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實習醫生日記之頑固失眠

實習醫生日記之頑固失眠

今日去我院某教授跟門診,有一位中年女性患者因“反復失眠20余年”來就診。在此之前我并不知道真正意義上的熊貓眼,不過今日可真的見識到了,特拍了一張照片:

實習醫生日記之—妊娠劇吐

實習醫生日記之—妊娠劇吐

劉某,女,32歲,第一次懷孕,停經已12周。該患者停經的第九周開始出現惡心嘔吐,開始時嘔吐尚不多,3-5次每天。后來嘔吐逐漸加重,7-8次每天,嘔不能食,嘔出食物及黃膽水。

實習醫生日記之豬蹄腳

實習醫生日記之豬蹄腳

組成 黃芪10克,黨參(或太子參)10克,丹參10克,炒白術10克,薏苡仁15克,仙鶴草15克,白花蛇舌草15克,甘草5克。功能 益氣活血,健運脾胃。主治 適用于治療慢性萎縮性胃炎,或伴有腸上皮化生等

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FDA爆出美國最臟藥廠 產品每毫升5萬多個菌落

字號:T|T|T
摘要:近日官網爆出美國制藥有限公司產品經檢查每毫升含菌量達并在其中檢出致病菌洋蔥伯克氏菌美國批評他們對微生物檢驗方法和方法驗證的不足和取樣和設施的缺陷并在在線清潔系統內發現生成了生物膜具體缺陷如下
FDA爆出美國最臟藥廠 產品每毫升5萬多個菌落

近日,FDA官網爆出美國Sage制藥有限公司產品經檢查每毫升含菌量達57000CFU,并在其中檢出致病菌——洋蔥伯克氏菌。美國FDA批評他們對微生物檢驗方法和方法驗證的不足和取樣和設施的缺陷,并在在線清潔(CIP)系統內發現生成了生物膜具體缺陷如下:
1. Your firm failed to establish anddocument the accuracy, sensitivity, specificity, and reproducibility of itstest methods (21 CFR 211.165(e)).
你公司未能制訂和記錄其檢測方法的準確度、靈敏度、專屬性和重復性(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.
你們在你們的工廠生產了許多藥品溶液(如2%葡萄糖酸氯己定),并且還有生產其它藥品的委托生產安排(例如Sage的Perox-A-Mint,是由ChemRite CoPac, Inc. (“ChemRite”)為你們生產的),采用XX為你們生產。你們使用了XX方法來剔除你們自己場所生產的以及委托場所生產的藥品的微生物污染。該XX篩選方法XX用于檢查你們液體藥品的微生物污染對于其既定用途來說是不充分的。你們試圖驗證你們的XX微生物檢出方法,但未能證明其能夠可靠地重復檢測出你的產品中是否有致病菌。
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.
你們在2016年3月使用XX方法檢測Comfort Shield大的三包產品(批號53957)中是否有微生物污染。XX檢測并未檢出微生物污染。然后你們將該批產品放行銷售。
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.
在你們收到3個消費者投訴該產品的變變色情況之后,你們啟動了對你們留樣的檢測,同時采用了修訂后的USP微生物限度方法和XX方法。兩種方法都發現有微生物污染。值得注意的是,在該批產品中,USP修訂后的方法XX檢出超過57,000CFU/ml的超標值,還檢出洋蔥伯克氏菌,一種致病菌。
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:
你們的藥品通常在醫院或臨床使用,其中患者可能會對洋蔥伯克氏菌和其它致病菌注射有著較高脆弱性。在你們產品中檢出的致病菌數量和類型對于作出適當批次處理決策來說是非常關鍵的,而你們用以檢查你們產品是否有微生物污染的微生物篩選方法并不能持續可靠地在你們放行銷售之前檢出你們藥品中的洋蔥伯克氏菌。例如,2006年開始,你們公司執行了至少4次與洋蔥伯克氏菌污染有關的產品召回,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種可以持續檢出洋蔥伯克氏菌的篩選方法,這些產品在剛開始可能就不會被放行。
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,在電話會議中FDA通知你你們的XX方法未充分驗證其檢出微生物的能力,包括洋蔥伯克氏菌的存在。在2016年11月30日的后續會議中,FDA建議你們使用經過確認的藥典方法來檢查所有散裝藥品溶液和制劑微生物檢測,直到你們對XX方法的適用性做出進一步評估。在11月的會議中,你公司的管理層同意繼續努力評估XX方法,如可能,則進行驗證。但是,你們并未承諾在XX方法被驗證之前使用藥典方法。
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.
根據你們公司的微生物計數程序 QTP-079“如果沒有經過驗證的XX方法檢查來核查該樣品是否符合微生物計數可接受標準,則應采用傳統方法檢測。”你公司仍缺乏經過驗證的XX方法。而你們的回復指出你們修訂了你們的SOP“微生物回收驗證”,其中參考了你們試圖XX的驗證方法,SOP修訂并未說明方法的充分性或證明其等同或優于USP<61>“無菌藥品微生物檢查:微生物計數法檢測”和USP<62>“無菌藥品微生物檢查:致病菌檢測”,這兩個章節是用于檢測致病菌,如洋蔥伯克氏菌以及計算總微生物數水平的。
Deficiencies in the (b)(4) method validationinclude the following.
在XX方法驗證中的缺陷包括以下:
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稀釋倍數。USP<62>要求稀釋倍數為1:10。你們的稀釋倍數比USP方法大了XX倍,其檢測度不足以排除致病菌的存在和不可接受的總計數。
It does not account for the enrichment step called for in USP <62>.
它未考慮USP<62>中要求的增菌步驟。
It does not include the scraping step during sample preparation, which your submitted laboratory data indicates is required to validate organism recovery.
它未包括樣品制備過程中的刮擦步驟,你提交的化驗室數據指標需要驗證生物回收率
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.
它缺乏證據證明小量不同微生物,包括受傷和受抑制微生物能被可靠回收。具體來說,樣品對洋蔥伯克氏菌的影響數據(你公司定義為樣品對不同微生物生長抑制效果)是采用的新鮮生長培養物,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.
未完整描述每種用于挑戰的生物所得的微生物回收結果。未能始終如一地確證微生物挑戰研究中回收到的生長物種類。
It does not establish potential sample interference factors (e.g., enhancing or quenching) for each product formulation.
它未為每種藥品配方建立可能的樣品對照因子(例如,增強的或放寬松)。
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)).
你們公司未能建立科學合理和適當的取樣計劃和檢測方法,設計用以確保中控物料和制劑成品符合適當的鑒別、劑量、質量和純度標準(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.
你們的書面微生物計數程序是不充分的,無法確保每批產品可以銷售。尤其是你們的方法缺乏充分的條款在得到陽性結果時實施XX檢測,以確保回收率和對微生物污染的進一步評估。
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.
如果原始樣品在使用XX方法檢測時,發現受到污染,并不要求進行深入分析。相反,你們使用修訂后的USP方法YY檢測一個較小數量的附加樣品。如果在此小數量樣品中未發現生長,則你們不要求進行進一步檢測。你們缺乏對此XX樣品具有代表性的科學論證,允許對XX中的陽性結果進行適當的評估。在此基礎上,XX結果被用作“合格檢測”,而不是用作評價和調查批污染的程度和類型。
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.
在你們的回復中,你們還描述了XX檢測是破壞性的,你們主張“因此樣品制備處理后不適合回收或用于進一步測試”。你們的回復是不充分的。你們用于確保XX篩選方法得到陽性結果之后的計數和鑒別方案缺乏足夠的詳細信息。其中,你們的方案不能確保XX檢測充分評估給定批中污染出現的程度和類型,或使用具有代表性的樣品。另外,方案未能確保對所有可疑批污染進行適當的調查,包括當防腐劑可能對某些微生物產生抑制效果時。最后,方案未提供在XX初始篩選測試中檢出的微生物污染的可能類別。
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)).
你公司未能對設備和工器具按適當的時間間隔進行清潔、維護,在適當時根據藥品的屬性進行消毒和/或滅菌以防止出現可能會改變藥品安全性、鑒別、劑量、質量或純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.
你們在生物負載分析報告(XX產品XX線中控生物負載/清潔監管分析))中的可接受標準未將洋蔥伯克氏菌包括在致病菌的清單中。這完全無視你們工廠重復發生洋蔥伯克氏菌污染問題的歷史,以及2016年在你們工廠進行的根本原因調查發現在你們的XX產品XX線的在線清潔(CIP)系統內發現生成了生物膜。你們公司在這些CIP系統的清潔樣品中培養并鑒別出洋蔥伯克氏菌。此根本原因分析是在召回受到洋蔥伯克氏菌污染的產品之后實施的。
Drugs Made for You by ChemRite
你們公司由ChemRite生產的藥品
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.
你們委托了ChemRite生產Sage Perox-A-Mint。由于上述所列違規情況,你們使用上述討論的XX方法檢測的這些產品均為摻假藥。同時,由于在FDA于2017年6月29日簽發給ChemRite的警告信515029中所列的原因,這些藥品也被認為是摻假藥。此外,ChemRite使用了與生產你們的口服溶液相同的設備來生產有毒的工業級汽車洗劑和蠟制品。你們有責任確保你們所有的藥品生產符合CGMP,包括監管由你們的分包商ChemRite代表你們所執行的生產操作。分包商是生產商的延伸,你們應確保你們的藥品符合FDCA的501(a)(2)(B) 部分,確保其安全性、鑒別、劑量、質量和純度。參見FDA指南文件“藥品委托生產安排:質量協議”。(生物谷 Bioon.com) 溫馨提示:87%用戶都在生物谷APP上閱讀,掃描立刻下載! 天天精彩!
FDA爆出美國最臟藥廠 產品每毫升5萬多個菌落
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