5.7 Considerations forAutomation
5.7自動操作注意事項
Automated methods offer opportunitiesfor increased precision and reproducibility; however, bias may be introduced.In particular, the sampling probe and the sample lines warrant attention asplaces where inaccuracies may occur. Deviations from the procedure described in<711>, such as resident sampling probes, sampling through the stirringelement shaft (hollow-shaft sampling), or fiber-optic probes, should bevalidated. Other aspects of automation validation may include carryover ofresidual drug, effect of an in-residence probe, adsorption of drug, andcleaning and/or rinse cycles. Validation is performed using the automateddissolution system including materials. Therefore, any change in materials willrequire demonstration of suitability based on the validation attributes thatare impacted by the change.
自動化的方法可以增加精密度和重複性，但可能會引入偏差，特別是取樣探針和樣品序列可能發生錯誤的地方值得注意，在（711）中描述了分析方法偏差，比如，保留取樣針、通過攪拌元件軸（空心軸採樣）、或者光纖維進樣，都應該進行驗證，自動進樣其他方面的驗證包括夾帶的殘留藥物、探針內的殘留藥物影響、藥物吸附、清洗和/或清洗周期。使用自動溶解解系統，材料也需要進行驗證。根據驗證屬性受變化的影響，因此材料的任何變化都需要證明適用性。
Manual andautomated procedures should be compared to evaluate the interchangeability ofthe procedures. This is done by performing two automated runs at each dosageconcentration, using all sampling points, compared to manually sampled runs ofthe same samples. The effect of the in-resident probe cannot be determined bysampling both ways from the same vessel. Results should be consistent with therequirements for intermediate precision if the procedures are to be considered interchangeable.The difference in the mean value for dissolution results between any twoconditions using the same strength should not exceed an absolute 10% at timepoints with <85% dissolved nor exceed 5% for time points >85%. Acceptancecriteria may be product specific, and other statistical tests and limits may beused.
手動和自動程序應該進行對比研究，評估程序的可互換性。這是通過在每一劑量濃度兩個自動運行程序，使用所有採樣點比較同一樣品的手動採樣運行。通過同一容器中兩種採樣方式，不能確定內置探針的作用。如果程序認為是可以交換的，試驗結果應與中間精密度的要求相一致。同一濃度在任一兩個條件之間的溶出結果平均值在溶出<85%的點絕對誤差不應超過10%，>85%的點絕對誤差不得超過5%。可接受標準可以用於特定產品、也可以使用其他統計方法和範圍。
Revalidationmay be necessary when the automated system is used with different formulationsbecause of the interaction with excipients. Dissolution media containingsurfactants or lipids may require additional validation efforts.
自動化系統用於不同的劑型時需要進行再驗證，因為賦形劑之間可能會相互作用。包含表面活性劑和脂質的溶出介質也需要另外進行驗證。
6. ACCEPTANCE CRITERIA
6.可接受標準
The acceptance criteria should be consistent withhistorical release or stability data. There is an expectation that acceptable batcheswill have results that fall within the acceptance criteria and that allmanufactured batches should have similar dissolution behavior, thushighlighting the importance of having a method that is not highly variable. Theacceptance criteria and time point(s), therefore, should discriminate betweenan acceptable and an unacceptable batch. In addition, the dissolution testresults are viewed as a link to the pivotal clinical trial batches. Whenchanges in dissolution rate have been shown to affect bioavailabilitysignificantly, the dissolution test and acceptance criterion should distinguishbatches with unacceptable bioavailability (19). Likewise, when changesin the formulation and manufacturing process significantly affect dissolutionand such changes are not controlled by another aspect of the specification, thedissolution test and criteria should distinguish these changes.
驗收標準應與歷史釋放或穩定性數據相一致。我們期望可接受的批次的預期試驗結果在驗收標準範圍內，所有的出廠批次具有類似的溶出行為，因此方法的耐用性是需要重點考慮的。因此，驗收標準和取樣時間點應該能夠區分可接受與不可接受批次。此外，溶出的試驗結果與臨床試驗關鍵批次連結。當改變溶出速率顯著影響生物利用度時，溶出試驗和可接受標準應該能夠區分生物利用度不可接受的批次（19）。否則，當處方和工藝過程改變顯著影響溶出時，這些變量不受質量標準的控制，溶出試驗和溶出標準應該能夠區分這些改變。
6.1 Immediate-Release DosageForms
6.1速釋劑型
Although release and stability data are collectedduring dosage form development, it is common to record the entire dissolution profileor the amount of drug dissolved at specified intervals, such as 10, 20, 30, 40,50, and 60 min or 15, 30, 45, and 60 min. At registration, dissolution for animmediate-release tablet usually becomes a single-point test. The acceptancecriterion and test time are established by evaluating the dissolution profiledata. The acceptance criterion for a dissolution test is a function of Q,which is expressed as a percentage of label claim of drug dissolved at aspecified time. Typical Q values are in the range of 75%–80% dissolved. Qvalues in excess of 80% are not generally used because allowance needs tobe made for assay and content uniformity ranges.
雖然在劑型開發過程中收集到的釋放和穩定性數據，通常繪製整個溶出曲線圖或者計算出在指定時間間隔藥物的溶出量，比如在10、20、30、40、50和60分鐘，或在15、30、45和60分鐘。在註冊時，速釋片的溶出經常採用單點測試，通過對溶出曲線數據進行評估確定可接受標準和測試時間。溶出試驗的可接受標準用函數Q表示，Q表示為在指定時間藥物溶出佔標示量的百分比。Q值通常在75%-80%的溶出範圍內，Q值超過80%通常不能使用，因為需要考慮分析和含量均勻度的範圍。
6.2 Delayed-Release DosageForms
6.2延遲釋放劑型
The discussion about dissolution of delayed-releasedosage forms in <711> focuses on enteric-coated dosage forms, which is themost common delayed-release dosage form. A dissolution test for adelayed-release tablet or capsule is a two-part test, and each part hasacceptance criteria. First, the dosage forms are exposed to an acid medium,followed by exposure to a buffer medium. To ensure that the enteric coatingperforms properly, a 「NMT」 acceptance criterion is indicated in <711> forthe acid stage. The medium used for an acid stage is usually 0.1 N HCl, and theduration of this stage is typically 2 h. The dosage forms are then exposed to abuffer medium, usually 0.05 M phosphate buffer at pH 6.8, but other buffers andpH targets may be used if justified. The duration of the buffer stage isusually 45 min for compendial tests, but this duration may vary, depending onthe drug product. As with immediate-release dosage forms, a Q value andtime point are determined by evaluating the entire dissolution profile.
在<711>部分，主要對腸溶緩釋劑型的溶出度進行討論，也是最常見的緩釋劑型。緩釋片或膠囊的溶出度試驗分為兩部分，每部分都有可接受標準。第一部分，劑型在酸性介質中的釋放，隨後暴露在緩衝介質中，為了確保腸溶包衣正常進行，在<711>部分對在酸性介質中「不小於」接受標準的情況進行了說明，酸性介質通常是0.1N鹽酸，通常持續釋放2小時，然後放在緩衝鹽介質中，通常是0.05M磷酸鹽緩衝液（pH=6.8）。如果有正當理由可使用其他緩衝劑和pH範圍，根據藥典試驗，緩衝階段的釋放時間通常為45分鐘。但這個持續時間是可以變化的，取決於製劑。正如即時釋放劑型，通過評估整個溶出曲線圖來決定Q值和取樣時間點。
6.3 Extended-Release DosageForms
6.3延長釋放劑型
A dissolution test for an extended-release dosageform is generally similar to that used for an immediate- or delayed-release drugproduct, except that the duration of the test is longer, and at least threetime points are specified for pharmacopeial purposes (20). Additionalsampling times may be required for drug approval purposes. An early time point,usually 1–2 h, is chosen to show that dose dumping is not probable. Anintermediate time point is chosen to define the in vitro release profile of thedosage form, and a final time point is chosen to show essentially completerelease of the drug (20). The time points for the test should bedetermined by evaluating the dissolution profile across the desired testduration. Often, additional time points are obtained during dosage formdevelopment to aid with selecting the appropriate time points for thespecification or monograph.
延長釋放的溶出度試驗通常和即時釋放和延遲釋放相似，所不同的是測試的持續時間較長，藥典規定至少三個時間點（20）。考慮到藥物的審評目的，需要增加取樣點。在時間點的早期，通常1-2小時，不可能產生劑量傾卸，選擇中間時間點作為劑型的體外釋放曲線，選擇的最後時間要能表明藥物基本完全釋放（20）。評估跨過所需的測試時間的溶出曲線來確定測試時間點。通常情況下，質量標準或藥典正文中合適時間點的選擇有助於在製劑開發過程中增加取樣時間點。
As with an immediate- or delayed-release drugproduct, the acceptance criteria and time points for an extended-release drugproduct should discriminate between an acceptable and an unacceptable batch.The acceptance criteria for the first stage of testing (L1) should beestablished on the basis of available batch data (19,20). If humanbioavailability data are available for formulations exhibiting differentrelease rates, then an in vitro/in vivo relationship may be used to establishacceptance criteria (19,20). Acceptance criteria for the second (L2) andthird (L3) stages are derived from the L1 criteria using Acceptance Table2 in <711>.
正如立即或延遲釋放的藥物產品，延長釋放的藥物產品的可接受標準和時間點應該能夠區分可接受和不可接受的批次。在試驗的第一階段，根據可用的批次數據建立可接受標準（19,20）。如果人體的生物利用度數據表現出製劑的不同釋放速率，那麼體外/體內關係可用於建立可接受標準（19,20）。第二（L2）和第三（L3）階段的可接受標準來源於L1標準（在<711>中使用表2可接受標準）。
6.4 Multiple Dissolution Tests
6.4多個溶解度試驗
Typically, monographs for extended-release dosageforms contain multiple dissolution tests representing specific products.Inaccordance with General Notices and Requirements 4.10.10, theappropriate test, if not Test 1, is indicated on the product labeling.For example, the USP monograph for Oxycodone HydrochlorideExtended-Release Tablets (21) lists two dissolution tests, each of whichhas either three or four time points. If the Tablets are analyzed using Test2 and the dissolution results comply with the criteria provided in themonograph, the labeling for Tablets can indicate that the Tablets meet USP DissolutionTest 2.Multiple dissolution tests also can be found in monographs forimmediate- and delayed-release dosage forms. For example,the USP monographsfor Levothyroxine Sodium Tablets and Pantoprazole SodiumDelayed-Release Tablets provide four dissolution tests (22,23).
通常情況下，正文中的延長釋放劑型代表的特定產品包含多個溶出試驗。符合4.10.10凡例和要求，如果不是測試1，在產品標籤上註明所進行的適用試驗，說明。例如，美國藥典正文中列出了鹽酸羥考酮緩釋片劑（21）的兩個溶出試驗，每個試驗各取三個或四個時間點。如果使用試驗2對片劑進行分析，溶出結果與正文中提供的標準相符合，片劑標籤可以標明片劑符合美國藥典溶出試驗2。在即時和延遲釋放的藥典正文中發現多個溶出試驗，例如，美國藥典正文中提供了左甲狀腺素鈉片和泮託拉唑鈉緩釋片四種溶出試驗（22,23）。
6.5 Interpretation ofDissolution Results
6.5溶出結果說明
The Interpretationsection of <711> discusses immediate-, delayed-, and extended-releasedosage forms. The discussion for each of these release patterns is expandedhere with examples to assist with applying the criteria during the variousstages of testing. Understanding how these criteria are applied will assist insetting appropriate acceptance criteria.
在<711>說明部分討論了即時釋放、延遲和延長劑型。在不同測試階段，在不同測試階段，運用標準有助於用實例對這些釋放模式的討論進一步擴展。理解了這些標準適用範圍有助於制定相應的可接受標準。
6.5.1 IMMEDIATE-RELEASE DOSAGEFORMS
6.5.1即時釋放劑型
Once the Qvalue is established, the dissolution test is a staged test of threelevels. In the first level of testing called S1, six dosage forms are tested.Each dosage form must be Q + 5% (absolute percentage points) dissolvedat a specified time. For example, the time and tolerances in a monograph wouldbe:
Time: 30 min
Tolerances:NLT 80% (Q) of the labeled amount of 「drug substance」 is dissolved.
一旦Q值確定，溶出試驗在測試階段需要三個濃度水平。在測試的第一個濃度水平被稱為S1，用6片進行測試。每種劑型在指定時間點溶出度必須是Q +5％（絕對百分點）。例如，在正文中提到的時間和允許偏差分別為：
時間：30分鐘
允許偏差：Q值不小於80%為「藥物活性物質」標示量的80%被溶出。
If the Q valuefor a 200-mg label claim (LC) immediate-release tablet is specified as 80% andthe time point is 30 min, then NLT 85% LC (170 mg) of the drug substance ineach tablet must be dissolved at 30 min.
如果200mg標示量（LC）的即時釋放片的Q值指定為80%，時間點是30分鐘，那麼在每個片子中在30分鐘溶出必須不小於標示量（170mg）的85%。
If thiscriterion is not met, then 6 additional tablets are tested at level 2 (S2).To pass the S2 acceptance criteria, the average of all 12 tabletsmust be equal to or greater than Q (80% LC; 160 mg in the aboveexample), and no tablet has less than Q –15% (65% LC; 130 mg in theabove example).
如果不能滿足這個標準，那麼在濃度2（S2）用另外6片進行測試。12片的平均值必須等於或大於Q值（標示量的80%，在上面的例子中160mg），沒有片子少於Q-15%（標示量的 80%，在上面的例子中130mg），表明通過S2的可接受標準。
If thesecriteria are not met, then level 3 or S3 testing must be performed by testing12 additional tablets. To pass S3, the average of all 24 tablets must be equalto or greater than Q (80% LC; 160 mg in the above example). Twoadditional criteria must be met as well: 1) no more than 2 tablets are lessthan Q – 15% (65% LC; 130 mg in the above example), and 2) no tablet isless than Q – 25% dissolved (55% LC; 110 mg in the above example.)
如果都不能滿足這些標準，那麼在濃度3或（S3）用另外12片進行測試。24片的平均值必須等於或大於Q值（標示量的80%，在上面的例子中160mg），表明通過S3的可接受標準。兩個增加的標準必須滿足：1)不超過兩片是（標示量的65%，在上面的例子中130mg）,2）.沒有片子小於Q-25%（標示量的55%，在上面的例子中110mg）。
6.5.2 DELAYED-RELEASE DOSAGEFORMS
6.5.2延遲釋放劑型
An aliquot of the acid medium from each vessel isanalyzed at the end of the acid stage. For the acid stage, the acceptance criteriahave three levels. Level 1 (A1) testing is passed if no individual valueexceeds 10% dissolved. If the A1 criteria are not met, then the dissolutiontest is performed on 6 additional dosage forms for level 2 (A2) testing. LevelA2 criteria are passed if the average of all 12 dosage forms in the acid stageis NMT 10% dissolved and if no individual dosage form is more than 25% dissolved.Level 3 testing is performed if the A2 criteria are not met. The A3 criteriaare passed if the average of all 24 dosage forms in the acid stage is NMT 10%dissolved and if no individual tablet is more than 25% dissolved. For thespecial case in which the solubility of the drug in an acidic medium because ofconversion to the free acid is too low to support an acceptance criterion ofnot more than 10% the drug product should be exposed to the acid stage for thedefined duration and then exposed to the buffered medium. Alternate acceptancecriteria for the acid stage based on drug solubility may be justified.
在酸性階段結束時分析每個溶出杯中的酸性介質。酸階段，可接受標準有三個濃度。如果溶出度單個值沒超過10% ，濃度1（A1）測試通過。如果不能滿足A1標準，則在溶出試驗用另外6個片劑型在濃度別2（A2）中進行測試。如果通過A2標準，所有12個劑型在酸性階段的溶出度平均值不超過10％，如果每片溶出度不超過25％。在特殊情況下，該藥物在酸性介質中因轉化為游離酸，溶解度太低，不符合質量標準中不超過10%的製劑應該暴露在酸性階段持續釋放然後暴漏在緩衝介質中。在酸性階段根據藥物溶解度制定的可選擇標準是合理的。
For delayed-releasedosage forms, the total percentage dissolved is determined by adding themeasured amounts in the acid and buffer phases for each individual dosage form.These calculated values are then compared to staged acceptance criteria (B1,B2, and B3) that are based on a Q value. The B1, B2, and B3 criteria areidentical to those for the immediate release S1, S2,and S3 criteria.
對於延遲釋放劑型，溶解度的總百分比是通過每片在酸性和緩衝階段測得的量來確定的。
比較這些計算值，然後，根據Q值分階段比較驗收標準（B1，B2，和B3）。B1，B2、B3標準和即時釋放S1，S2、S3標準相同
6.5.3 EXTENDED-RELEASE DOSAGEFORMS
6.5.3延長釋放劑型
In the following hypothetical example, which isused to describe the criteria for a extended-release dosage form, the time pointsare 1, 4, and 8 h. The acceptance range for each time point is as follows:
• Between 24%and 44% LC drug substance dissolved at 1 h
• Between 56%and 76% LC drug substance dissolved at 4 h
• NLT 85% LCdrug substance dissolved at 8 h.
Acceptanceranges are often expressed in tabular form in the USP–NF (see Table 3):
在下面假設的例子中，用於描述延長釋放劑型在時間點為1、4和8小時的釋放標準，每個時間點的可接受範圍如下：
在1小時間主藥溶出度介於標示量的24％和44％
在4小時主藥溶出度介於標示量的56％和76％
在8小時主藥溶出度不小於85％。
在USP-NF（見表3）列出了通常可接受範圍。
表3.L1標準
時間（h）
溶出度數值
1
24-44%
4
56%-76%
8
不小於85%
Six tablets are analyzed at Level 1 (L1);acceptance criteria are met if no individual value lies outside each of thestated ranges,and no individual value is less than the percentage specified forthe final time point. If the L1 criteria are not met, then 6 additional tabletsare analyzed at level 2 (L2). The L2 criteria are met if these three conditionsare met:
1. Theaverage value of the 12 tablets lies within each of the stated ranges and isNLT the stated range of the final time point.
2. None ofthe 12 tablets is >10% of the labeled content outside each of the statedranges.
3. None ofthe 12 tablets is >10% of the labeled content below the stated amount at thefinal test time.
For the above example, the L2 acceptance criteriafor the 12 tablets (see Table 4) are as follows:
在濃度1（L1）分析了6片，如果每片都在規定的範圍之內，並且沒有一個值小於最終時間點指定的百分比，滿足可接受標準。
如果不能滿足L1條件，則用另外6片在2級（L2）進行分析。如果下面這三個條件都滿足，那麼滿足L2標準：
1.12片的平均值均在所規定述範圍內且不小於最後時間點規定範圍。
2.12片中沒有一片大於標示含量10％，且每片在規定範圍之外。
3. 12片中沒有一片大於標示含量10％，且低於最終測試時間點規定值。
上述例子中12片L2驗收標準列於表4：
表4.L2標準
1h
4h
8h
平均
24-44%
56%-76%
不小於85%
每片
14%-54%
46%-86%
不小於75%
If the L2criteria are not met, then 12 additional tablets are tested at level 3 (L3).The L3 criteria are met if these five conditions are met:
1. Theaverage value of the 24 tablets lies within each of the stated ranges and isNLT the stated range of the final time
point.
2. NMT 2 ofthe 24 tablets are >10% of labeled content outside each of the statedranges.
3. NMT 2 ofthe 24 tablets are >10% of the labeled content below the stated amount atthe final test time.
4. None ofthe 24 tablets is >20% of the labeled content outside each of the statedranges.
5. None ofthe 24 tablets is >20% of the labeled content below the stated amount at thefinal test time.
The L3acceptance criteria for the 24 tablets in the above example are summarized in Table5:
如果沒有滿足二級標準，那麼另外12片在3級（L3）進行測試。如果滿足這五個條件符合L3標準：
1、24片的平均值均在上述的每個範圍內，且不低於最後時間點的範圍
2、24片中不超過2片>標示含量的10％，且每片在規定範圍之外。
3、24片中不超過2片>標示含量的10％，且低於最終時間點規定值。
4、24片中沒有1片標示含量>20％，且每片都在規定範圍之外，
5、24片中沒有1片標示含量> 20％，且低於最終測試時間點規定值。
上述例子中24片L3可接受標準列於表5
表 5.L3標準
1h
4h
8h
平均
在14％-54％範圍之外不超過2片，任何一片都在4％-64％的範圍之內
在46％-86％的範圍之外不超過2片，任一片都在：36％-96％的範圍之內
釋放度<75％不超過2片，每一片的釋放度都不超過65％
（全文完）
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