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 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 be conducted of the drug product when determining if a drug product stability test method 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 be necessary when the routes of degradation and the suitability of the analytical procedures can 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:

• data from stress testing of drug substance

  原料药的强降解试验数据

• reference materials for process impurities and degradants

  工艺杂质和降解产物的对照物质

• 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

• 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 the analytical methods and on degradation pathways of the drug substance may be available 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 the accuracy, sensitivity, specificity, and reproducibility of test methods shall be established and documented. Further, section 211.166(a)(3) requires that stability test methods be reliable, meaningful, and specific, which means that the content of active ingredient, degradation products, and other components of interest in a drug product can be accurately measured 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 are to be used to ensure that one’s test methods are stability-indicating. However, evaluating the specificity of the test methods during forced degradation studies (i.e., exposing drug to extremes of pH, temperature, oxygen, etc.) of

drug substance and drug product often is necessary to ensure that stability test methods are stability-indicating. But in certain circumstances conducting a forced degradation study of just the drug substance may be sufficient to evaluate the stability-indicating properties 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 conduct forced degradation studies of the drug product, the specificity of the test method should be evaluated for its ability to assay drug substance, degradants, and impurities, in the presence of each other, without interference. The evaluation also should provide assurance that there is not a potential for interaction between drug substance, degradants, impurities, excipients, and

container-closure system during the course of the shelf-life of the 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 extent of the forced degradation studies conducted as well as the rationale for concluding that a test method is stability-indicating should 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 in Injections test for a Large Volume Parenteral (LVP), is it acceptable to take the average among the units tested to determine if the batch meets its specification 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 units tested in each batch/lot when following this method because the purpose of this method is to measure and limit intra-batch variability.

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-visible particles. USP <788> provides two tests for detecting such particulates--light obscuration and microscopic assay. Both are generally accepted for use in testing LVPs and small volume parenterals (SVP) for the determination of sub-visible particulate matter. Normally, samples are first tested by the light obscuration method; if the sample fails the specified limits, the microscopic assay method can then be used. However, the microscopic method can be the sole test if there is a documented technical reason or interference from the product under test that would 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 is probably due to the sample preparation method for the light obscuration test (USP

<788>). At least 2, 5-mL aliquots from each sampled unit or the pooled sample (see below) are to be used in the particulate count determination,

and the results from these aliquots are to be averaged for comparison with the specification. Note that the average is of the results from examining each aliquot and not between units. (The results of the first aliquot examined by light obscuration are to be discarded, and the subsequent aliquots--2 or more--are retained.) Pooling units prior to analysis is permitted only if the volume in each unit is less than 25 mL, in which case 10 or more units may be pooled. If the volume in the SVP or LVP is 25 mL or more per unit, single units are to be examined by this 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 because particulate matter is assumed to be non-uniformly dispersed throughout the lot. The intent

of assessing results from each individual unit is to ensure adequate representation of the lot and to detect potential variation within a lot.

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 and SVP units having a volume of 25mL or more, the USP states that the number of units

tested depends on statistically sound sampling plans, and sampling plans should be based on consideration of product volume, numbers of particles historically found to be present in comparison to limits, particle size distribution of particles present, and variability of particle counts between units. The USP also suggests that the 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 with the 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 for detecting 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 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 monitoring residues routinely and for cleaning validation. But 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 not a trivial exercise because we know that some 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 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. The established limit, or the amount of residue detected for comparison to the specification, should correct for the target materials composition of carbon. As for any cleaning method, recovery studies are necessary (211.160(b)). 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.

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 to detect 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 very accurate and reliable when calibrated correctly, these types of analyzers can only

detect the identification and strength of oxygen. They are unable to detect contaminants or impurities that may be present, such as hydrocarbons or

arsenic compounds. According to the USP General Notices, Foreign Substances and Impurities section, it is manifestly impossible to include in

each monograph a test for every impurity, contaminant, or adulterant that might be present. The USP monograph test for oxygen does not include

an impurity screen and other analyzers may need to be used. For example, assays for hydrocarbon impurities are routinely conducted during the

oxygen manufacturing process even though the USP does not list hydrocarbons as an impurity. Also, alternative methods may be needed to test high-pressure cylinders 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 oral solid and liquid dosage forms repackaged into unit-dose containers based on guidance in 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 revision of FDAs Compliance Policy Guide Section 480.200 (CPG 7132b.11), “Expiration

Dating of Unit-Dose Repackaged Drugs,” was announced in the Federal Register. The draft CPG specifies certain conditions when it may be possible to assign up to twelve month expiration-dating to non-sterile solid and liquid oral drug products repackaged into unit-dose containers without conducting new stability studies to support the length of expiration-dating on the repackaged products. The draft CPG was prompted by United States Pharmacopeia (USP) standards for assigning up to a twelve month beyond-use date to non-sterile solid and liquid oral dosage forms dispensed in unit-dose containers. (“Beyond-use date” is USP’s pharmacy dispensing term for specifying a date on a prescription container beyond which a patient should not use the product.) If finalized, FDA’s draft CPG would replace the current version of CPG Section 480.200. The current version of CPG Section 480.200 was finalized in March 1995 and provides conditions under which FDA will not initiate action for assigning up to six month expiration dating for drug products repackaged into unit-dose containers without 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 commercially repackaged drugs to determine the suitability of the draft revision of CPG Section 480.200. Until the stability study is complete and FDA evaluates all comments submitted to the public docket in response to the May 2005 Federal Register Notice of Availability, the agency does not intend 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 the draft 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。