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FDA官网cGMP问答: QC部分1. Many leading analytical balance manufacturers providebuilt-in "auto calibration" features in their balances. Are suchauto-calibration procedures acceptable instead of external performance checks? Ifnot, then what should the schedule for calibration be? 许多领先的天平生产商为其天平提供内置式“自动校正”功能。这样的自动校正程序是否可以替代外部性能测试呢？如果不能，那么校正计划应该是怎样的？ The auto-calibration feature of a balance may not be relied uponto the exclusion of an external performance check (211.68). For a scale with a built-in auto-calibrator, we recommend that external performancechecks be performed on a periodic basis, but less frequently as compared to a scalewithout this feature. The frequency of performance checks depends on thefrequency of use of the scale and the criticality and tolerance of the processor analytical step. Note that all batches of a product manufactured between twosuccessive verifications would be affected should the check ofthe auto-calibrator reveal a problem. Additionally, the calibration of anauto-calibrator should be periodically verified--a common frequency is oncea year--using National Institute of Standards and Technology (NIST)-traceablestandards or NIST-accredited standards in use in other countries. 天平的自动校正功能不能完全替代外部性能检查(211.68)。对于具有内置式自动校正装置的衡器来说，我们建议定期实施外部性能检查，但相比于没有此功能的衡器其频次可以低一点。性能检查的频次取决于衡器使用的频次，以及工艺或分析步骤的关键程度和允差。注意，如果自动校正装置检查中发现有问题的话，则两次连续校正之间所生产的所有批次产品均会受到影响。另外，应定期采用国家标准技术局 (NIST) 的可追溯标准或其它国家所用的经NIST 认证的标准来核查自动校正装置的校正---通常是一年一次。 2. Do CGMPs require that forced degradation studies always beconducted of the drug product when determining if a drug product stability testmethod is stability-indicating? 在确定一个药品稳定性测试方法是否具有稳定性指示性时，CGMP是否要求都对药品都进行强降解试验？
No. Drug product stress testing (forced degradation) may not benecessary when the routes of degradation and the suitability of the analytical procedurescan be determined through use of the following: 不是。如果降解途径和分析方法的适当性可以通过使用以下资料确定时，不一定要进行药品强降解试验： o data from stress testing of drug substance 原料药的强降解试验数据 o reference materials for process impurities and degradants 工艺杂质和降解产物的对照物质 o data from accelerated and long-term studies on drug substance 原料药加速和长期稳定性试验数据 o data from accelerated and long-term studies on drug product 制剂的加速和长期稳定性试验数据
Additional supportive information on the specificity of theanalytical methods and on degradation pathways of the drug substance may beavailable from literature sources. 从文献中也可以获得关于分析方法专属性和原料药降解途径的更多支持性信息。
Section 211.165(e) of the CGMP regulations states that theaccuracy, sensitivity, specificity, and reproducibility of test methods shallbe established and documented. Further, section211.166(a)(3) requires that stability test methods be reliable, meaningful, andspecific, which means that the content of active ingredient, degradationproducts, and other components of interest in a drug product can be accuratelymeasured without interference, often called "stability-indicating." CGMP 法规的第211.165（e）部分说应建立并记录分析方法的准确性、灵敏度、专属性和重复性。还有，第211.166(a)(3)部分要求稳定性分析方法是可靠的、有意义的以及具有专属性，这意味着可以准确测定制剂中活性成分、产物和其它有意义成分的含量，而不受到干扰，通常被称为“稳定性指示性”。
The CGMP regulations do not specify what techniques or tests areto be used to ensure that one’s test methods are stability-indicating. However,evaluating the specificity of the testmethods during forced degradation studies (i.e., exposing drug to extremes ofpH, temperature, oxygen, etc.) of drug substance and drug product often is necessary to ensurethat stability test methods are stability-indicating. But in certaincircumstances conducting a forced degradation study of justthe drug substance may be sufficient to evaluate the stability-indicatingproperties of a test method. CGMP 法规并没有指定用于确保分析方法具有稳定性指示的技术或测试。但是，为了确保稳定性试验所用分析方法具备稳定性指示性，在原料药和制剂强降解研究（即将药物暴露于极端的pH 值、温度、氧气等环境）中评估一个分析方法的专属性通常是有必要的。而在一定情形下，仅仅对原料药进行强降解试验可能就足以评估分析方法的称定性指示性特性了。
Generally, in determining whether it is necessary to conductforced degradation studies of the drug product, the specificity of the testmethod should be evaluated for its ability to assay drugsubstance, degradants, and impurities, in the presence of each other, withoutinterference. The evaluation also should provide assurance that there is not apotential for interaction between drug substance, degradants, impurities,excipients, and container-closure system during the course of the shelf-life ofthe finished drug product. 一般来说，在确定是否有必要对制剂实施强降解研究时，应该对分析方法的专属性进行评估，查看其是否有能力在原料药、降解产物和杂质共存时对这些成分进行分析，而不会被干扰。评估还应保证原料药、降解产物、杂质、辅料和容器密闭系统之间在制剂成品的货架其内不会发生相互反应。
Last, the rationale for any decision made concerning the extentof the forced degradation studies conducted as well as the rationale forconcluding that a test method is stability-indicatingshould be fully documented. 最后，要全面记录所实施的强降解试验的程度决策合理性，以及得到结论说一个分析方法具有稳定性指示性的合理性论证。
3. When performing the USP <788> Particulate Matter inInjections test for a Large Volume Parenteral (LVP), is it acceptable to takethe average among the units tested to determine if the batch meets itsspecification for this attribute? 在对大容量注射剂（LVP）做USP<788>注射剂中颗粒物检测时，是否可以采用受测单元测试结果的平均值来确定该批次是否符合此项目标准？
No. It is not acceptable to take the average among the LVP unitstested in each batch/lot when following this method because the purpose of thismethod is to measure and limit intra-batchvariability. 不可以。按照此方法检测时，采用每批次里受测LVP单元的平均值是不能接受的，因为此方法的目的是测量并限制批内差异。
"Particulate matter" refers to small, sub-visibleparticles. USP <788> provides two tests for detecting suchparticulates--light obscuration and microscopicassay. Both are generally accepted for use in testing LVPs and small volumeparenterals (SVP) for the determination of sub-visible particulate matter.Normally, samples are first tested by the light obscuration method; if thesample fails the specified limits, the microscopic assay method can then beused. However, the microscopic method can be the sole test if there is adocumented technical reason or interference from the product under test thatwould make the light obscuration method unsuitable or the results invalid. "颗粒物"指很小的、肉眼不可见的颗粒物。USP<788>提供了两种检测方法来检出此类颗粒物---光阻法和显微镜方法。两种方法用于LVP和小容量注射剂（SVP）检查用于确定不可见颗粒物时一般都是可以接受的。一般来说，会先采用光阻法来检测，如果样品不符合指定的标准，则可以再使用显微镜法。而如果有文件记载的技术原因或来自产品的干扰，会让光阻法不适合或结果无效，则显微镜法则可以单独测试。
Confusion about when averaging data is and is not acceptable isprobably due to the sample preparation method for the light obscuration test(USP <788>). At least 2, 5-mL aliquots from each sampled unitor the pooled sample (see below) are to be used in the particulate countdetermination, and the results from these aliquots are to be averaged forcomparison with the specification. Note that the average is of the results fromexamining each aliquot and not between units. (Theresults of the first aliquot examined by light obscuration are to be discarded,and the subsequent aliquots--2 or more--are retained.) Poolingunits prior to analysis is permitted only if the volume in each unit is lessthan 25 mL, in which case 10 or more units may be pooled. If the volume inthe SVP or LVP is 25 mL or more per unit, single units are to be examined bythis method (USP <788>). 对于什么时候可以对数据进行平均，什么时候不可以平均的迷惑可能是由于光阻法样品制备方法引起的（USP<788>）。在颗粒物计数检测中，从每个取样单位中或倾出样品（见下）中要取用至少2.5ml 液体，从这些液体检测中所得的结果要进行平均计算，然后和标准进行比较。注意，这些用于平均值计算的结果是来源于同一液体的检验，而不是不同受检单元（光阻法检测的第一份液体结果要弃除，保留之后的结果---2 个或更多）。只是当每个单元的体积小于25ml 时，才允许在检验之前将制剂从包装里倾倒出来，这时可能会需要倒出10个或更多包装单位。如果每个SVP 或LVP 单元里的体积为25ml 或更多，则应该使用一个单元供本法检测（USP<788>）。
Results among the test units cannot be averaged becauseparticulate matter is assumed to be non-uniformly dispersed throughout the lot.The intent of assessing results from each individual unit is to ensureadequate representation of the lot and to detect potential variation within alot. 不同制剂单位的结果不能做平均计算，因为颗粒物被认为是不均匀地分散在一个批次中。评估每个单独包装单位的结果意在确保足以代表该批次，并能检出一个批次内潜在的差异。
As to the number of individual units to be tested for LVP andSVP units having a volume of 25mL or more, the USP states that the number ofunits tested depends on "statistically sound samplingplans," and "sampling plans should be based on consideration ofproduct volume, numbers of particles historically found to be present incomparison to limits, particle size distribution of particles present, andvariability of particle counts between units." The USP also suggests thatthe total number of units tested for any given batch may be less than 10 units(for LVP and pooled SVPs) with proper justification. This is consistent withthe CGMP requirement for statistical sampling plans (see 211.165). 到于体积达到或超过25ml 的LVP 和SVP 包装单位里要被检测的单个包装单位的数量，USP说该数量取决于“统计学合理的取样计划”，以及“取样计划应基于产品体积、历史上发现的颗粒物数量相比于限度、所发现的颗粒物的粒径分布、不同包装单位之间颗粒物计数差异的考虑”。USP 还建议对于任何指定的批号，如果有适当的论证，要检测的包装单位总数量可以少于10 个单位（对于LVP 和倾出SVP）。 这与统计学取样计划的CGMP 要求是一致的（参见211.165）。 4. Can Total Organic Carbon (TOC) be an acceptable method fordetecting residues of contaminants in evaluating cleaning effectiveness? 总有机碳（TOC）是否可以作为清洁效果评估里污染物残留检测的方法？
Yes. Since the publication of the inspection guide on cleaningvalidation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues. 可以。自从1993 年清洁验证检查指南发布之后，已有大量研究被发布用以证明TOC在污染物残留测量中的充分性。
We think TOC or TC can be an acceptable method for monitoringresidues routinely and for cleaning validation. But in order for TOC to be functionallysuitable, it should first be established that a substantial amount of thecontaminating material(s) is organic and contains carbon that can be oxidizedunder TOC test conditions. This is not a trivial exercise because we know thatsome organic compounds cannot be reliably detected using TOC. 我们认为TOC 或TC 用作残留的日常监测方法和清洁验证方法是可以接受的。但是为了确保TOC 方法的适用性，首先应该确定主要数量的污染物是有机物，并且含有可以在TOC 测试条件下被氧化的碳。这种做法并不过分，因为我们知道有些有机化合物使用TOC 是无法可靠检出的。
TOC use may be justified for direct surface sample testing aswell as indirect (rinse water) sample testing. In either case, because TOC doesnot identify or distinguish among differentcompounds containing oxidizable carbon, any detected carbon is to be attributedto the target compound(s) for comparing with the established limit. Thus, afirm should limit 'background' carbon (i.e., carbon from sources other than thecontaminant being removed) as much as possible. The established limit, or theamount of residue detected for comparison to the specification, should correctfor the target material's composition of carbon. As for any cleaning method,recovery studies are necessary (211.160(b)). If TOC samples are being held forlong periods of time before analysis, a firm should verify the impact of sampleholding time on accuracy and limit of quantitation. 可以通过论证证明TOC 能用于直接表面取样测试，以及间接（淋洗）取样测试。两种情况，由于TOC 并无法识别或区分出含有易氧化碳的不同化合物，所有检出的碳都会计为目标化合物，与既定限度进行比较。因此，公司应尽可能限制“背景”碳（即，不是需要清除的污染物来源的碳）。所制订的限度，或者是所检出用于与标准相比较的残留数量，均应使用目标物料的碳含量进行计算。所有的清洁方法均需进行回收率研究（211.160（b））。如果TOC 样品放置时间过长才进行检测，公司应确认样品放置时长对定量准确性和定量限的影响。
5. Would a paramagnetic or laser oxygen analyzer be able todetect all possible contaminants or impurities in a medical gas? 顺磁或激光氧 分析仪是否可以检出医用气体中所有可能的污染物或杂质？
No. Although, paramagnetic and laser oxygen analyzers are veryaccurate and reliable when calibrated correctly, these types of analyzers canonly detect the identification and strength of oxygen. They areunable to detect contaminants or impurities that may be present, such ashydrocarbons or arsenic compounds. According to the USP General Notices, ForeignSubstances and Impurities section, "it is manifestly impossible to includein each monograph a test for every impurity, contaminant, oradulterant that might be present." The USP monograph test for oxygen doesnot include an impurity screen and other analyzers may need to be used. Forexample, assays for hydrocarbon impurities are routinely conducted during the oxygen manufacturing process even though the USP does not listhydrocarbons as an impurity. Also, alternative methods may be needed to test high-pressurecylinders for cleaning solution residues. 不能。虽然顺磁和激光氧分析仪在正确校正的情况下是非常准确可靠的，但这类分析仪只能鉴别以及检出氧含量，而不能检出可能的污染物和杂质，如，碳氢化合物或砷化合物。根据USP 通则，异物和杂质部分，“显然，在每一个各论中包括对所有杂质、污染物和可能出现的伪药成分的检测是不可能的”。USP 各论中对氧气的检测并不包括杂质筛选，如果要做，则可能需要使用其它的分析仪。例如，尽管USP 里并没有将碳氢化合物列为杂质，但一般在氧气生产过程中都会检测碳氧化合物。还有，可能需要有替代方法来检测高压气瓶的清洁溶液残留。 6. Can up to twelve month expiration-dating be assigned to oralsolid and liquid dosage forms repackaged into unit-dose containers based on guidancein the May 2005 draft revision of Compliance Policy Guide, Section 480.200(7132b.11), “Expiration Dating of Unit Dose Repackaged Drugs”? 在将固体口服和液体口服制剂重新包装至单剂量容器后，是否可以根据2005 年修订后的《符合性方针指南》第480.200（7132b.11）草案“单位剂量重新包装药品有效期计算”给定12 个月的有效期呢？
No. In May 2005, a Notice of Availability of the draft revisionof FDA's Compliance Policy Guide Section 480.200 (CPG 7132b.11), “Expiration Dating of Unit-Dose Repackaged Drugs,” was announced in theFederal Register. The draft CPG specifies certain conditions when it may be possibleto assign up to twelve month expiration-dating to non-sterile solid and liquidoral drug products repackaged into unit-dose containers without conducting newstability studies to support the length of expiration-dating on the repackagedproducts. The draft CPG was prompted by United States Pharmacopeia (USP)standards for assigning up to a twelve month "beyond-use date" tonon-sterile solid and liquid oral dosage forms dispensedin unit-dose containers. (“Beyond-use date” is USP’s pharmacy dispensing termfor specifying a date on a prescription container beyond whicha patient should not use the product.) If finalized, FDA’s draft CPG wouldreplace the current version of CPG Section 480.200. The current versionof CPG Section 480.200 was finalized in March 1995 and provides conditionsunder which FDA will not initiate action for assigning up to six monthexpiration dating for drug products repackaged into unit-dose containerswithout conducting new stability studies. 不可以。2005 年5 月，《联邦通讯》发布了修订后的《符合性方针指南》第480.200（7132b.11）草案“单位剂量重新包装药品有效期计算”通知。CPG 草案指明在某些条件下可以为重新包装至单剂量容器的非无菌固体口服和液体口服制剂给定12 个月有效期，而不需要新的稳定性研究数据来支持重新包装后药品的有效期长度。CPG 草案是由USP 标准推出的，它为分装至单剂量容器中的非无菌固体和液体口服制剂给定“超出使用日期”12 个月。（“超出使用日期”是USP 的药房配药术语，用于在处方容器上指定一个日期，超出这个日期后患者就不应该再服用此药）。如果最终定稿，FDA 的CPG 草案会替代当前的CPG 第480.200 部分。当前的CPG 第480.200 部分是在1995 年3月定稿的，它指定了在哪些条件下将药品重新包装至单剂量容器中，可以给定6 个月有效期，而不需要进行新的稳定性研究，FDA 不会 采取措施。
FDA is conducting a stability study of certain commerciallyrepackaged drugs to determine the suitability of the draft revision of CPGSection 480.200. Until the stability study iscomplete and FDA evaluates all comments submitted to the public docket in responseto the May 2005 Federal Register Notice of Availability, the agency does notintend to make a final decision on the draft revision of CPG Section 480.200.Consequently, at this time and until FDA announces a final decision on thedraft CPG, the current CPG ection.480.200, which was finalized in March 1995,is in effect. FDA 正在对某些商业化重新包装的药品进行稳定性研究，以确定修订后CGP 第480.200 部分草案的适用性。在完成稳定性试验，FDA 对所有提交到公众信箱的对2005 年5 月《联邦通讯》中发布的通知的建议进行评估之前，当局并无意将草案变成最终决定。因此，目前阶段，在FDA 宣布CPG 草案定稿之前，现行的1995 年3 月定稿的CPG 第480.200 部分还是有效的。 (由于公众号篇幅字数限制，以下只提供中文版) 7. 使用一个未经验证的方法来检测药品成分或制剂是否恰当？
CGMP 法规要求使用经过验证的方法对制剂生产用原料、在制物料和成品进行日常检验(21 CFR 211.160, 211.165(e), and 211.194)。方法验证研究提供证据证明一个方法符合其既定用途。该用途一般是用于测量特定的物料的指标是否符合既定的质量标准（参见FDA 行业指南，ICH Q2（R1））。
但是FDA 了解在对潜在的质量问题或缺陷进行调查的过程中，一些特定情形下使用根据科学合理的原则（例如，足够的准确性和精密度）开发但未全面验证的分析方法可能也是适当的。例如，调查药品或其组分（例如，肝素中OSCS）中的异常杂质或可能污染物可能会显示需要日常质量控制检测之外的方法。此类检测可能对于快速充分评估问题和保护公众健康来说是很关键的。在某些调查中进行检测时，可能不太现实也不合适对方法的耐用性和重现性进行全面的评估。
当一个公司，不管因为什么原因，使用未经验证的方法检验药物成分或药品时，很重要的一点是要认识，相比于经过验证的方法，未经验证的方法其检测结果的不确定度更大。当然，所获得的结果数据可能会给出重要信息，需要立即采取纠正措施。相应地，我们期望所有此类对药物成分或药品的检测结果要进行审核，以评估是否需要跟进措施（211.192 and 211.180(e)）。 8. FDA 是否撤回了1987 年指南“鲎试剂检测作为人用注射用药、生物制品和医疗器械的成品内毒素检测”？
是的，FDA 撤回了1987 年的指南。1987 年的指南被认为过时了，不能反映出当局对此主题当前的看法。
9. 药品生产商在哪儿能找到关于内毒素检测的信息？
USP 在通论<85>细菌内毒素测试中发布了内毒素测试建议和可接受标准。SP<85>提供了药品的检测方法和计算限度。必要时，FDA 可以提供另外的指南来澄清当局目前对使用LAL 以及其它内毒素检测方法的想法。 10. 如果一个药品曾经被暴露在青霉素中，是不是只要没有检出青霉素残留，就可以放行该非青药物呢？
21 CFR 211.176 青霉素污染允许销售经过法定方法检测并且未发现受到青霉素污染的非青药物。但是，只有要符合其它所有适用的CGMP要求前提下，该放行才是可以接受的。在有些情形下，公司不恰当地应用了§ 211.176 来销售不在CGMP 条件下生产的药物。尤其是，21 CFR 211.42(d)要求青霉素药物的生产操作应该在与其它非青人药隔离的设施中进行。类似地，21 CFR 211.46(d)要求青霉素和非青药物的 空气处理系统完全独立。
例如，如果一个非青药物是在一个与青霉素生产区域共用的设备或空气处理系统的设施里生产的（违反§ 211.46(d))，则非青药物就不能只是通过检测来达到CGMP 符合性要求了。而如果在青霉素专用区域和其它独立的生产区域之间的一扇门被无意间打开，导致其它区域可能暴露于青霉素中，检测这些非青药物中的青霉素残留则可以支持其放行销售。
但是，根据21 CFR 211.165，所有非青药物检测和放行取样计划和可接受标准，包括所有青霉素污染检测，必须足以确保受测药物符合其所有质量标准。 11. 一个生产青霉素制剂的工厂是否可以清除污染，重新改造用于非青霉素制剂的生产？改造后不再其中生产青霉素药品。
可以，但是污染清除可能会非常难。污染清除过程必须包括科学合理的研究，证明污染清除用试剂的有效性，在污染清洁前后在整个区域进行统计学意义取样以验证其清洁度，对这些样品采用经过验证的具有适当检出限的分析方法进行适当检测。CGMP 法规21 CFR 211.176 要求如果非青霉素药品有合理可能性曾经暴露于青霉素交叉污染的话，则非青霉素药品必须进行测试，证明其无青霉素残留，如果使用法定方法检测发现可以检出青霉素，则该药品不得销售。如果污染清除做的不是很有效，则可能会存在此合理可能性。尽管CGMP法规并没有禁止清除污染并改变其用途，但对青霉素残留的清洁难度可能会导致此过程相当艰难。 12. 非青霉素药品中的青霉素残留是否有可接受水平？
没有。在非青霉素药品中没有建立青霉素产品的安全水平（参见FDA行业指南，以下参考文献）。在21CFR 211.42(d)和211.46(d)中的CGMP规定要求青霉素生产设施和空气处理系统必须与其它药品生产用生产设施和空气处理系统要充分隔离。21 CFR 211.176 说非青霉素药品中如果根据法定方法检测并发现有青霉素残留的话，则不能销售。如果证明有替代方法等同或优于所引用的方法，则也可以使用替代方 法来检出青霉素残留。 13. 多剂量容器中的注射用药品中，进入抽取一定剂量的次数是否是确定有效期的一个因素？
一般来说不是。除多剂量容器标示了指定体积剂特定的次数外，在药品用完或达到其有效期之前，从多剂量容器中抽取药品的次数是没有限制的。对于多剂量容器的基本担忧是多次穿刺容器塞子可能会导致药品污染。尽管为此类药品的制订的有效期是基于药品稳定性的，稳定性方案应包括测试和评估容器密闭完整性的要求。容器密闭完整性测试可以包括使用泄漏测试从物理方面测试密闭系统的密封性，以及监测系统防止微生物污染的能力。对于多剂量注射药品的容器，功能性测试可以包括自封能力测试，采用皮下注射针穿刺容器塞子（参见以下USP 参考文献）。另外，多剂量容器中的注射用制剂通常配方中含有抗微生物剂或防腐剂----或者内含抗微生物的成分----必须符合批准的申报资料（NDA/ANDA，BLA）和/或USP 要求。 14. 在将在制品/中间体粉料混合物和研磨物、待放行丸/粒、片芯用于最终制剂时，如果没有单独的稳定性研究，能放多久？ 对于理化性质稳定和在制品/中间体物料，对其进行基于风险的科学评估有助于识别出哪种物料属性和工艺参数可能会影响其将用于生产的制剂成品的关键质量属性。此评估的设计应确保所存贮的物料（在适当的存贮条件下）在指定的时间段内仍适合用于制剂成品的生产中，而不需要进行正式的稳定性研究来验证存贮期限。在有些情形下，风险评估可以包括所存贮物料的取样和检测（由风险评估决定在哪个阶段），以验证生产存贮期限。
但是，对于不稳定性的物料，或者是对于存贮时间已超出风险评估所定的期限的物料，公司应根据批准的稳定性试验方案进行稳定性研究以验证存贮期限。稳定性试验应包括对在制品/中间物料存贮直至其用于制剂成品生产的时长，应包括对使用了该在制品/中间物料所生产的制剂成品批次的长期监测。
在后一种情形下，当生成了适当的稳定性数据时，公司应根据在制品/中间物料的生产/放行日期来计算制剂成品批次的有效期，而不是根据制剂成品的生产日期来计算。
FDA cGMP问答：青霉素药物（2014更新） Questions andAnswers on Good Manufacturing Practices Good GuidancePractices, Level 2 Guidance Buildings and Facilities 厂房与设施 1. What isPenicillin? 什么是青霉素？ Penicillin isdefined as a group of natural or semi-synthetic antibiotics derived from fungistrains of the genus Penicillium. Generally, all penicillin share athree-carbon, one-nitrogen, and four-member cyclic amide structure, known asthe beta-lactam ring. 青霉素是指一些由青霉素类霉菌发酵而成的自然或半合成抗生素。一般来说，所有青霉素都具备相同结构，即三个碳，一个氮，四元环酰氨结构，即通常所说的β-内酰胺环。 2. What are thePenicillin drugs? 什么是青霉素药物？ The Manual ofClinical Microbiology, 9th edition, identifies penicillin drugs as follows: 临床微生学手册第九版将青霉素药分类如下 NaturalPenicillins: 全发酵青霉素类 Benzylpenicillin* (commonly known as penicillin G) 苄青霉素（通常也称为青霉素G） Benzylpenicilloyl-polylysine (BPP) 苄基青霉素多熔素（BPP） Phenoxymethyl penicillin* (commonly known as penicillin V) 苯氧基青霉素（即青霉素V） Semi-syntheticPenicillins: 半合成青霉素类 Methicillin 甲氧苯青霉素 Nafcillin 乙氧萘青霉素 Cloxacillin* 邻氯青霉素 Dicloxacillin* 双氯青霉素 Ampicillin* 氨苄青霉素 Amoxicillin* 阿莫西林 Bacampicillin 巴氨西林 Pivampicillin 匹氨西林 Carbenicillin 羟苄青霉素 Ticarcillin* 替卡西林 Azlocillin 阿洛西林 Mezlocillin 美洛西林 Piperacillin 哌拉西林 Hetacillin* 海他西林 *Penicillinsapproved for veterinary use “项为兽用青霉素 Please be awarethat penicillin trade names may vary by region and country. Manufacturers,including repackers, are responsible for knowing whether their drug ispenicillin. FDA’s “Approved Drug Products with Therapeutic EquivalenceEvaluations” (Orange Book) or Drugs@FDA, both of which are located at FDA’swebsite, enable searching by trade name (i.e., proprietary name) and by activeingredient name (i.e., generic or non-proprietary name). 需要注意的是青霉素的商品名可能因国家和地区差异而不同。生产商，包括分装商有责任知晓他们生产的药品是否青霉素。自FDA官方网站上公布的FDA的“已批准药品及其药学等效性评价”（橙皮书）或Drugs@FDA，可以用商品名（即专利商品名）和活性成分（即仿制或非专利名）进行查阅。 3. Iscross-contamination a concern with penicillin drugs? 交叉污染在青霉素药的是否受到重视？ Yes, penicillincan be a sensitizing agent that triggers a hypersensitive exaggerated allergicimmune response in some people. Differences in the chemically substituted6-aminopenicillanic acid side chain can generate allergic reactions rangingfrom skin rashes to life-threatening anaphylaxis. 是的。青霉素是高致敏药物，有些人可能会出现严重的过敏反应。根据6-氨基青霉素酸侧链不同，可能引发的从皮疹至危及生命的过敏反应。 4. Are therespecial manufacturing requirements for Penicillin drugs? 对青霉素药品的生产有特殊的要求吗？ Yes, allpenicillin finished pharmaceutical manufacturers, including repackers, arerequired by the CGMP regulations to establish a comprehensive control strategydesigned to prevent cross-contamination of other drugs with penicillin. Theserequirements include: 是的。所有青霉素制剂的生产商，包括分装商，应按照CGMP要求建立全面控制策略以防止青霉素与其他药品之间的交叉污染。包括： 21 CFR 211.42(d): Separation of facility and equipment 设施和设备的隔离 21 CFR 211.46(d): Separate air handling systems (HVAC) 空调净化系统的隔离 21 CFR 211.176: Test for traces of penicillin where possible exposure exits. 可能暴露的地方痕量青霉素的检测 PenicillinActive Pharmaceutical Ingredients (APIs) are also required to be manufacturedunder CGMPs in accordance with Section 501(a)(2)(B) of the Federal Food, Drug,and Cosmetic Act. FDA has published internationally harmonized guidance on themanufacture of APIs; see International Conference on Harmonization (ICH) Q7AGood Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.Chapter 4, section 4.4 of this guidance describes actions API manufacturers,including those who manufacture or package APIs or penicillin intermediates,are to follow to ensure such material is contained and does not contaminateother drugs.青霉素原料药的生产也要求符合联邦食品药品和化妆品法案501(a)(2)(B)的CGMP要求。FDA已经公布了原料药生产的ICH指南，见ICH Q7A 活性药物成分的GMP，该指南第四章第4.4部分指出了原料药生产商，包括青霉素原料药和中间体的生产和分装商，应采取的措施，以保证包含该物料，且未污染其他药品。 References: 参考文献 1. Yao, JosephD. C., and Robert C. Moellering, Jr. “Antibacterial Agents.” Manual of ClinicalMicrobiology. 9th ed. Washington D.C., ASM, 2007 “抗生素试剂”临床微生物手册，第9版 2. FDA CGMPregulations (21 C.F.R. Parts 210-211) FDA CGMP法规（21CFR第210-211部分） 3. The FederalFood, Drug, & Cosmetic Act 501(a)(2)(B) 联邦食品、药品和化妆品法案501(a)(2)(B) Contact forfurther information: 更多信息请联络 Edwin Melendez,Consumer Safety Officer CDER/OC/DMPQ/MAPCB Division ofManufacturing and Product Quality (HFD-320): CGMP Subject Contacts
5. Why is FDA concerned about drug contamination with halogenated anisolecompounds, such as 2,4,6-tribromoanisole (TBA)? 为什么FDA要考虑药品被卤代苯甲醚化合物，如2，4，6-三溴苯甲醚（TBA）的污染？ Reports, including some dating back several decades, describe a moldy ormusty odor in food (and wine) products due to contamination with trace amountsof halogenated anisole compounds such as 2,4,6-tribromoanisole (TBA). An odor attributable to the presence of a halogenated anisolecompound can be detected by consumers even when the offending compound ispresent at parts per billion or lesser levels. Recently, an upward trendin consumer complaints about musty or moldy odor led a drug firm to identifyTBA as the odor-causing compound. The firm’s investigation of thisincident led to the detection of TBA in several oral products. The firmtraced all of the contamination back to the use of certain wooden pallets usedto transport drug packaging materials. TBA is prone to volatilize andadsorb onto articles stored near the TBA source. Because of theirvolatility, it appears that even minute levels of halogenated anisole compoundscan adversely affect a large quantity of product in a single contaminationincident. 曾有报道，包括一些几十年的报道，描述食品（和红酒）中有一种发霉的气味是由于痕量2,4,6-三溴苯甲醚（TBA）污染所致。当这卤代苯甲醚存在时，即使当这种刺激性物质的浓度只有十亿分之一或更低水平时，消费者也能感觉到其气味。最近，由于消费者关于发霉气味的投诉导致药厂鉴别出TBA是气味来源物的案例呈上升趋势。公司对该事件的调查发现在几种口服药品中检出TBA。公司追踪了所有污染物直到药品运输中包装用的某些木质托盘，发现TBA易于挥发，并被存贮在TBA附近的产品吸收。由于其挥发性，即使是数分钟的时间，卤代苯甲醚化合物也可能在一个污染事故中不可逆地影响大量药品。 Date: 3/12/2010
6. Are there any health effects associated with ingestion ofhalogenated anisole compounds? 摄取卤代苯甲醚化合物是否会对健康产生任何影响？ Although there is no meaningful toxicological data on TBA at these levels,the health risks appear to be minimal. Currently available data indicatethat serious adverse health effects have not resulted from ingestion of drugsor foods contaminated with halogenated anisole compounds at the levels ofcontamination that have been reported. However, there are some reports ofgastrointestinal events by consumers who also report sensing a foul odor, ortaste, in drug products contaminated with the typical trace levels ofTBA. Even if the health effects are minimal, FDA is concerned thatpatients sensing an unusual odor that is not intrinsic to the product will stoptaking their medication. 尽管还没有任何关于TBA在此程度上的有意义的毒理学数据，健康风险貌似非常小。目前已有数据表明，被卤代苯甲醚化合物在已有报道水平所污染的食品和药品摄入不会对健康产生严重的负面影响。但是，也有一些关于消费者肠胃反应事件的报道称，当事人在典型的痕量水平TBA污染的药品中感觉到恶臭气味，或味道。即使其对健康的影响非常小，患者由于感觉到药品中固有的气味而停止服药仍引起FDA的关注。 Date: 3/12/2010
7. Has FDA identified the source of the halogenated anisole compoundsthat have recently contaminated drug products? FDA是否已经找到了近期污染药品的卤代苯甲醚的污染源？ The source of TBA-contaminated drug products appears to have been2,4,6-tribromophenol (TBP), a chemical used as a wood preservative. Certain fungi are able to survive in TBP-treated wood by converting TBPto its anisole analog, TBA[1]. In the recent contaminationincident, an investigation found that TBP-treated wood was used to manufacturepallets that were then used to ship and store drug packaging material. Currently, the use of halogenated phenolic compounds to preserve wood appearsto be very rare as this practice is either discouraged or prohibited in manyregions of the world, including the US. However, TBP treatment of woodcontinues in some regions that supply wood to the US and other countries. 被TBA污染的药品的污染源貌似是2,4,6-三溴基苯酚（TBP），一种用作木制品防腐剂的化学物质。一些真菌可以将TBP转化为其卤代对应物TBA，从而在TBP处理后的木制品中存活。在的污染事件中，一次调查发现TBP处理后的木材用于生产托盘，这些托盘用于运输和存贮药包材。目前，卤代苯酚化合物用作木材防腐剂是非常少的，因为它在世界很多地区，包括美国，要么是不鼓励，要么是禁止的。但是，在有些地区，仍采用TBP处理木材，这些木材被供应给美国和其它国家。 Date: 3/12/2010
8. What is FDA’s expectation for preventing contamination of drugproducts with halogenated anisole compounds? FDA对防止药品被卤代苯甲醚化合物污染的期望如何？ FDA recommends that manufacturers and distributors take precautions toprevent the use of wood products treated with or exposed to a halogenatedphenolic preservative anywhere in supply chain. This includes allfacilities that manufacture, hold, or distribute drug products, components, orpackaging materials. We recommend that manufacturers not store drugproducts, components, or packaging materials near wood or wood-derived storagematerials unless there is assurance that the wood material has not been treatedwith a halogenated phenolic preservative.
FDA建议生产商和分销商在供应链中注意不要使用采用卤代苯酚防腐剂处理过或曾暴露于卤代苯酚防腐剂的木制品，其中包括所有生产、存贮或销售药品、化合物和包材的场所。我们建议生产商不要将药品、化合物或包材存贮在木材或木制品存贮材料附近，除非可以保证木质材料未被采用卤代苯酚防腐剂处理。 FDA further recommends that manufacturers establish agreements and requestcertification from suppliers to provide assurance that halogenated phenolicpreservatives are not present. Manufacturers should also be vigilant tothe characteristic odor of the offending compounds so they can intervene beforeproduct is contaminated or further distributed. FDA还建议生产商与供应商签订协议，要求供应商提供证书保证不存在卤代苯酚防腐剂。生产商还要警惕有刺激性化合物的特征气味，这样可以在产品被污染或销售前介入处理。 Date: 3/12/2010
9. Are there any standards applicable to preventing contamination ofdrug products with halogenated anisole compounds? 是否有什么标准适用于防止药品被卤代苯甲醚化合物污染？ U.S. (ASTM) and international standards (International Standard forPhytosanitary Measures (ISPM)) recommend heat treatment, or fumigation withmethyl bromide, for the preservation of wood-derived packaging storagematerials, including wood pallets. For more information, includingcertification to these standards, refer to Standard Practice for Treatmentand/or Marking of Wood Packaging Materials (ASTM D 6253-05a) and Guidelines forRegulating Wood Packaging Material in International Trade (ISPM 15). 美国ASTM和国际标准ISPM推荐对木制包装存贮材，包括木质托盘采用热处理，或甲基溴熏蒸。更多信息，包括这些标准的证明，请参见木质包材处理和/或标记标准规范（ASTM D6253-05a）和国际贸易中木质包材管理指南（ISPM 15）。 Date: 3/12/2010
10. Can contamination of drug products with halogenated anisolecompounds be detected? 药品中的卤代苯甲醚可以被检出吗？ Although methods for detection exist and might be practical for periodicscreening, FDA expects that manufacturers prevent such contamination throughadherence to Current Good Manufacturing Practices (CGMPs). ACGMP-compliant quality system will ensure that assurances are obtained fromsuppliers and that measures are taken to prevent exposure to problematiccompounds. Manufacturers of finished pharmaceuticals are reminded thatthe CGMP regulations at 21 CFR 211.56(c) require written procedures forsanitation designed to prevent the contamination of equipment, components, drugproduct containers, closures, packaging, labeling materials, and drugproducts. Analogous recommendations for manufacturers of activepharmaceutical ingredients are included in internationally harmonized (EuropeanUnion, Japan, United States) guidance for industry ICH Q7, Good ManufacturingPractice for Active Pharmaceutical Ingredients (section 4.72). 尽管有这样的检出方法可以用于定期筛选，FDA仍期望生产商通过实施CGMP来防止这类污染。一个符合CGMP的质量体系会保证从供应商处获得保证，及采取措施防止暴露于有问题的化合物中。要提醒制剂生产商GCMP在21CFR211.56(c)中要求设计书面消毒程序以防止设备、部件、药品容器、密闭系统、包装、标签材料和药品污染。对于活性药用物质的类似推荐包括在ICH指南Q7中（和4.72部分）。 [1] Trichlorophenol (TCP) is another example of a compound that can beconverted to a halogenated anisole compound.三氯苯酚TCP是另一个可以转化为卤代苯甲醚化合物的例子。
References: Contact for further information: Date: 3/12/2010
FDA官网CGMP问答：设备部分FDA问答 设备 问题最后更新201508 Questions and Answers on Current Good ManufacturingPractices—Equipment 1. Manyleading analytical balance manufacturers provide built-in"auto-calibration" features in their balances. Are suchauto-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？ Theauto-calibration feature of a balance may not be relied upon to the exclusionof an external performance check (211.68). For a scale with a built-inauto-calibrator, we recommend that external performance checks be performed ona periodic basis, but less frequently as compared to a scale without thisfeature. The frequency of performance checks depends on the frequency ofuse of the scale and the criticality and tolerance of the process or analyticalstep. Note that all batches of a product manufactured between twosuccessive verifications would be affected should the check of theauto-calibrator reveal a problem. Additionally, the calibration of anauto-calibrator should be periodically verified--a common frequency is once ayear--using National Institute of Standards and Technology (NIST)-traceablestandards 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 l 21 CFR 211.68:Automatic, mechanical, and electronic equipment l 自动、机械和电子设备 l 21 CFR211.160(b)(4): General requirements (Lab Controls) l 通用要求（实验室控制） l USP Chapter<41> Weights and Balances l 砝码和天平 l See also: ASTM standard E 617: Standard Specification for Laboratory Weights andPrecision Mass Standards (this standard is incorporated into the USP byreference; other widely recognized standards may be acceptable) l 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） Date: 8/4/2004
2. 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？ No. The CGMP regulations neitherapprove nor prohibit specific equipment for use in manufacturing ofpharmaceutical products (with the exception of asbestos and fiber-releasingfilters, see 211.72). We do not maintain a list of approved equipment. Firms are afforded the flexibility to select equipment that bestsatisfies their particular needs and that is capable of meeting the relevant CGMPrequirements. Each firm is responsible for selecting all equipment usedin their manufacturing process to produce quality product in accordance withCGMP. They are also responsible for selecting the appropriate intendeduse for the equipment's operation, and are free to modify standard equipmentdesigns to best suit their process and that are compatible with the productunder 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 ofappropriate design to facilitate operations for its intended use and forcleaning and maintenance (see 211.63 and 211.67) and, that any equipment surfacein contact with components, in-process materials, or drug products not bereactive, additive, or absorptive so as to "alter the safety, identity,strength, quality, or purity of the drug product beyond the official or otherestablished 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 l 21 CFR 211.63:Equipment design, size, and location设备设计，尺寸和定位 l 21 CFR 211.65:Equipment construction设备结构 l 21 CFR 211.67:Equipment cleaning and maintenance设备清洁和维护 l 21 CFR 211.68:Automatic, mechanical, and electronic equipment自动、机械和电子设备 l 21 CFR 211.72:Filters过滤器 Date: 5/18/2005
3. CanTotal Organic Carbon (TOC) be an acceptable method for detecting residues ofcontaminants 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 theinspection guide on cleaning validation in 1993, a number of studies have beenpublished 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 methodfor monitoring residues routinely and for cleaning validation. In order for TOCto be functionally suitable, it should first be established that a substantialamount of the contaminating material(s) is organic and contains carbon that canbe oxidized under TOC test conditions. This is an important exercise becausesome 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 directsurface sample testing as well as indirect (rinse water) sample testing. Ineither case, because TOC does not identify or distinguish among differentcompounds containing oxidizable carbon, any detected carbon is to be attributedto the target compound(s) for comparing with the established limit. Thus, afirm should limit 'background' carbon (i.e., carbon from sources other than thecontaminant being removed) as much as possible. If TOC samples are being heldfor long periods of time before analysis, a firm should verify the impact ofsample 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 l 21 CFR 211.67:Equipment cleaning and maintenance.设备清洁和维护 l 21 CFR211.160(b): General requirements (Laboratory Controls)通用要求（实验室控制） l USP 643 TotalOrganic Carbon总有机碳 l Guide toInspections of Cleaning Validation, 1993清洁验证检查 Date: 5/18/2005 4. A firmhas multiple media fill failures. They conducted their media fills using TSB(tryptic soy broth) prepared by filtration through a 0.2 micron sterilizingfilter. Investigation did not show any obvious causes. What couldbe the source of contamination? 一个公司的培养基灌装失效了。他们的培养基灌装用的是经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 recentlyhad multiple media fill failures. The media fill runs, simulating thefilling process during production, were conducted inside an isolator. Thefirm used TSB (non-sterile bulk powder) from a commercial source, and preparedthe 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 thecontaminating organism using conventional microbiological techniques, includingthe use of selective (e.g., blood agar) and nonselective (e.g., TSB and trypticsoy agar) media, and examination under a microscope. The contaminant waseventually identified to be Acholeplasma laidlawii by using 16S rRNA genesequence. The firm subsequently conducted studies to confirm the presenceof Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not acontaminant from the process, but from the media source. 一个公司增菌培养基灌装失效，培养基的灌装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。 Acholeplasmalaidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cellmembrane and have no cell wall. They are not susceptible to beta-lactamsand do not take up Gram stain. Individual organisms are pleomorphic(assume various shape from cocci to rods to filaments), varying in size from0.2 to 0.3 microns or smaller. It has been shown that Acholeplasmalaidlawii is capable of penetrating a 0.2 micron filter, but is retained by a0.1 micron filter (see Sundaram, et al.). Acholeplasma laidlawii is known to beassociated with animal-derived material, and microbiological media is oftenfrom animal sources. Environmental monitoring of mycoplasma requiresselective 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, thisfirm has decided to filter prepared TSB, for use in media fills, through a 0.1micron filter (note: we do not expect or require firms to routinely use 0.1micron filters for media preparation). In the future, the firm will usesterile, irradiated TSB when it becomes available from a commercial supplier. (Firm's autoclave is too small to permit processing of TSB for mediafills, so this was not a viable option.) The firm will continuemonitoring for mycoplasma and has revalidated their cleaning procedure toverify its removal. In this case, a thorough investigation by the firmled to a determination of the cause of the failure and an appropriatecorrective 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 l 21 CFR 211.113:Control of microbiological contamination微生物污染的控制 l 21 CFR 211.72:Filters过滤器 l 21 CFR211.84(d)(6): Testing and approval or rejection of components, drug productcontainer, and closures药物成分、制剂包材和密封材料的检测和放行或拒收 l Sundaram, S.,Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane filtration forremoval of diminutive bioburden organisms in pharmaceutical products andprocesses. 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 l Kong, F., James,G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific PCR foridentification of common contaminant mollicutes in cell culture. Appl. Environ.Microbiol. 2001 Jul; 67(7): 3195-200. l Murray, P.,Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of Clinical MicrobiologyASM Press, Sixth Edition.临床微生物学手册第六版 Date: 5/18/2005
5. Whatare the cleaning validation requirements for potent compounds (e.g., compoundsthat are cytotoxic, mutagenic, or have high pharmacologic activity), and isdedicated equipment required? 高活性化合物（例如，毒性、基本诱变性或高药物活性）的清洁验证要求是什么？是否需要使用专用设备呢？ Separation or dedication of equipmentand facilities for the manufacture of potent compounds is not specificallyrequired by CGMP regulations. However, manufacturers should identify drugs withsuch risks and define the controls necessary to eliminate risk of productcross-contamination in nondedicated equipment and facilities. Such controlsinclude proper cleaning, cleaning validation, and other contaminant controls.Firms must validate that cleaning procedures are adequate to ensure thatcross-contamination does not occur. CGMP regulations establish requirements toguide development and execution of cleaning validation plans. CGMP规定并未明确要求高效价化合物的生产是否需要使用单独的或专用设备设施。但是，生产商应识别出具有风险的药品，制订必要的控制措施以消除产品在非专用设备和设施中发生交叉污染的风险。这种控制包括进行适当的清洁、清洁验证和其它污染物控制。公司必须验证其清洁程序足以确保不会发生交叉污染。CGMP法规建立了要求，用以指导开发和实施清洁验证计划。 In designing a facility, firms shouldcarefully evaluate manufacturing processes to determine the best proceduralcontrols and floor plan—optimizing the flow of materials, equipment, andpeople—to help prevent product contamination. 在设计设施时，公司应谨慎评估生产工艺，以确定最佳的程序控制和平面而已----优化物料、设备和人员流向----以帮助防止产品污染。 References: 参考文献 · 21 CFR 211.42: Design and construction features · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.42: 设计和建设要求 · 21 CFR 211.67: 设备清洁和维护 Date: 6/8/2015
6. How doI perform cleaning validation, including for homeopathic drug products? 我应该如何实施清洁验证，包括顺势疗法药品？ 21 CFR 211.67(a) requires that anyequipment, including dedicated and multipurpose equipment, is “cleaned,maintained, and, as appropriate for the nature of the drug, sanitized and/orsterilized at appropriate intervals to prevent malfunctions or contaminationthat would alter the safety, identity, strength, quality, or purity of the drugproduct beyond the official or other established requirements.” You musttherefore ensure that residues (e.g., active ingredients, cleaning agents) areadequately removed from product contact surfaces of all equipment duringproduct changeovers and/or between production campaigns, depending on the typesof materials and surfaces in use. 21 CFR 211.67(a)要求所有设备，包括专用和多用途设备都应“以适当的时间间隔根据药品的特性进行清洁、维护、灭菌和/或消毒以防止可能会改变药品安全性、性状、剂量、质量或纯度使其超出官方或其它既定要求以外的故障或污染”。因此你们必须确保根据物料类型和在用表面的不同，在更换产品和/或产品阶段性生产之间要将残留物（例如，活性成分、清洁剂）从所有设备与产品接触的表面清除充分。 Cleaning procedures should bewell-documented and consistent for their intended use. Cleaning validationprograms should provide assurance that residues are effectively removed fromproduct contact surfaces, and manufacturers should select test methods thatdemonstrate their effectiveness. FDA does not provide extensive guidance onconducting cleaning validation but does recommend consulting guidelinespublished by various trade and professional associations for additionalinformation (e.g., International Society for Pharmaceutical Engineering,Parenteral Drug Association). 清洁程序应有良好记录，并与其既定用途相一致。清洁验证计划应确保能从产品接触的表面有效清除残留，生产商应选择能够证明其有效性的检验方法。FDA并不提供关于如何实施清洁验证的深入指南，但建议参考由不同贸易和专业协会发布的指南获取更多信息（例如，ISPE，PDA）。 Reference: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护
Date: 6/8/2015
7. Doesequipment need to be clean enough to meet limits based on the most sensitivepossible methods of residue detection or quantification? 设备清洁是否需要满足根据能获得的最灵敏的残留检出和定量方法所制订的限度？ No. CGMPs require that equipment becleaned to prevent contamination that “would alter the safety, identity,strength, quality, or purity of the drug product beyond the official or otherestablished requirements” (see 21 CFR 211.67). The preamble to the CGMPregulations (see 43 FR 45014) indicates that this phrase was added becauseabsolute cleanliness for multiuse equipment is neither valuable nor feasible inmany circumstances. The degree of cleanliness needed, therefore, cannot dependon the method of detection because improvements in method sensitivity wouldnecessitate ever-lower limits and ever-increasing wash cycles. Equipment shouldbe as clean as can be reasonably achieved to a residue limit that is documentedto be safe, causes no product quality concerns, and leaves no visible residues.Contamination that is reasonably avoidable and removable is never consideredacceptable. 不需要。CGMP要求设备清洁能够防止污染，“不会改变药品的安全性、属性、剂量、质量或纯度超出官方或其它既定要求以外”（参见21CFR211.67）。CGMP法规前言（参见43FR45014）说，增加该词是因为对于多用途设备来说，在许多情况开，绝对清洁没有价值，也不现实。因此，所需清洁的程序不能依赖于检出方法，因为方法灵敏度的提高会需要建立前所未有的低限，增加清洁工作。设备的清洁应该合理可以达到一个残留限度，这个限度应该有文件论述是安全的，不会引起药品质量问题，不会留下可见残留。可能合理避免并且可以清除的污染绝对不会被认为是可以接受的。 References: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护 · CGMP最终规定前言 (43 FR 45014, Sept 29, 1978) Date: 6/8/2015 8. Dofirms need to quantify the total amount of residue remaining on equipmentsurfaces after manufacturing a product (before cleaning) to support cleaningvalidation studies? 公司是否需要在生产完一个药品之后（清洁之前）对设备表面的残留总量进行定量以支持清洁验证研究？ No. In validating original cleaningprocedures, firms need not quantify the level of chemical contaminationremaining after manufacturing a product and before cleaning. Firms must,however, ensure that they validate proposed cleaning procedures as for routineuse and should not pre-clean or otherwise attempt to make it easier for theprocedures being validated to meet their cleaning objectives. 不需要。在验证初始清洁程序时，公司不需要在一个产品生产完成后清洁之前对化学污染残留水平进行定量。但是，公司必须确保他们验证的是准备作为日常用途的清洁程序，而不应该在验证之前做预清洁，也不应该试图让程序更加易于验证，以符合其清洁目标。 For example, batches significantlysmaller than full-scale would not offer sufficient assurance that the cleaningprocedure could reliably remove residues to acceptable levels after full-scaleproduction. The material being cleaned should be manufactured at a similarscale and manner as during validation. Also, firms should sample equipment thatis stored uncleaned for a longer time than validated to demonstrate that theircleaning procedures are effective. 例如，大大小于全批量的批次就不能提供足够的保证，确保清洁程序能够将批量放大后生产情况下的残留可靠清除至可接受的水平。验证中，应以相似的批量和方式生产被清洁的物料。还有，公司应在设备未清洁状态保持比验证时间更长之后再取样，以证明其清洁方法是有效的。 Once equipment surfaces are cleaned byvalidated procedures, firms generally are not expected to analytically examinethem after each cleaning. (Manual cleaning methods may be an exception to thisgeneral rule because of inherent variability in operator compliance andabilities.) However, a residue-monitoring program whose frequency and methodshave been determined by risk assessment is recommended. 一旦设备表面使用验证过的方法进行了清洁，则公司一般不需要在每次清洁后进行分析。（人工清洁方法可能是例外，因为操作人员本身固有的符合性和能力方法的差异）。不管怎样，建议采用风险评估来确定残留监测计划的频次和方法。 Reference: 参考文献 · FDA 检查指南：清洁工艺验证 Date: 6/8/2015 9. Shouldlaboratory glassware be included in a firm's equipment cleaning validationprogram? 化验室玻璃仪器应包括在公司的设备清洁验证计划中吗？ No. FDA does not expect laboratoryglassware to be included in the processing equipment cleaning validationprogram.Glassware must, of course, be clean, and CGMP regulationsconsider laboratory equipment to be included within the scope of 21 CFR 211.67.Cleanliness is best assessed by inspecting laboratory procedures for thefollowing: 不需要。FDA不要求将化验室玻璃仪器包括在工艺设备清洁验证计划中。玻璃仪器当然是要清洁的，CGMP规定认为化验室设备包括在21CFR211.67范围内。要通过检查化验室程序来对清洁进行最佳评估： · Use of nondedicated glassware and other equipment · 使用非专用玻璃仪器和其它非专用仪器 · Method validation (e.g., ruggedness) · 方法验证（例如，耐用性） · Absence of extraneous or interfering data in the resultsof sample analyses · 样品分析中没有异物，也没有分析结果数据的干扰 Laboratory cleaning procedures mayinclude repetitive rinses with the solvent used to prepare the analyte, followedby oven drying. The equipment need not be swabbed or otherwise tested to ensureremoval of potentially contaminating residues. A firm may elect to sample itsglassware for residual contamination to exclude or explore the possibility ofinterference in the case of particularly sensitive analyses ordifficult-to-clean compounds. 化验室清洁程序可以包括使用配制分析物的溶剂反复淋洗，然后用烘箱干燥。设备如果不是不需要擦拭，则需要进行测试以确保清除了潜在污染残留。公司可以抽取玻璃仪器样品检测残留污染，以排除或查看特别敏感的分析或难以清洁化合物产生干扰的可能性。 The possibility of carryovercontamination affecting a method’s performance or integrity of the results isgenerally considered of low risk to the product and consumers, with theexception of potent compounds. Contaminated laboratory equipment, however, shouldnot be a frequent excuse for rejecting or discarding aberrant results.Glassware that is not properly cleaned can make it difficult to determine ifthe source of aberrant analytical results is related to the unclean glasswareor residues from manufacturing equipment. We expect firms to maintainlaboratory equipment in a clean and sanitary manner to provide confidence inthe analytical results. 除高效价化合物以外，一般认为残留污染可能影响方法效果和检验结果完整性产生的风险对于产品和消费者来说很小。但是，受污染的化验室设备不应该频繁成为拒绝和舍弃异常结果的借口。清洁不当的玻璃仪器会使得难以判定异常分析结果的来源到底是与不清洁的玻璃仪器相关，还是来自生产设备。我们期望公司能维护化验室设备的清洁和卫生，保证分析结果的可信度。 Reference: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护 Date: 6/8/2015 10. Whatis an acceptable level of detergent residue, and what is the basis for arrivingat this level, if any? 清洁剂残留的可接受水平是多少？如果有一个水平的话，达到此水平的基础是什么？ It is the firm’s responsibility toestablish acceptance limits and to be prepared to provide the basis for thoselimits to FDA. Thus, there is no universal standard for levels of detergentresidue. Residues must not exceed their established acceptance limits and mustnot adversely alter drug product safety, efficacy, quality, or stability (seereferences below). 公司有责任建立可接受限度，准备将这些限度制订的基础提交给FDA。因此，没有通用的清洁剂残留水平标准。残留必须不得超过公司既定的可接受限度，必须不得改变药品的安全性、有效性、质量和稳定性（参见以下参考文献）。 References: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护
Date: 6/8/2015
11. If a procedure’s ability to clean a piece of equipment madeof a particular material, such as 316 stainless steel, is acceptable and validated,can that “material-specific” cleaning procedure be applied to other pieces ofequipment and compounds without extensive validation? 如果有一个程序有能力清洁由特定材料，例如316不锈钢，制成的设备并到达可接受水平，并且该程序经过了验证，是否可以将这个“材料特定”的清洁程序应用到其它的设备和化合物上，而不再进行更为广泛的验证呢？ No. In establishing an effectivecleaning procedure for a particular piece of equipment, firms must consider itsmaterial of construction/fabrication, exact design, conditions of use, and, inparticular, the specific substances that could contaminate the equipment. Therefore,to demonstrate proof of cleaning for a given piece of equipment, firms shouldhave data that relate to all of these factors. 不可以。在为一个特定的设备建立有效的清洁程序时，公司必须考虑其结构材质、设计、使用条件和，尤其是可能会污染该设备的特定物质。因此，想要证明一个清洁程序适用于指定的设备，公司应具备与所有这些因素相关的数据。 References: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护
Date: 6/8/2015
12. Is testing rinse solution enough to support residuedeterminations for cleaning validation? 是否可以用测试淋洗液来支持清洁验证里的残留检测？ No. For cleaning validation, rinsesamples alone would not be acceptable; firms should also measure the residue orcontaminant on the equipment surface using a direct method (if feasible). Onedisadvantage of rinse samples is that the rinse solvent may not remove theresidue or contaminant. Rinse samples are capable of sampling large surfaceareas, particularly ones that are difficult to access; therefore, some firmsuse both swab and rinse samples during the course of their cleaning validation.This is acceptable if the rinse solvent has been demonstrated to dissolveresidues of concern and is otherwise suitable for use on the surfaces to besampled. 不可以。清洁验证中，只有淋洗样品是不能接受的，公司还应使用直接方法（如可行的话）检测设备表面的残留或污染物。淋洗样品的一个缺点是淋洗溶剂可能不能清除残留或污染物。淋洗样品能够对大的表面取样，尤其是难以接触到的地方，因此，有的公司在清洁验证中使用擦拭和淋洗两种取样方法。如果已证明淋洗溶剂可以溶解所关注的残留物，并且适合于其所需取样的表面，则可以接受。 For routine equipment cleaning aftervalidation, a residue-monitoring program whose frequency and methods have beendetermined by risk assessment is recommended to demonstrate that the validatedprocess continues to consistently clean the equipment. 对于验证之后的日常设备清洁，建议根据风险评估来决定残留监测计划的频次和方法，以证明经过验证的工艺能够持续一致地清洁该设备。 The purpose of cleaning validation is todemonstrate that a particular cleaning process will consistently clean theequipment to a predetermined standard; the sampling and analytical test methodsshould be scientifically sound and should provide adequate scientific rationaleto support the validation. 清洁验证的目的是证明指定的清洁工艺能一致清洁设备达到既定的标准，取样和分析方法应科学合理，应提供足够的科学合理性来支持验证。 References: 参考文献 · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.67: 设备清洁和维护 Date: 6/8/2015 13. Does FDA prefer one type of material over another (e.g.,polyvinylidene difluoride over stainless steel) for construction of recirculatingloops in water for injection (WFI) systems? FDA是否更喜欢注射水（WFI）系统的循环系统使用某种材料超过喜欢另一种（例如，相比不锈钢，更喜欢聚偏（二）氟乙烯）？ No. There is no official agencypreference for one material over another. Whatever material a firm selects forits WFI system must be suitable for its intended use. This holds true forvirtually all production equipment. 不。官方机构对材料没有倾向性。不管选择什么材料用于WFI系统，公司必须保证其适合既定用途。这实际上适用于所有的生产设备。 When evaluating the suitability of a WFIsystem’s piping, consider the surface texture or finish of the piping’sinterior wall (e.g., smoothness, waviness), its ability to resist hightemperatures and pressures, and its ability to withstand sterilizing andsanitizing agents and procedures. 在评估WFI系统的管道适用性时，要考虑表面结构和管内壁的抛光情况（例如，光滑度，波度），高温和压力耐受能力，以及承受灭菌和消毒剂和过程的能力。 Equipment surfaces that are in contactwith components, in-process materials, or drug products must not be reactive,additive, or absorptive so as to alter the drug product’s safety, identity,strength, quality, or purity beyond its official or established requirements. 与化合物、中间物料或药品相接触的设备表面必须不能发生反应，不会释放物质，也不会吸收物质，以避免使得药品的安全性、属性、剂量、质量或纯度发生变化超出其官方或既定要求以外。 References: 参考文献 · 21 CFR 211.65: Equipment construction · 21 CFR 211.67: Equipment cleaning and maintenance · 21 CFR 211.65: 设备构造 · 21 CFR 211.67: 设备清洁和维护 Date: 6/8/2015 | 
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