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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? 

許多領(lǐng)先的天平生產(chǎn)商為其天平提供內(nèi)置式“自動校正”功能,。這樣的自動校正程序是否可以替代外部性能測試呢？如果不能,，那么校正計(jì)劃應(yīng)該是怎樣的,？

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.

天平的自動校正功能不能完全替代外部性能檢查 (211.68)。對于具有內(nèi)置式自動校正裝置的衡器來說,，我們建議定期實(shí)施外部性能檢查,，但相比于沒有此功能的衡器其頻次可以低一點(diǎn)。性能檢查的頻次取決于衡器使用的頻次,，以及工藝或分析步驟的關(guān)鍵程度和允差,。注意，如果自動校正裝置檢查中發(fā)現(xiàn)有問題的話,，則兩次連續(xù)校正之間所生產(chǎn)的所有批次產(chǎn)品均會受到影響,。另外，應(yīng)定期采用國家標(biāo)準(zhǔn)技術(shù)局 (NIST) 的可追溯標(biāo)準(zhǔn)或其它國家所用的經(jīng)NIST 認(rèn)證的標(biāo)準(zhǔn)來核查自動校正裝置的校正---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? 

在確定一個(gè)藥品穩(wěn)定性測試方法是否具有穩(wěn)定性指示性時(shí),，CGMP 是否要求都對藥品都進(jìn)行強(qiáng)降解試驗(yàn)？

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,。如果降解途徑和分析方法的適當(dāng)性可以通過使用以下資料確定時(shí),，不一定要進(jìn)行藥品強(qiáng)降解試驗(yàn)：

• data from stress testing of drug substance

  原料藥的強(qiáng)降解試驗(yàn)數(shù)據(jù)

• reference materials for process impurities and degradants

  工藝雜質(zhì)和降解產(chǎn)物的對照物質(zhì)

• data from accelerated and long-term studies on drug substance

  原料藥加速和長期穩(wěn)定性試驗(yàn)數(shù)據(jù)

• data from accelerated and long-term studies on drug product

  制劑的加速和長期穩(wěn)定性試驗(yàn)數(shù)據(jù)

Additional supportive information on the specificity of the analytical methods and on degradation pathways of the drug substance may be available from literature sources.

從文獻(xiàn)中也可以獲得關(guān)于分析方法專屬性和原料藥降解途徑的更多支持性信息。

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 法規(guī)的第211.165（e）部分說應(yīng)建立并記錄分析方法的準(zhǔn)確性,、靈敏度,、專屬性和重復(fù)性。還有,，第211.166(a)(3)部分要求穩(wěn)定性分析方法是可靠的,、有意義的以及具有專屬性,，這意味著可以準(zhǔn)確測定制劑中活性成分、產(chǎn)物和其它有意義成分的含量,，而不受到干擾,，通常被稱為“穩(wěn)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 法規(guī)并沒有指定用于確保分析方法具有穩(wěn)定性指示的技術(shù)或測試,。但是,，為了確保穩(wěn)定性試驗(yàn)所用分析方法具備穩(wěn)定性指示性，在原料藥和制劑強(qiáng)降解研究（即將藥物暴露于極端的pH 值,、溫度,、氧氣等環(huán)境）中評估一個(gè)分析方法的專屬性通常是有必要的。而在一定情形下,，僅僅對原料藥進(jìn)行強(qiáng)降解試驗(yàn)可能就足以評估分析方法的稱定性指示性特性了。

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.

一般來說,，在確定是否有必要對制劑實(shí)施強(qiáng)降解研究時(shí),， 應(yīng)該對分析方法的專屬性進(jìn)行評估，查看其是否有能力在原料藥,、降解產(chǎn)物和雜質(zhì)共存時(shí)對這些成分進(jìn)行分析,，而不會被干擾。評估還應(yīng)保證原料藥,、降解產(chǎn)物,、雜質(zhì)、輔料和容器密閉系統(tǒng)之間在制劑成品的貨架其內(nèi)不會發(fā)生相互反應(yīng),。

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,，要全面記錄所實(shí)施的強(qiáng)降解試驗(yàn)的程度決策合理性，以及得到結(jié)論說一個(gè)分析方法具有穩(wěn)定性指示性的合理性論證,。

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? 

在對大容量注射劑（LVP）做USP<788>注射劑中顆粒物檢測時(shí),，是否可以采用受測單元測試結(jié)果的平均值來確定該批次是否符合此項(xiàng)目標(biāo)準(zhǔn)？

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,。按照此方法檢測時(shí),，采用每批次里受測LVP 單元的平均值是不能接受的，因?yàn)榇朔椒ǖ哪康氖菧y量并限制批內(nèi)差異,。

'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.

'顆粒物'指很小的,、肉眼不可見的顆粒物。USP<788>提供了兩種檢測方法來檢出此類顆粒物---光阻法和顯微鏡方法,。兩種方法用于LVP和小容量注射劑（SVP）檢查用于確定不可見顆粒物時(shí)一般都是可以接受的,。一般來說，會先采用光阻法來檢測,，如果樣品不符合指定的標(biāo)準(zhǔn),，則可以再使用顯微鏡法,。而如果有文件記載的技術(shù)原因或來自產(chǎn)品的干擾，會讓光阻法不適合或結(jié)果無效,，則顯微鏡法則可以單獨(dú)測試,。

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>).

對于什么時(shí)候可以對數(shù)據(jù)進(jìn)行平均，什么時(shí)候不可以平均的迷惑可能是由于光阻法樣品制備方法引起的（USP<788>）,。在顆粒物計(jì)數(shù)檢測中,，從每個(gè)取樣單位中或傾出樣品（見下）中要取用至少2.5ml 液體，從這些液體檢測中所得的結(jié)果要進(jìn)行平均計(jì)算,，然后和標(biāo)準(zhǔn)進(jìn)行比較,。注意，這些用于平均值計(jì)算的結(jié)果是來源于同一液體的檢驗(yàn),，而不是不同受檢單元（光阻法檢測的第一份液體結(jié)果要棄除,，保留之后的結(jié)果---2 個(gè)或更多）。只是當(dāng)每個(gè)單元的體積小于25ml 時(shí),，才允許在檢驗(yàn)之前將制劑從包裝里傾倒出來,，這時(shí)可能會需要倒出10個(gè)或更多包裝單位。如果每個(gè)SVP 或LVP 單元里的體積為25ml 或更多,，則應(yīng)該使用一個(gè)單元供本法檢測（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.

不同制劑單位的結(jié)果不能做平均計(jì)算，因?yàn)轭w粒物被認(rèn)為是不均勻地分散在一個(gè)批次中,。評估每個(gè)單獨(dú)包裝單位的結(jié)果意在確保足以代表該批次,，并能檢出一個(gè)批次內(nèi)潛在的差異。

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).

到于體積達(dá)到或超過25ml 的LVP 和SVP 包裝單位里要被檢測的單個(gè)包裝單位的數(shù)量,，USP 說該數(shù)量取決于“統(tǒng)計(jì)學(xué)合理的取樣計(jì)劃”,，以及“取樣計(jì)劃應(yīng)基于產(chǎn)品體積、歷史上發(fā)現(xiàn)的顆粒物數(shù)量相比于限度,、所發(fā)現(xiàn)的顆粒物的粒徑分布,、不同包裝單位之間顆粒物計(jì)數(shù)差異的考慮”。USP 還建議對于任何指定的批號,，如果有適當(dāng)?shù)恼撟C,，要檢測的包裝單位總數(shù)量可以少于10 個(gè)單位（對于LVP 和傾出SVP）。

這與統(tǒng)計(jì)學(xué)取樣計(jì)劃的CGMP 要求是一致的（參見211.165）,。

4. Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness? 

總有機(jī)碳（TOC）是否可以作為清潔效果評估里污染物殘留檢測的方法,？

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。自從1993 年清潔驗(yàn)證檢查指南發(fā)布之后,，已有大量研究被發(fā)布用以證明TOC 在污染物殘留測量中的充分性,。

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.

我們認(rèn)為TOC 或TC 用作殘留的日常監(jiān)測方法和清潔驗(yàn)證方法是可以接受的。但是為了確保TOC 方法的適用性,，首先應(yīng)該確定主要數(shù)量的污染物是有機(jī)物,，并且含有可以在TOC 測試條件下被氧化的碳,。這種做法并不過分，因?yàn)槲覀冎烙行┯袡C(jī)化合物使用TOC 是無法可靠檢出的,。

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 material's 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.

可以通過論證證明TOC 能用于直接表面取樣測試,，以及間接（淋洗）取樣測試。兩種情況,，由于TOC 并無法識別或區(qū)分出含有易氧化碳的不同化合物,，所有檢出的碳都會計(jì)為目標(biāo)化合物，與既定限度進(jìn)行比較,。因此,，公司應(yīng)盡可能限制“背景”碳（即，不是需要清除的污染物來源的碳）,。所制訂的限度,，或者是所檢出用于與標(biāo)準(zhǔn)相比較的殘留數(shù)量，均應(yīng)使用目標(biāo)物料的碳含量進(jìn)行計(jì)算,。所有的清潔方法均需進(jìn)行回收率研究（211.160（b））,。如果TOC 樣品放置時(shí)間過長才進(jìn)行檢測，公司應(yīng)確認(rèn)樣品放置時(shí)長對定量準(zhǔn)確性和定量限的影響,。

5. Would a paramagnetic or laser oxygen analyzer be able to detect all possible contaminants or impurities in a medical gas? 順磁或激光氧

分析儀是否可以檢出醫(yī)用氣體中所有可能的污染物或雜質(zhì)？

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,。雖然順磁和激光氧分析儀在正確校正的情況下是非常準(zhǔn)確可靠的,，但這類分析儀只能鑒別以及檢出氧含量，而不能檢出可能的污染物和雜質(zhì),，如,，碳?xì)浠衔锘蛏榛衔铩８鶕?jù)USP 通則,，異物和雜質(zhì)部分,，“顯然，在每一個(gè)各論中包括對所有雜質(zhì),、污染物和可能出現(xiàn)的偽藥成分的檢測是不可能的”,。USP 各論中對氧氣的檢測并不包括雜質(zhì)篩選，如果要做,，則可能需要使用其它的分析儀,。例如，盡管USP 里并沒有將碳?xì)浠衔锪袨殡s質(zhì),，但一般在氧氣生產(chǎn)過程中都會檢測碳氧化合物,。還有，可能需要有替代方法來檢測高壓氣瓶的清潔溶液殘留,。

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”? 

在將固體口服和液體口服制劑重新包裝至單劑量容器后,，是否可以根據(jù)2005 年修訂后的《符合性方針指南》第480.200（7132b.11）草案“單位劑量重新包裝藥品有效期計(jì)算”給定12 個(gè)月的有效期呢,？

No. In May 2005, a Notice of Availability of the draft revision of FDA's 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,，《聯(lián)邦通訊》發(fā)布了修訂后的《符合性方針指南》第480.200（7132b.11）草案“單位劑量重新包裝藥品有效期計(jì)算”通知,。CPG 草案指明在某些條件下可以為重新包裝至單劑量容器的非無菌固體口服和液體口服制劑給定12 個(gè)月有效期，而不需要新的穩(wěn)定性研究數(shù)據(jù)來支持重新包裝后藥品的有效期長度,。CPG 草案是由USP 標(biāo)準(zhǔn)推出的,，它為分裝至單劑量容器中的非無菌固體和液體口服制劑給定“超出使用日期”12 個(gè)月。（“超出使用日期”是USP 的藥房配藥術(shù)語,，用于在處方容器上指定一個(gè)日期,，超出這個(gè)日期后患者就不應(yīng)該再服用此藥）。如果最終定稿,，F(xiàn)DA 的CPG 草案會替代當(dāng)前的CPG 第480.200 部分,。當(dāng)前的CPG 第480.200 部分是在1995 年3月定稿的，它指定了在哪些條件下將藥品重新包裝至單劑量容器中,，可以給定6 個(gè)月有效期,，而不需要進(jìn)行新的穩(wěn)定性研究，F(xiàn)DA 不會

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 正在對某些商業(yè)化重新包裝的藥品進(jìn)行穩(wěn)定性研究,，以確定修訂后CGP 第480.200 部分草案的適用性。在完成穩(wěn)定性試驗(yàn),，F(xiàn)DA 對所有提交到公眾信箱的對2005 年5 月《聯(lián)邦通訊》中發(fā)布的通知的建議進(jìn)行評估之前,，當(dāng)局并無意將草案變成最終決定。因此,，目前階段,，在FDA 宣布CPG 草案定稿之前，現(xiàn)行的1995 年3 月定稿的CPG 第480.200 部分還是有效的,。

(由于公眾號篇幅字?jǐn)?shù)限制,，以下只提供中文版)

7. 使用一個(gè)未經(jīng)驗(yàn)證的方法來檢測藥品成分或制劑是否恰當(dāng)？

CGMP 法規(guī)要求使用經(jīng)過驗(yàn)證的方法對制劑生產(chǎn)用原料,、在制物料和成品進(jìn)行日常檢驗(yàn)(21 CFR 211.160, 211.165(e), and 211.194),。方法驗(yàn)證研究提供證據(jù)證明一個(gè)方法符合其既定用途。該用途一般是用于測量特定的物料的指標(biāo)是否符合既定的質(zhì)量標(biāo)準(zhǔn)（參見FDA 行業(yè)指南,，ICH Q2（R1））,。

但是FDA 了解在對潛在的質(zhì)量問題或缺陷進(jìn)行調(diào)查的過程中，一些特定情形下使用根據(jù)科學(xué)合理的原則（例如,，足夠的準(zhǔn)確性和精密度）開發(fā)但未全面驗(yàn)證的分析方法可能也是適當(dāng)?shù)?。例如，調(diào)查藥品或其組分（例如，肝素中OSCS）中的異常雜質(zhì)或可能污染物可能會顯示需要日常質(zhì)量控制檢測之外的方法,。此類檢測可能對于快速充分評估問題和保護(hù)公眾健康來說是很關(guān)鍵的,。在某些調(diào)查中進(jìn)行檢測時(shí)，可能不太現(xiàn)實(shí)也不合適對方法的耐用性和重現(xiàn)性進(jìn)行全面的評估,。

當(dāng)一個(gè)公司,，不管因?yàn)槭裁丛颍褂梦唇?jīng)驗(yàn)證的方法檢驗(yàn)藥物成分或藥品時(shí),，很重要的一點(diǎn)是要認(rèn)識,，相比于經(jīng)過驗(yàn)證的方法，未經(jīng)驗(yàn)證的方法其檢測結(jié)果的不確定度更大,。當(dāng)然,，所獲得的結(jié)果數(shù)據(jù)可能會給出重要信息，需要立即采取糾正措施,。相應(yīng)地,，我們期望所有此類對藥物成分或藥品的檢測結(jié)果要進(jìn)行審核，以評估是否需要跟進(jìn)措施（211.192 and 211.180(e)）,。

8. FDA 是否撤回了1987 年指南“鱟試劑檢測作為人用注射用藥,、生物制品和醫(yī)療器械的成品內(nèi)毒素檢測”？

是的,，F(xiàn)DA 撤回了1987 年的指南,。1987 年的指南被認(rèn)為過時(shí)了，不能反映出當(dāng)局對此主題當(dāng)前的看法,。

9. 藥品生產(chǎn)商在哪兒能找到關(guān)于內(nèi)毒素檢測的信息,？

USP 在通論<85>細(xì)菌內(nèi)毒素測試中發(fā)布了內(nèi)毒素測試建議和可接受標(biāo)準(zhǔn)。SP<85>提供了藥品的檢測方法和計(jì)算限度,。必要時(shí)，F(xiàn)DA 可以提供另外的指南來澄清當(dāng)局目前對使用LAL 以及其它內(nèi)毒素檢測方法的想法,。

10. 如果一個(gè)藥品曾經(jīng)被暴露在青霉素中,，是不是只要沒有檢出青霉素殘留，就可以放行該非青藥物呢,？

21 CFR 211.176 青霉素污染允許銷售經(jīng)過法定方法檢測并且未發(fā)現(xiàn)受到青霉素污染的非青藥物,。但是，只有要符合其它所有適用的CGMP要求前提下,，該放行才是可以接受的,。在有些情形下，公司不恰當(dāng)?shù)貞?yīng)用了§ 211.176 來銷售不在CGMP 條件下生產(chǎn)的藥物,。尤其是,，21 CFR 211.42(d)要求青霉素藥物的生產(chǎn)操作應(yīng)該在與其它非青人藥隔離的設(shè)施中進(jìn)行。類似地，21 CFR 211.46(d)要求青霉素和非青藥物的

空氣處理系統(tǒng)完全獨(dú)立,。

例如,，如果一個(gè)非青藥物是在一個(gè)與青霉素生產(chǎn)區(qū)域共用的設(shè)備或空氣處理系統(tǒng)的設(shè)施里生產(chǎn)的（違反§ 211.46(d))，則非青藥物就不能只是通過檢測來達(dá)到CGMP 符合性要求了,。而如果在青霉素專用 區(qū)域和其它獨(dú)立的生產(chǎn)區(qū)域之間的一扇門被無意間打開,，導(dǎo)致其它區(qū)域可能暴露于青霉素中，檢測這些非青藥物中的青霉素殘留則可以支持其放行銷售,。

但是,，根據(jù)21 CFR 211.165，所有非青藥物檢測和放行取樣計(jì)劃和可接受標(biāo)準(zhǔn),，包括所有青霉素污染檢測,，必須足以確保受測藥物符合其所有質(zhì)量標(biāo)準(zhǔn)。

11. 一個(gè)生產(chǎn)青霉素制劑的工廠是否可以清除污染,，重新改造用于非青霉素制劑的生產(chǎn),？改造后不再其中生產(chǎn)青霉素藥品。

可以,，但是污染清除可能會非常難,。污染清除過程必須包括科學(xué)合理的研究，證明污染清除用試劑的有效性,，在污染清潔前后在整個(gè)區(qū)域進(jìn)行統(tǒng)計(jì)學(xué)意義取樣以驗(yàn)證其清潔度,，對這些樣品采用經(jīng)過驗(yàn)證的具有適當(dāng)檢出限的分析方法進(jìn)行適當(dāng)檢測。CGMP 法規(guī)21 CFR 211.176 要求如果非青霉素藥品有合理可能性曾經(jīng)暴露于青霉素交叉污染的話,，則非青霉素藥品必須進(jìn)行測試,，證明其無青霉素殘留，如果使用法定方法檢測發(fā)現(xiàn)可以檢出青霉素,，則該藥品不得銷售,。如果污染清除做的不是很有效，則可能會存在此合理可能性,。盡管CGMP法規(guī)并沒有禁止清除污染并改變其用途,，但對青霉素殘留的清潔難度可能會導(dǎo)致此過程相當(dāng)艱難。

12. 非青霉素藥品中的青霉素殘留是否有可接受水平,？

沒有,。在非青霉素藥品中沒有建立青霉素產(chǎn)品的安全水平（參見FDA 行業(yè)指南，以下參考文獻(xiàn)）,。在21CFR 211.42(d)和211.46(d)中的CGMP規(guī)定要求青霉素生產(chǎn)設(shè)施和空氣處理系統(tǒng)必須與其它藥品生產(chǎn)用生產(chǎn)設(shè)施和空氣處理系統(tǒng)要充分隔離,。21 CFR 211.176 說非青霉素藥品中如果根據(jù)法定方法檢測并發(fā)現(xiàn)有青霉素殘留的話，則不能銷售,。如果證明有替代方法等同或優(yōu)于所引用的方法,，則也可以使用替代方

法來檢出青霉素殘留,。

13. 多劑量容器中的注射用藥品中，進(jìn)入抽取一定劑量的次數(shù)是否是確定有效期的一個(gè)因素,？

一般來說不是,。除多劑量容器標(biāo)示了指定體積劑特定的次數(shù)外，在藥品用完或達(dá)到其有效期之前,，從多劑量容器中抽取藥品的次數(shù)是沒有限制的,。對于多劑量容器的基本擔(dān)憂是多次穿刺容器塞子可能會導(dǎo)致藥品污染。盡管為此類藥品的制訂的有效期是基于藥品穩(wěn)定性的,，穩(wěn)定性方案應(yīng)包括測試和評估容器密閉完整性的要求,。容器密閉完整性測試可以包括使用泄漏測試從物理方面測試密閉系統(tǒng)的密封性，以及監(jiān)測系統(tǒng)防止微生物污染的能力,。對于多劑量注射藥品的容器,，功能性測試可以包括自封能力測試，采用皮下注射針穿刺容器塞子（參見以下USP 參考文獻(xiàn)）,。另外,，多劑量容器中的注射用制劑通常配方中含有抗微生物劑或防腐劑----或者內(nèi)含抗微生物的成分----必須符合批準(zhǔn)的申報(bào)資料（NDA/ANDA，BLA）和/或USP 要求,。

14. 在將在制品/中間體粉料混合物和研磨物,、待放行丸/粒、片芯用于最終制劑時(shí),，如果沒有單獨(dú)的穩(wěn)定性研究,，能放多久？

對于理化性質(zhì)穩(wěn)定和在制品/中間體物料,，對其進(jìn)行基于風(fēng)險(xiǎn)的科學(xué)評估有助于識別出哪種物料屬性和工藝參數(shù)可能會影響其將用于生產(chǎn)的制劑成品的關(guān)鍵質(zhì)量屬性,。此評估的設(shè)計(jì)應(yīng)確保所存貯的物料（在適當(dāng)?shù)拇尜A條件下）在指定的時(shí)間段內(nèi)仍適合用于制劑成品的生產(chǎn)中，而不需要進(jìn)行正式的穩(wěn)定性研究來驗(yàn)證存貯期限,。在有些情形下,，風(fēng)險(xiǎn)評估可以包括所存貯物料的取樣和檢測（由風(fēng)險(xiǎn)評估決定在哪個(gè)階段），以驗(yàn)證生產(chǎn)存貯期限,。

但是,，對于不穩(wěn)定性的物料，或者是對于存貯時(shí)間已超出風(fēng)險(xiǎn)評估所定的期限的物料,，公司應(yīng)根據(jù)批準(zhǔn)的穩(wěn)定性試驗(yàn)方案進(jìn)行穩(wěn)定性研究以驗(yàn)證存貯期限,。穩(wěn)定性試驗(yàn)應(yīng)包括對在制品/中間物料存貯直至其用于制劑成品生產(chǎn)的時(shí)長,，應(yīng)包括對使用了該在制品/中間物料所生產(chǎn)的制劑成品批次的長期監(jiān)測,。

在后一種情形下，當(dāng)生成了適當(dāng)?shù)姆€(wěn)定性數(shù)據(jù)時(shí),，公司應(yīng)根據(jù)在制品/中間物料的生產(chǎn)/放行日期來計(jì)算制劑成品批次的有效期,，而不是根據(jù)制劑成品的生產(chǎn)日期來計(jì)算。