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【转载】2005 FDA cGMP问答:设备(自译中英文)  

2012-11-27 19:28:32|  分类: 生物医药产业 |  标签: |举报 |字号 订阅

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Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance Equipment


Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances.  Are such auto-calibration procedures acceptable instead of external performance checks?  If not, then what should the schedule for calibration be? 许多一流的天平制造商为其产品提供内置“自动校正”程序。这种自校程序是否可以代替外校?如果不可以,校正周期应如何制订?
Is there a list of CDER-approved drug manufacturing equipment? 药品生产设备是否有一个批准的清单?
Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?  (updated 5/18/2005) 总有机碳(TOC)是否可以作为检测清洁效果残留的方法?
A firm has multiple media fill failures. They conducted their media fills using TSB prepared by filtration through 0.2F m-sterilizing filter.  Investigation did not show any obvious causes.  What could be the source of contamination? 一个公司的培养基填充失效了。他们的培养基填充用的是经0.2μm无菌滤器过滤的TSB(胰蛋白酶大豆肉汤)。调查未发现明显原因。可能是受到什么污染?

 

 1.  Many leading analytical balance manufacturers provide built-in "auto calibration" features in their balances.  Are such auto-calibration procedures acceptable instead of external performance checks?  If not, then what should the schedule for calibration be? 许多一流的天平制造商为其产品提供内置“自动校正”程序。这种自校程序是否可以代替外校?如果不可以,校正周期应如何制订?

The auto-calibration feature of a balance may not be relied upon to the exclusion of an external performance check (211.68).  For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less frequently as compared to a scale without this feature.  The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step.  Note that all batches of a product manufactured between two successive verifications would be affected should the check of the auto-calibrator reveal a problem.  Additionally, the calibration of an auto-calibrator should be periodically verified--a common frequency is once a year--using National Institute of Standards and Technology (NIST)-traceable standards or NIST-accredited standards in use in other countries.天平的自校程序可能与外校程序(211.68)并不矛盾。我们推荐对于具有内置式自校程序的天平,其外校仍应周期进行,但校正频次可以比无自校程序的天平低。其校正频次取决于天平的使用频率,和工艺或分析步骤的关键性和允许误差。注意对自校程序的检查显示的问题会对两次连续校正间所有生产的批次产生影响。另外,应采用NIST或其他可溯源标准,对自校程序进行周期校验,频次通常为一年一次。

References:参考文献


21 CFR 211.68: Automatic, mechanical, and electronic equipment自动、机械和电子设备
21 CFR 211.160(b)(4): General requirements (Lab Controls)通用要求(实验室控制)
USP Chapter <41> Weights and Balances砝码和天平
See also:  ASTM standard E 617: Standard Specification for Laboratory Weights and Precision Mass Standards (this standard is incorporated into the USP by reference; other widely recognized standards may be acceptable) 实验室砝码和精密重量标准的质量标准 (该标准被USP采用,其它公认标准亦可以接受)

Contact for further information:更多信息请联系

Mike Gavini, CDER
gavinim@cder.fda.gov




 2.  Is there a list of approved drug manufacturing equipment? 药品生产设备是否有一个批准的清单?

No.  The CGMP regulations neither approve nor prohibit specific equipment for use in manufacturing of pharmaceutical products (with the exception of asbestos and fiber-releasing filters, see 211.72).  We do not maintain a list of approved equipment.  Firms are afforded the flexibility to select equipment that best satisfies their particular needs and that is capable of meeting the relevant CGMP requirements.  Each firm is responsible for selecting all equipment used in their manufacturing process to produce quality product in accordance with CGMP.  They are also responsible for selecting the appropriate intended use for the equipment's operation, and are free to modify standard equipment designs to best suit their process and that are compatible with the product under process.没有。CGMP法规从来没有批准或禁止某种设备用于药品生产中(除石棉和掉纤维的过滤器外,见211.72)。我们并没有列出批准设备的清单。公司可以自由选择最能满足他们工艺特殊要求的设备,同时满足相应的CGMP要求。每一公司负责选择用于自己生产工艺的设备,以生产出满足CGMP要求的产品。同时,公司负责根据其用途选择合适合地操作,并可自由地对标准设备设计进行改造以适应其工艺,并与该工艺下的产品相适应。

The CGMPs require that equipment be of appropriate design to facilitate operations for its intended use and for cleaning and maintenance (see 211.63 and 211.67) and, that any equipment surface in contact with components, in-process materials, or drug products not be reactive, additive, or absorptive so as to "alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements" (see 211.65).根据CGMP要求,设备设计应利于操作及其用途,以及清洁和维护(见211.63 和 211.67),并且所有设备与药物成分、在制产品或药物成品相接触的表面应不会与物料发生反应,不会有成分进入物料或吸收物料,以致“改变产品的安全性、均一性、剂量、质量或纯度,使偏离正式的或其他已确立的要求”。

References:参考文献


21 CFR 211.63: Equipment design, size, and location设备设计,尺寸和定位
21 CFR 211.65: Equipment construction设备结构
21 CFR 211.67: Equipment cleaning and maintenance设备清洁和维护
21 CFR 211.68: Automatic, mechanical, and electronic equipment自动、机械和电子设备
21 CFR 211.72: Filters过滤器

Contact for further information:更多信息请联系

Anthony Charity, CDER
charitya@cder.fda.gov

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 3.  Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness? 总有机碳(TOC)是否可以作为检测清洁效果残留的方法?

Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.可以。自从1993年清洁验证的检查指南颁布后,已有大量研究发表,论证TOC足以用于污染残留的检测。

TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC.总有机碳(TOC)或总碳(TC)可用于日常残留监测和清洁验证。为保证TOC的适用性,应首先确认所含的物料为有机物,其中的碳可以在TOC的测试条件下被氧化。这个问题很重要,因为有些有机化合物用TOC并不能保证被检出。

TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation. 残留TOC检测可以用于直接表面取样,亦可用于间接(淋洗样)取样样品的测试。任何一种情况下,因为TOC对不同含可氧化碳化合物进行区分,所以任何检出的碳都会包括在检测标的化合物中,与已有的标准进行比较。因而,公司应尽可能对“背景”碳(即非目标污染物来源的碳)进行限制。如果样品在TOC检测前放置了较长时间,公司应确认样品留置时间对精确度和定量限产生的影响。

References:参考文献


21 CFR 211.67: Equipment cleaning and maintenance.设备清洁和维护
21 CFR 211.160(b): General requirements (Laboratory Controls)通用要求(实验室控制)
USP 643 Total Organic Carbon总有机碳
Guide to Inspections of Cleaning Validation, 1993清洁验证检查

Contact for further information:更多信息请联系

Abi D'Sa, CDER
dsaa@cder.fda.gov

Brian Hasselbalch, CDER
hasselbalchb@cder.fda.gov

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 4.  A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through 0.2 micron sterilizing filter.  Investigation did not show any obvious causes.  What could be the source of contamination? 一个公司的培养基填充失效了。他们的培养基填充用的是经0.2μm无菌滤器过滤的TSB(胰蛋白酶大豆肉汤)。调查未发现明显原因。可能是受到什么污染?

A firm recently had multiple media fill failures.  The media fill runs, simulating the filling process during production, were conducted inside an isolator.  The firm used TSB (non-sterile bulk powder) from a commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter.  An investigation was launched to trace the source of contamination.  The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media, and examination under a microscope.  The contaminant was eventually identified to be Acholeplasma laidlawii by using 16S rRNA gene sequence.  The firm subsequently conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used.  Therefore, it was not a contaminant from the process, but from the media source. 一个公司增菌培养基填充失效,培养基的填充模拟生产工艺在一个隔离器中进行。公司采用的是市售TSB(非无菌批量粉),经过一个0.2um无菌过滤器制备无菌溶液。公司启动了调查,以追踪污染来源,调查采用了传统微生物技术,包括使用选择性(例如血琼脂)和无选择性(例如TSB和胰酪胨大豆琼脂)培养基,在显微镜下检查,仍未能成功分离出,或复原污染微生物。污染物最终被鉴定为莱氏无胆甾原体,原因是使用了16S rRNA基因序列,公司随即进行研究以确认在使用的TSB批次中存在该莱氏无胆甾原体。因而,此污染不是来源于工艺,而是来源于培养基。

Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane and have no cell wall.  They are not susceptible to beta-lactams and do not take up Gram stain.  Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in size from 0.2 to 0.3 microns or smaller.  It has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma laidlawii is known to be associated with animal-derived material, and microbiological media is often from animal sources.  Environmental monitoring of mycoplasma requires selective media (PPLO broth or agar).莱氏无胆甾原体属于支原体的一种。支原体只有个细胞膜而没有细胞壁,它不容易受到β-内酰胺传染,不被革兰氏染液染色,单体呈现为多形态(呈现多种形状,从球菌形到棒状,到细丝),大小不一,从0.2um到0.3um或更小。莱氏无胆甾体被发现可以穿过0.2um滤膜,但会被0.1um过滤器截留,其一般会存在于动物来源物料中,以及通常由动物来源制备的微生物培养基中,支原体的环境监控需要采用选择性培养基(PPLO肉汤或琼脂)。

Resolution:解决方法

For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter (note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation).  In the future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier.  (Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.)  The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify its removal.  In this case, a thorough investigation by the firm led to a determination of the cause of the failure and an appropriate corrective action. 目前,该公司已决定对制备的TSB用0.1um滤膜进行过滤以用于培养基填充(注:我们并未期望或要求公司常规地采用0.1um过滤培养基液)。将来,如果有商业供应情况下,该公司会对TSB进行灭菌、去辐射(公司的灭菌器太小无法进行TSB培养基填充,因此该方法不现实)。公司将继续对支原体进行监控,并已重新验证其清洁程序以确认支原体已被除去。在这种情况下,公司所进行的彻底调查找到了失败的原因,并制订了适当的纠正措施。

References:参考文献


21 CFR 211.113: Control of microbiological contamination微生物污染的控制
21 CFR 211.72: Filters过滤器
21 CFR 211.84(d)(6): Testing and approval or rejection of components, drug product container, and closures药物成分、制剂包材和密封材料的检测和放行或拒收
Sundaram, S., Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane filtration for removal of diminutive bioburden organisms in pharmaceutical products and processes. PDA J. Pharm. Sci. Technol. 1999 Jul-Aug; 53(4): 186-201.用隔膜过滤去除药品或工艺中的微小有机物的应用
Kong, F., James, G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific PCR for identification of common contaminant mollicutes in cell culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.
Murray, P., Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of Clinical Microbiology ASM Press, Sixth Edition.临床微生物学手册 第六版

Contact for further information:更多信息请联系

Brenda Uratani, CDER
uratanib@cder.fda.gov

 

Date created: August 4, 2004, updated May 18, 2005
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