR 211.165(e))。
You produce some bulkdrug solutions at your facility (e.g., 2% chlorhexidine gluconate) and haveentered into contract manufacturing arrangements for the production of otherdrugs (e.g., Sage Perox-A-Mint, manufactured for you byChemRite CoPac, Inc.(“ChemRite”)). You use the (b)(4) method to screen for microbiologicalcontamination in drugs produced entirely at your facility and thosemanufactured under contract. This (b)(4) screening method (b)(4)formicrobiological examination of your liquid drug products is not adequate forits intended use. You attempted to validate your (b)(4) microbialdetection method, but were not able to demonstrate that it could reliably andrepeatedly determine whether objectionable microorganisms were present in yourdrugs.
你们在你们的工厂生产了许多药品溶液（如2%葡萄糖酸氯己定），并且还有生产其它药品的委托生产安排（例如Sage的Perox-A-Mint，是由ChemRite CoPac, Inc. (“ChemRite”)为你们生产的），采用XX为你们生产。你们使用了XX方法来剔除你们自己场所生产的以及委托场所生产的药品的微生物污染。该XX筛选方法XX用于检查你们液体药品的微生物污染对于其既定用途来说是不充分的。你们试图验证你们的XX微生物检出方法，但未能证明其能够可靠地重复检测出你的产品中是否有致病菌。
You screened your Comfort Shield large three-packproduct (lot 53957) for presence/absence of microbiological contamination inMarch, 2016, using the (b)(4) method. The (b)(4) test did notdetect the presence of microbial contamination. You then released this lot fordistribution.
你们在2016年3月使用XX方法检测Comfort Shield大的三包产品（批号53957）中是否有微生物污染。XX检测并未检出微生物污染。然后你们将该批产品放行销售。
After receiving three consumer complaints fordiscoloration of this product, you initiated testing of your retains using boththe modified U.S. Pharmacopeia (USP) microbiological limits method and the (b)(4)method. Both analyses found microbial contamination. Notably, the USP modifiedmethod (b)(4) found an exceedingly high microbial count of over 57,000CFU/ml, and also identified Burkholderia cepacia, an objectionablemicroorganism, in this product lot.
在你们收到3个消费者投诉该产品的变变色情况之后，你们启动了对你们留样的检测，同时采用了修订后的USP微生物限度方法和XX方法。两种方法都发现有微生物污染。值得注意的是，在该批产品中，USP修订后的方法XX检出超过57,000CFU/ml的超标值，还检出洋葱伯克氏菌，一种致病菌。
Your drugs are often used in hospital or clinicalsettings in which patients may have a higher vulnerability to infection with B.cepacia and other objectionable organisms. Detecting numbers and types ofobjectionable microorganisms in your products is critical to making appropriatebatch disposition decisions, yet the microbiological screening method on whichyou rely to examine your products for the presence of microbiologicalcontamination has not consistently and reliably detected the presence of B.cepacia in your drugs before you released them for distribution. Forexample, since 2006, your firm conducted at least four recalls for productsassociated with B. cepacia contamination, including:
你们的药品通常在医院或临床使用，其中患者可能会对洋葱伯克氏菌和其它致病菌注射有着较高脆弱性。在你们产品中检出的致病菌数量和类型对于作出适当批次处理决策来说是非常关键的，而你们用以检查你们产品是否有微生物污染的微生物筛选方法并不能持续可靠地在你们放行销售之前检出你们药品中的洋葱伯克氏菌。例如，2006年开始，你们公司执行了至少4次与洋葱伯克氏菌污染有关的产品召回，包括：
2006年 Comfort shield 3% dimethicone cloths
2008年 2% chlorhexidine gluconate cloths
2014年 Comfort Shield 3% dimethicone cloths
2016年 3% dimethicone cloths
2% chlorhexidine gluconate cloths
M-Care cleansing cloths
Comfort Bath cleansing wash cloths
Had your firm been utilizing a screening methodcapable of consistently detecting B. cepacia, these products may nothave been released in the first instance.
如果你公司使用的是一种可以持续检出洋葱伯克氏菌的筛选方法，这些产品在刚开始可能就不会被放行。
During a June 28, 2016, teleconference, FDA informedyou that your (b)(4) method (b)(4) has not been adequatelyvalidated for detecting the presence of microorganisms, including the presenceof B. cepacia. In a subsequent meeting on November 30, 2016, FDA advisedyou to use a verified compendial method for all bulk drug solutions andfinished product microbiological testing until you could further assess thesuitability of the (b)(4)method. In the November meeting, your firm’smanagement agreed to continue efforts to assess the (b)(4) method, andif possible, validate it. However, you did not commit to using a compendialmethod until the (b)(4) method could be validated.
在2016年6月28日，在电话会议中FDA通知你你们的XX方法未充分验证其检出微生物的能力，包括洋葱伯克氏菌的存在。在2016年11月30日的后续会议中，FDA建议你们使用经过确认的药典方法来检查所有散装药品溶液和制剂微生物检测，直到你们对XX方法的适用性做出进一步评估。在11月的会议中，你公司的管理层同意继续努力评估XX方法，如可能，则进行验证。但是，你们并未承诺在XX方法被验证之前使用药典方法。
According to your firm’s Microbial EnumerationQTP-079, “classical method testing should be performed for samples that do nothave validated (b)(4) method testing to verify whether or not samplesmeet the microbial enumeration acceptance criteria.” Your firm continues tolack a validated (b)(4) method. While your response indicates that yourevised your SOP Microbial Recovery Validation, which references yourattempted (b)(4) validation method, the SOP modifications did notaddress the method inadequacies or demonstrate equivalence or superiority toUSP <61>Microbial Examination of Nonsterile Products: MicrobialEnumeration Tests and USP <62> Microbial Examination of NonsterileProducts: Tests for Specified Organisms at detecting objectionableorganisms such as B. cepacia and enumerating total microbial countlevels.
根据你们公司的微生物计数程序 QTP-079“如果没有经过验证的XX方法检查来核查该样品是否符合微生物计数可接受标准，则应采用传统方法检测。”你公司仍缺乏经过验证的XX方法。而你们的回复指出你们修订了你们的SOP“微生物回收验证”，其中参考了你们试图XX的验证方法，SOP修订并未说明方法的充分性或证明其等同或优于USP<61>“无菌药品微生物检查：微生物计数法检测”和USP<62>“无菌药品微生物检查：致病菌检测”，这两个章节是用于检测致病菌，如洋葱伯克氏菌以及计算总微生物数水平的。
Deficiencies in the (b)(4) method validationinclude the following.
在XX方法验证中的缺陷包括以下：
It specifies a (b)(4) dilution factor. USP <62> requires a 1:10 dilution factor. Your dilution factor is (b)(4)times greater than the USP method and provides insufficient detectability to rule out the presence of objectionable microorganisms and unacceptable total counts.
它指明了XX稀释倍数。USP<62>要求稀释倍数为1：10。你们的稀释倍数比USP方法大了XX倍，其检测度不足以排除致病菌的存在和不可接受的总计数。
It does not account for the enrichment step called for in USP <62>.
它未考虑USP<62>中要求的增菌步骤。
It does not include the scraping step during sample preparation, which your submitted laboratory data indicates is required to validate organism recovery.
它未包括样品制备过程中的刮擦步骤，你提交的化验室数据指标需要验证生物回收率
It lacks evidence that small numbers of various microorganisms, including those that are injured and stressed, can be reliably recovered. Specifically, sample effect (defined by your firm as the inhibitory effect of a sample on the growth of various microorganisms) data for B. cepacia was collected using a fresh-grown culture, not a stressed organism.
它缺乏证据证明小量不同微生物，包括受伤和受抑制微生物能被可靠回收。具体来说，样品对洋葱伯克氏菌的影响数据（你公司定义为样品对不同微生物生长抑制效果）是采用的新鲜生长培养物，而不是受抑制的生物。
Microbial recovery results for each challenge organism are not fully described. The identity of recovered growth from organism challenge studies was not always verified.
未完整描述每种用于挑战的生物所得的微生物回收结果。未能始终如一地确证微生物挑战研究中回收到的生长物种类。
It does not establish potential sample interference factors (e.g., enhancing or quenching) for each product formulation.
它未为每种药品配方建立可能的样品对照因子（例如，增强的或放宽松）。
2. Your firm failed to establishscientifically sound and appropriate sampling plans and test proceduresdesigned to assure that in-process materials and drug products conform toappropriate standards of identity, strength, quality, and purity (21 CFR211.160(b)).
你们公司未能建立科学合理和适当的取样计划和检测方法，设计用以确保中控物料和制剂成品符合适当的鉴别、剂量、质量和纯度标准（21 CFR 211.160(b)）。
Your written procedures for microbial enumeration areinsufficient to ensure that each batch is acceptable for distribution. Inparticular, your method lacks adequate provisions for performing (b)(4)testing when a positive result is obtained to ensure recovery and furtherevaluation of the microbiological contamination.
你们的书面微生物计数程序是不充分的，无法确保每批产品可以销售。尤其是你们的方法缺乏充分的条款在得到阳性结果时实施XX检测，以确保回收率和对微生物污染的进一步评估。
An original sample found to be contaminated using the (b)(4)test is not further analyzed. Instead, a small additional sample is testedusing a modified USP method (b)(4). If no growth is detected in thissmall sample, you require no further testing. You lack scientific justificationthat this (b)(4) sample is representative of the batch, and allows forproper evaluation of the positive result in (b)(4). As a result, the (b)(4)test is effectively used as a “confirmatory test,” rather than using it toevaluate and investigate the extent and type of contamination in the batch.
如果原始样品在使用XX方法检测时，发现受到污染，并不要求进行深入分析。相反，你们使用修订后的USP方法YY检测一个较小数量的附加样品。如果在此小数量样品中未发现生长，则你们不要求进行进一步检测。你们缺乏对此XX样品具有代表性的科学论证，允许对XX中的阳性结果进行适当的评估。在此基础上，XX结果被用作“合格检测”，而不是用作评价和调查批污染的程度和类型。
In your response, you also describe the (b)(4)test as destructive, which you contend “makes the processed (b)(4)preparations unsuitable for recovery and further testing.” Your response isinadequate. Your protocol for assuring subsequent enumeration andidentification when a positive result is obtained by the (b)(4) methodscreening test (b)(4) lacks sufficient detail. Among other things, yourprotocol does not ensure that (b)(4) testing adequately evaluates theextent and type of contamination present in the given batch, or that it employsa representative sample of the batch. Furthermore, the protocol does not assurethat appropriate investigations of any objectionable batch contamination areperformed, including when a preservative might have some efficacy against thegiven microbe. Lastly, the protocol does not provide for potentialspeciation of the detected microbial contamination in the(b)(4) initialscreening test.
在你们的回复中，你们还描述了XX检测是破坏性的，你们主张“因此样品制备处理后不适合回收或用于进一步测试”。你们的回复是不充分的。你们用于确保XX筛选方法得到阳性结果之后的计数和鉴别方案缺乏足够的详细信息。其中，你们的方案不能确保XX检测充分评估给定批中污染出现的程度和类型，或使用具有代表性的样品。另外，方案未能确保对所有可疑批污染进行适当的调查，包括当防腐剂可能对某些微生物产生抑制效果时。最后，方案未提供在XX初始筛选测试中检出的微生物污染的可能类别。
3. Your firm failed to clean,maintain, and, as appropriate for the nature of the drug, sanitize and/orsterilize equipment and utensils at appropriate intervals to preventmalfunction or contamination that would alter the safety, identity, strength,quality, or purity of the drug product beyond the official or other establishedrequirements (21 CFR 211.67(a)).
你公司未能对设备和工器具按适当的时间间隔进行清洁、维护，在适当时根据药品的属性进行消毒和/或灭菌以防止出现可能会改变药品安全性、鉴别、剂量、质量或纯度使其超出官方或其它既定要求的故障和污染。(21 CFR 211.67(a)).
Your acceptance criteria included in your bioburdenanalysis report (Analysis of In-Process Bioburden/Cleaning Surveillance for (b)(4)Line (b)(4)) failed to include B. cepacia on the listof objectionable organisms. This is despite the fact that your facilityhas a history of recurring B. cepacia contamination issues and that a2016 root cause investigation conducted in your facility revealed a biofilm hadbecome established within the Clean-in-Place (CIP) system servicing (b)(4) lines(b)(4). Your firm cultured and identified B. cepacia within thesecleaning samples from the CIP system. This root cause analysis was conductedfollowing the recall of product contaminated with B. cepacia.
你们在生物负载分析报告（XX产品XX线中控生物负载/清洁监管分析））中的可接受标准未将洋葱伯克氏菌包括在致病菌的清单中。这完全无视你们工厂重复发生洋葱伯克氏菌污染问题的历史，以及2016年在你们工厂进行的根本原因调查发现在你们的XX产品XX线的在线清洁（CIP）系统内发现生成了生物膜。你们公司在这些CIP系统的清洁样品中培养并鉴别出洋葱伯克氏菌。此根本原因分析是在召回受到洋葱伯克氏菌污染的产品之后实施的。
Drugs Made for You by ChemRite
你们公司由ChemRite生产的药品
You have engaged ChemRite to manufacture SagePerox-A-Mint, (b)(4). These products, which you test using the(b)(4)method discussed above, are adulterated as enumerated in the precedingviolations. They are also adulterated for the reasons set forth in WarningLetter 515029, issued by FDA to ChemRite on June 29, 2017. Among other things,ChemRite manufactured your oral solution drugs using the same equipment inwhich ChemRite manufactured toxic industrial-grade car washes and waxes. Youare responsible for ensuring that all of your products are manufactured inaccordance with CGMP, including oversight of the manufacturing operationsconducted by your contractor, ChemRite, on your behalf. Contractors areextensions of the manufacturer, and you are required to ensure that your drugsare made in accordance with section 501(a)(2)(B) of the FD&C Act toensure safety, identity, strength, quality, and purity. See FDA’s guidancedocument, Contract Manufacturing Arrangements for Drugs: QualityAgreements,www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm353925.pdf.
你们委托了ChemRite生产Sage Perox-A-Mint。由于上述所列违规情况，你们使用上述讨论的XX方法检测的这些产品均为掺假药。同时，由于在FDA于2017年6月29日签发给ChemRite的警告信515029中所列的原因，这些药品也被认为是掺假药。此外，ChemRite使用了与生产你们的口服溶液相同的设备来生产有毒的工业级汽车洗剂和蜡制品。你们有责任确保你们所有的药品生产符合CGMP，包括监管由你们的分包商ChemRite代表你们所执行的生产操作。分包商是生产商的延伸，你们应确保你们的药品符合FDCA的501(a)(2)(B) 部分，确保其安全性、鉴别、剂量、质量和纯度。参见FDA指南文件“药品委托生产安排：质量协议”。