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1. Introduction介紹
During the last few years the suitability of dissolution specifications has been discussed in marketing authorisation procedures. Some referrals concerning this topic have been raised through the CMD(h).
It is not the intention of this reflection paper to ask for additional in-vivo and in-vitro development studies according to current requirements.
A decision tree is proposed to make the evaluation process more transparent. However there may be some drugs with very narrow therapeutic ranges or products where there is prior knowledge of critical dissolution behaviour (e.g. sublingual or orodispersible tablets with some buccal absorption), which still have to be evaluated on a case by case basis.
在過去的幾年里，在上市程序中討論了溶出質(zhì)量標準的適用性。通過CMD（h）提出了一些關于該主題的推薦。本反思指南的目的不是根據(jù)當前要求進行額外的體內(nèi)和體外研究。
本文提出了一個決策樹，以使評估過程更加透明。然而，可能有一些治療范圍非常狹窄的藥物或事先了解關鍵溶解行為的產(chǎn)品（例如，具有一些舌吸收的舌下或口服可分散片），這些仍然需要根據(jù)具體情況進行評估。
1.1. Scope范圍
In the context of this reflection paper immediate release is identified as at least 75% (Q) of the active substance is dissolved within 45 minutes. The Q derives from the Ph. Eur. (5.17.1) recommendation for conventional release dosage forms.
在該反思文件中，溶出被定義為至少75% (Q)的活性物質(zhì)在45分鐘內(nèi)溶出。Q點來源于自Ph. Eur(5.17.1)的常規(guī)釋放建議。
This paper discusses the suitability of the dissolution method and the specifications for in vitro dissolution of orally administered generic drug products with immediate release characteristics. Where applicable, this reflection paper should be read in connection with the principles of relevant guidelines listed as references. The dissolution specification should ensure batch to batch consistency and, ideally, signal potential problems with in vivo bioavailability (e.g. bioinequivalence).
本文討論了溶出度方法和質(zhì)量標準的適用性，為具有速釋特性的口服仿制藥產(chǎn)品的體外溶出度。在適用的情況下，本反思文件應與作為參考列出的相關指南的原則一起閱讀。溶出度質(zhì)量標準應確保批與批之間的一致性，理想情況下，應指出以下潛在問題在活生物體內(nèi)生物利用度(例如生物不等效性)。
This reflection paper does not discuss the dissolution tests in three different buffers required as complementary to bioequivalence studies, those tests required in support of biowaiver of strengths or BCS biowaiver as defined in 4.2.1 and 4.2.2 and Appendix III respectively of the (human) Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**) or in the Guideline on the conduct of bioequivalence studies for veterinary medicinal products (EMA/CVMP/016/00-Rev.2).
本反思文件不討論作為生物等效性研究補充所需的三種不同緩沖液中的溶出度試驗，這些試驗用于支持生物等效性研究指南(CPMP/EWP/QWP/1401/98 rev . 1/Corr * *)的4.2.1和4.2.2以及附錄III或獸用藥品生物等效性研究指南(EMA/CVMP/016/00-Rev.2)中分別定義的生物強度豁免或BCS生物豁免。
1.2. Definitions定義
1.2.1. Dissolution specification溶出質(zhì)量標準
The dissolution specification is expressed in terms of the quantity (Q) of active substance dissolved in a specified time, expressed as a percentage of the content stated on the product label.
溶出度質(zhì)量標準以特定時間內(nèi)溶出的活性物質(zhì)的量(Q)表示，以產(chǎn)品標簽上注明的含量的百分比表示。
1.2.2. Discriminatory power區(qū)分力
The discriminatory power is the ability of a test procedure to discriminate between batches manufactured with different critical process parameters and /or critical material attributes which may have an impact on the bioavailability. Ideally all non-bioequivalent batches should be detected by the in vitro dissolution test results.
區(qū)分能力是指檢驗方法可區(qū)分不同關鍵工藝參數(shù)和/或關鍵材料屬性生產(chǎn)的批次的能力，這些參數(shù)和/或?qū)傩钥赡軐ι锢枚扔杏绊憽＠硐肭闆r下，所有非生物等效的批次都應通過體外檢測溶出試驗結(jié)果。
1.2.3. Biobatch生物批次
Biobatch is a batch used in a bioavailability study or in clinical testing. In the context of this Reflection Paper the biobatch is the batch of the applied product, which has been shown to be bioequivalent in a bioequivalence study of a generic vs. a reference drug product.
生物批次是用于生物利用度研究或臨床測試的批次。在本反思文件中，生物批次是指應用產(chǎn)品的批次，該批次已在仿制藥與參比藥品的生物等效性研究中被證明是生物等效的。
1.2.4. Side-batch邊界批次
A side-batch represents the intended lower in vitro release specification from the defined manufacturing process by setting process parameters within the range of maximum variability expected from process validation studies.
邊界批代表預期的下限在限度內(nèi)通過在工藝驗證研究預期的最大可變性范圍內(nèi)設置工藝參數(shù)，從規(guī)定的制造工藝中發(fā)布質(zhì)量標準。
2. Discussion討論
2.1. Dissolution test method溶出方法
2.1.1. Development of a dissolution method方法開發(fā)
A dissolution procedure intended to be used as a routine control test for immediate release drug products should be robust, reproducible and discriminatory in order to assure a consistent product quality and to detect product quality attributes, which, if altered, may affect the in vivo performance.
旨在用作速釋藥物常規(guī)控制試驗的溶出度方法應具有穩(wěn)定性、重現(xiàn)性和區(qū)分力，以確保一致的產(chǎn)品質(zhì)量并檢測產(chǎn)品質(zhì)量屬性，如果改變，可能會影響體內(nèi)性能。
For the development of such a dissolution procedure, the following aspects in particular should be considered:
在制定這種溶出方法時，應特別考慮以下方面:
•The selection of a suitable dissolution medium (composition, volume) should be based on the physico-chemical characteristics of the active substance(s) and the intended dose range of the drug product and the formulation to be tested. Sink conditions (see Ph. Eur. 5.17.1) should be attained but are not mandatory.
•選擇合適的溶出介質(zhì)(組成、體積)應基于活性物質(zhì)的物理化學特性以及待測藥物和制劑的預期劑量范圍。漏槽條件(參見歐洲藥典。5.17.1)，但不是強制性的。
•In general, an aqueous medium should be used and the pH should first be evaluated in the physiological pH range. The addition of surfactants should be avoided. When surfactants are used, for instance to achieve adequate release for poorly aqueous-soluble active substances, the type of surfactant should be justified. The concentration of the surfactant should be as low as possible and be justified by relevant solubility and dissolution data and an accompanying scientific discussion.
•一般而言，應使用水性介質(zhì)，pH值應首先在生理pH值范圍內(nèi)進行評估。應避免添加表面活性劑。當使用表面活性劑時，例如為了獲得水溶性差的活性物質(zhì)的充分釋放，表面活性劑的類型應該是合理的。表面活性劑的濃度應盡可能低，并由相關的溶解度和溶解數(shù)據(jù)以及伴隨的科學討論來證明。
•The selection of the dissolution apparatus is up to the applicant and should be sufficiently justified. The development of methods using the paddle apparatus should start with a stirring speed of 50 rpm; the development of methods using the basket apparatus should start with a stirring speed of 100 rpm. Higher stirring speeds or different basket mesh sizes may be applied with an appropriate justification.
•溶出度儀的選擇由申請人決定，并且應該有充分的理由。使用槳裝置的方法的開發(fā)應該從50 rpm的攪拌速度開始；使用籃式裝置的方法的開發(fā)應該從100 rpm的攪拌速度開始。適當調(diào)整時，可以采用更高的攪拌速度或不同的網(wǎng)籃尺寸。
A higher stirring speed may be justified by high variability of the results (e.g. > 20% RSD at time-points ≤ 10 minutes, > 10% RSD in the later phase for a sample size of 12) observed at lower speed rates due to hydrodynamic effects (e.g. coning) or other factors (e.g. tablet sticking). However, it is known that methods with increased stirring speeds may be less discriminatory. Increasing the stirring speed at the expense of the discriminatory power simply to reduce variability of the results or to obtain complete dissolution in a shorter time should be avoided.
由于流體動力效應(如錐體)或其他因素(如藥片粘連)，在較低速度下觀察到的結(jié)果可變性較高(如時間點≤ 10分鐘時的RSD > 20%，12個樣品量的后期RSD > 10%)，因此可以采用較高的攪拌速度。然而，眾所周知，提高攪拌速度的方法可能不太具有歧視性。應該避免僅僅為了減少結(jié)果的可變性或為了在更短的時間內(nèi)獲得完全溶解而以犧牲區(qū)分能力為代價來提高攪拌速度。
An increase of the stirring speed may be considered in case of over-discriminatory conditions towards in vivo performance. However, in all cases the dissolution profiles at increased stirring speeds should have sufficient discriminatory power for drug product quality control.
在對體內(nèi)性能過度歧視的情況下，可以考慮增加攪拌速度。然而，在所有情況下，在增加攪拌速度下的溶出曲線應該具有足夠的藥物產(chǎn)品質(zhì)量控制的區(qū)分能力。
•During development, the contribution of method parameters to the variability of the results should be investigated and reduced to a minimum.
•The discriminatory power should be discussed (see also section 1.2).
Further procedural recommendations on dissolution testing are provided in the European Pharmacopoeia.
•在開發(fā)過程中，應調(diào)查方法參數(shù)對結(jié)果可變性的影響，并將其降至最低。
•應討論區(qū)分力(另見第1.2節(jié))。
歐洲藥典提供了關于溶出度測試的進一步程序建議。
2.1.2. Test conditions and discriminatory power測試條件和區(qū)分力
Selection of quality control test conditions質(zhì)量控制測試條件的選擇
To allow extrapolation of the results of a bioequivalence study from the biobatch to commercial batches, it is necessary to have a suitable specification of the amount of active substance released at a specified time-point. The test conditions should enable discrimination between batches manufactured with different critical process parameters and /or critical material attributes which may have an impact on the bioavailability. Ideally all non-bioequivalent batches should be detected.
為了將生物等效性研究的結(jié)果從生物批次外推至商業(yè)批次，有必要對特定時間點釋放的活性物質(zhì)的量進行適當?shù)馁|(zhì)量控制。測試條件應能夠區(qū)分不同關鍵工藝參數(shù)和/或關鍵材料屬性生產(chǎn)的批次，這些參數(shù)和屬性可能會影響生物利用度。理想情況下，所有非生物等效的批次都應該被檢測到。
The dissolution results, under different test conditions during development, should be compared with the pharmacokinetic data generated to select the most suitable test conditions for routine testing (see section 1.2.1 and 1.2.2). Due to limited amount of in vivo data in the vast majority of generic applications, mathematical correlations may not be possible; however, all the relevant in vivo data available should be taken into consideration in choosing the most suitable in vitro dissolution test conditions.
應將開發(fā)過程中不同測試條件下的溶出度結(jié)果與生成的藥代動力學數(shù)據(jù)進行比較，以選擇最適合常規(guī)測試的測試條件(參見第1.2.1和1.2.2節(jié))。由于在絕大多數(shù)通用應用中體內(nèi)數(shù)據(jù)的數(shù)量有限，數(shù)學關聯(lián)可能是不可能的；然而，在選擇最合適的體外溶出度試驗條件時，應考慮所有可用的相關體內(nèi)數(shù)據(jù)。
Demonstrating discriminatory power區(qū)分力描述
The suitability of the test conditions for routine batch testing should be demonstrated using batches with different quality attributes. To achieve this, batches with meaningful changes compared to the applied finished product should be manufactured. Such changes may relate to the quantitative formulation, material specifications and/or using slightly modified process parameters. Current knowledge of both the characteristics derived from the Biopharmaceutics Classification System (BCS) and the finished product must be taken into account when choosing the quality attributes to change.
應當使用具有不同質(zhì)量屬性的批次來證明檢驗條件對于常規(guī)批次檢驗的適用性。為了實現(xiàn)這一點，應該生產(chǎn)與應用的成品相比有意義變化的批次。這種變化可能涉及定量處方、物料標準和/或使用稍微修改的工藝參數(shù)。在選擇要改變的質(zhì)量屬性時，必須考慮生物制藥分類系統(tǒng)(BCS)和成品的特性。
For instance, for a finished product where the in vivo absorption (rate and/or extent) is expected to be limited by solubility / intrinsic dissolution of the active substance, i.e. BCS II and IV, suitable quality attributes may be particle size of the active substance or other attributes that would have an impact on the in vivo dissolution. For a finished product where the in vivo absorption is expected to be limited by gastric emptying or intestinal permeability, i.e. containing BCS I or III class active substance with rapid or very rapid dissolution (refer to CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**), suitable quality attributes may be factors in the formulation and/or manufacturing process that will have an impact on the disintegration of the finished product and significantly affect the rate of in vitro dissolution.
例如，對于預期體內(nèi)吸收(速率和/或程度)受活性物質(zhì)的溶解度/固有溶出度(即BCS II和IV)限制的成品，合適的質(zhì)量屬性可以是活性物質(zhì)的粒度或?qū)w內(nèi)溶出度有影響的其他屬性。對于成品，其中體內(nèi)吸收預計會受到胃排空或腸滲透性的限制，即含有快速或非?？焖偃芙獾腂CS I或III類活性物質(zhì)(參見CPMP/EWP/QWP/1401/98 rev . 1/Corr * *)，合適的質(zhì)量屬性可能是配方和/或制造工藝中影響成品崩解并顯著影響體外溶解速率的因素。
Changes to the composition of the drug product to create a “bad batch” should be covered by the proposed qualitative batch formula and only the proportions of the employed excipients might be changed. The complete omission of one or more specific excipients from the formulation (e.g. binder, disintegrant) is not supported. The dissolution test conditions should be able to detect these changes by setting a suitable specification.
提定的定性批次處方應涵蓋為制造“不良批次”而對藥品成分進行的更改，且僅可更改所用輔料的比例。不支持制劑中完全省略一種或多種特定輔料(如粘合劑、崩解劑)。通過設定合適的質(zhì)量標準，溶出度試驗條件應能夠檢測這些變化。
Ideally, the in vitro dissolution test should predict the in vivo outcome, but sometimes in vitro dissolution tests are not predictive because they are over-discriminative. This is also acceptable because if dissolution profiles are not altered, in vivo equivalence can be assumed. Usually, in vivo data for batches with different quality attributes is not available. As dissolution test conditions are defined based on their ability to detect differences between batches with different quality attributes, and as these changes are of unknown in vivo relevance, it cannot be claimed that these dissolution test conditions are in vivo discriminative.
理想情況下，體外溶出度試驗應預測體內(nèi)結(jié)果，但有時體外溶出度試驗不具有預測性，因為它們具有過度的區(qū)分性。這也是可以接受的，因為如果不改變?nèi)艹銮€，可以假設體內(nèi)等效。通常，無法獲得不同質(zhì)量屬性批次的體內(nèi)數(shù)據(jù)。因為溶出度試驗條件是根據(jù)其檢測不同質(zhì)量屬性批次之間差異的能力定義的，而且這些變化是未知的體內(nèi)相關性，不能聲稱這些溶出度試驗條件在體內(nèi)是有區(qū)別的。
For drug products containing a BCS class I or class III active substances with very high solubility over the physiological pH range and with rapid or very rapid dissolution, it may not always be possible to detect any differences in dissolution behaviour after meaningful changes in relevant formulation, material specifications and/or manufacturing parameters have been made. In these cases the method may be considered to be adequate without further justification or be replaced by a disintegration test; for details see ICH Q6A or VICH GL39.
對于含有BCS類或III類活性物質(zhì)的藥品，在生理pH范圍內(nèi)具有非常高的溶解度，并且具有快速或非?？焖俚娜艹龆?，在對相關處方、材料標準和/或生產(chǎn)參數(shù)進行有意義的更改后，可能并不總是能夠檢測到溶出行為的任何差異。在這些情況下，該方法可能被認為是充分的，無需進一步證明，或由崩解試驗代替；詳情見ICH Q6A或VICH GL39。
2.1.3. Batches with different in vivo behaviour included in pharmaceutical development 藥物開發(fā)中包含的具有不同體內(nèi)行為的批次
In cases where several batches of the drug product have been tested during development in vivo leading to batches with acceptable pharmacokinetic parameters and those with non-acceptable pharmacokinetic parameters, dissolution test conditions should be chosen which allow discrimination between acceptable and non-acceptable batches by setting a suitable specification. Priority should be given to in-vivo discrimination over other factors influencing method selection.
如果在開發(fā)過程中已經(jīng)測試了幾個批次的藥品在體內(nèi)導致具有可接受藥代動力學參數(shù)的批次和具有不可接受藥代動力學參數(shù)的批次，應選擇溶出度試驗條件，通過設定合適的質(zhì)量標準來區(qū)分可接受批次和不可接受批次。相對于影響方法選擇的其他因素，應優(yōu)先考慮體內(nèi)區(qū)分力。
2.1.4. Only batches with acceptable in vivo behaviour included in pharmaceutical development藥物開發(fā)中僅包括具有可接受的體內(nèi)行為的批次
Side-batch approach邊界批次
Batches representing different in vitro dissolution profiles, derived from the defined manufacturing process by setting process parameters within the range of maximum variability expected from process validation studies, are so-called “side-batches”. The dissolution profiles of the side-batch can be used to set a suitable dissolution specification, when bioequivalence with the reference product is demonstrated. If the batches with the extreme range of in vitro dissolution profiles (i.e., fastest and slowest) are found to be bioequivalent to the reference product, then future batches with dissolution profiles within this range are also expected to be bioequivalent (when using the same manufacturing process). Thus, a suitable specification may be set based on the in vitro dissolution profile of the side- batch with the slowest dissolution, using the methodology described in section 2.
代表不同的批次通過在工藝驗證研究預期的最大可變性范圍內(nèi)設定工藝參數(shù)，從規(guī)定的生產(chǎn)工藝中獲得體外溶出曲線，稱為“邊界批”。當證明與參考產(chǎn)品具有生物等效性時，可使用邊界批的溶出度曲線來設定合適的溶出度標準。如果極端范圍的批次體外溶出曲線(即最快和最慢)被發(fā)現(xiàn)與參考產(chǎn)品具有生物等效性，那么溶出曲線在此范圍內(nèi)的未來批次也有望具有生物等效性(當使用相同的生產(chǎn)工藝時)。因此，可以使用第2節(jié)中描述的方法，根據(jù)具有最慢溶出度的副批次的體外溶出度曲線，設定合適的質(zhì)量標準。
Selection of test conditions versus in vivo trend測試條件的選擇與體內(nèi)趨勢
For a marketing authorisation application for a generic medicinal product, a bioequivalence study between a representative batch of the generic product (test) series versus the originator product on the market (reference) has to be performed. The acceptance criteria for bioequivalence are set for the pharmacokinetic parameters AUC and Cmax. The latter is an indication of dissolution speed in vivo; in case of the same AUC, a larger Cmax indicates faster in vivo dissolution. Complementary to a bioequivalence study, a comparison of the dissolution profiles (n=12) of test and reference batches used in the bioequivalence studies is required using the proposed test conditions of the generic drug product.
對于非專利藥品的上市許可申請，必須進行非專利產(chǎn)品(測試)系列的代表性批次與市場上的原研產(chǎn)品(參照)之間的生物等效性研究。為藥代動力學參數(shù)AUC和Cmax設定了生物等效性的接受標準。后者是體內(nèi)溶解速度的指標；在AUC相同的情況下，Cmax越大表示越快體內(nèi)溶解。作為生物等效性研究的補充，生物等效性研究中使用的受試批次和參比批次的溶出度曲(n=12)需要使用仿制藥產(chǎn)品的擬議測試條件進行比較。
To estimate the discriminatory power of the dissolution test it may be helpful to look at the in vivo data (point estimates and the respective confidence intervals) of the bioequivalence study. Due to the acceptance criteria for bioequivalence the point estimates for Cmax plus the respective 90% confidence interval of the generic product have to be between 80.00 % and 125.00 % (Guideline on the Investigation of Bioequivalence) of the Cmax of the reference product. According to the equivalence rules (opposite to a superiority test with the objective of detect statistical significant differences) small differences without clinical relevance will be accepted as long the 90% confidence interval fulfils these criteria.
為了估計溶出度試驗的區(qū)分能力，觀察體內(nèi)可能是有幫助的生物等效性研究的數(shù)據(jù)(點估計和各自的置信區(qū)間)。由于生物等效性的接受標準，Cmax的點估計值另外，非專利產(chǎn)品的90%置信區(qū)間必須在Cmax的80.00 %和125.00 %之間(生物等效性研究指南)參考產(chǎn)品的。根據(jù)等效性規(guī)則(與以檢測統(tǒng)計顯著差異為目標的優(yōu)勢檢驗相反)，只要90%置信區(qū)間滿足這些標準，不具有臨床相關性的微小差異將被接受。
In such a case the rank order of the in vivo and in vitro results should be compared. If a test product with significantly larger Cmax shows faster in vitro dissolution than the reference product, this may be used as an indicator for suitability of the chosen test conditions. The larger the difference and the lower the variability of the in vivo point estimates is, the greater the chance that this difference may also be reflected in vitro. In case of an opposite rank order, i.e. a test product with significantly larger Cmax shows slower in vitro dissolution behaviour or vice versa, the test conditions should be further optimised in order to reflect the in vivo trend, if possible.
在這種情況下，體內(nèi)的等級順序應比較體外結(jié)果。如果具有明顯更大Cmax的測試產(chǎn)品顯示更快體外溶出度，這可用作所選試驗條件適用性的指標。差異越大，差異的可變性越低體內(nèi)點估計值越大，這種差異也可能在體外得到反映。如果等級順序相反，即Cmax明顯較大的受試產(chǎn)品表現(xiàn)出較慢的體外溶出行為，反之亦然，則應進一步優(yōu)化試驗條件，以反映體內(nèi)趨勢，如果可能的話。
2.1.5. No batches with in vivo behaviour included in pharmaceutical development (BCS based biowaiver)藥物開發(fā)中不包括具有體內(nèi)行為的批次(基于BCS的生物豁免)
In certain instances the need for a bioequivalence study is waived based on fulfilling the criteria of the so called BCS-based biowaiver. In such instances there is no batch used in a bioavailability/bioequivalence study or in clinical testing (biobatch) and by analogy, the batch that has been shown to be equivalent with a reference product based on satisfactory in vitro dissolution data in at least three different pH media is considered to be the test batch.
在某些情況下，生物等效性研究的需要是基于滿足所謂的基于BCS的生物豁免標準。在這種情況下，不存在用于生物利用度/生物等效性研究或臨床試驗的批次(生物批次)，以此類推，根據(jù)在至少三種不同pH介質(zhì)中的體外溶出度數(shù)據(jù)，證明與參比產(chǎn)品相當?shù)呐伪灰暈樵囼炁巍?/span>
For more information see Appendix III in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**) and /or Guideline on the conduct of bioequivalence studies for veterinary medicinal products (EMA/CVMP/016/00-Rev.2).
有關更多信息，請參見生物等效性研究指南(CPMP/EWP/QWP/1401/98 rev . 1/Corr * *)的附錄III和/或獸用藥品生物等效性研究指南(EMA/CVMP/016/00-Rev.2)。
2.2. Setting Specifications質(zhì)量標準設定
When the dissolution test conditions have been chosen a suitable dissolution specification should be set. The dissolution specification limit is defined by a Q value, i.e. mean value, at a given time point, which allows discrimination between acceptable and non-acceptable batches. Batch results showing compliance with stage S1, S2 and S3 (Ph. Eur. 2.9.3.) are acceptable. The specification should be set in such a way so that during routine manufacture and testing it would be expected that compliance with S2 is attained.
選擇溶出度試驗條件后，應設定合適的溶出度質(zhì)量標準。溶出度質(zhì)量標準限值由給定時間點的Q值(即平均值)定義，可用于區(qū)分合格批次和不合格批次。顯示符合S1、S2和S3階段的批次結(jié)果(歐洲藥典。2.9.3.)都可以接受。質(zhì)量標準的設定應確保在常規(guī)制造和測試過程中，符合S2的要求。
Before setting the Q value, the time range allowing discrimination should be considered from the dissolution profile of the biobatch. Sampling time points should be sufficient to obtain a meaningful dissolution profile (c.f. human BE guideline, Appendix I; veterinary BE guideline, Section 8).
在設置Q值之前，應根據(jù)生物批次的溶出度曲線考慮允許區(qū)分的時間范圍。取樣時間點應足以獲得有意義的溶出曲線(參見人類be指南，附錄I；獸醫(yī)BE指南，第8節(jié))。
To ensure that the results of the bioequivalence study may be extrapolated to the drug product administered to the patient, all commercial batches should show similar behaviour compared to the biobatch. The dissolution profile of the biobatch, using test conditions providing discriminatory power should be used to set a suitable specification. Similar dissolution of two batches may be assumed in case of differences of less than 10% of the label claim in their mean results. Therefore, the Q value is recommended to be set on the basis of the biobatch dissolution result (mean value of 12 units) minus 10%.
為了確保生物等效性研究的結(jié)果可以推斷出用于患者的藥品，所有商業(yè)批次應顯示與生物批次相似的行為。生物批次的溶出度曲線應使用提供鑒別能力的測試條件來設定合適的質(zhì)量標準。如果兩個批次的平均結(jié)果差異小于標簽聲明的10%,則可以假定兩個批次的溶出度相似。因此，建議在生物批次溶出度結(jié)果(12個單位的平均值)減去10%的基礎上設置Q值。
The acceptance criterion Q value is usually set in the range between 75-85% (5% intervals) to demonstrate discriminatory power and satisfactory dissolution. A limit greater than 85% is not relevant. Usually the time points 15, 30 or 45 minutes would be sufficient, but other time points may be used if justified. It is not considered relevant to choose a time point before 15 minutes.
驗收標準Q值通常設定在75-85% (5%的區(qū)間)之間，以證明鑒別能力和令人滿意的溶出度。大于85%的限制是不相關的。通常時間點15、30或45分鐘就足夠了，但是如果合理的話也可以使用其他時間點。選擇15分鐘之前的時間點被認為是不相關的。
How to read the recommendations in the Annex:附件的推薦
The recommendations in the Annex are meant as guidance for setting the specification. The discriminatory power is closely linked to the time point and Q value chosen. If time points/Q values other than proposed in the decision tree would lead to discriminatory power, this is also acceptable.
附錄中的建議旨在作為設定規(guī)范的指南。辨別能力與選擇的時間點和Q值密切相關。如果決策樹中建議的時間點/Q值之外的時間點/Q值會導致歧視性功效，這也是可以接受的。
•If dissolution of the biobatch is larger than or equal to 95% in 15 minutes, the specification may be set to Q=85% after 15 minutes;
•如果生物批次在15分鐘內(nèi)的溶出度大于或等于95%，則質(zhì)量標準可設定為15分鐘后Q=85%；
•If dissolution of the biobatch is less than 95% but larger than or equal to 85% in 15 minutes, the specification (Q) may be set to 75%, 80% or 85% whichever is closer to Q=biobatch result -10% at 15 minutes;
•如果生物批次在15分鐘內(nèi)的溶出度小于95%，但大于或等于85%，則質(zhì)量標準(Q)可設定為75%、80%或85%，取更接近Q = 15分鐘時生物批次結(jié)果-10%的值；
•If dissolution of the biobatch is larger than or equal to 85% only after 30 minutes, the specification (Q) may be set to 75%, 80% or 85% whichever is closer to Q=biobatch result -10% at 30 minutes;
•如果生物批次的溶出度僅在30分鐘后大于或等于85%,則質(zhì)量標準(Q)可設定為75%、80%或85%,以更接近Q = 30分鐘時生物批次結(jié)果-10%為準；
•If dissolution of the biobatch is larger than or equal to 85% only after 45 minutes, the specification may be set to 75%, 80% or 85% after 45 minutes. In case dissolution of the biobatch is less than or equal to 85% after 45 minutes, a minimum of 75% at 45 minutes should be specified if possible. Otherwise, if the dissolution specification (Q) is less than 75% after 45 minutes, the dissolution specification should be based on more than one time point (see Annex: Decision tree for the principles for setting specifications).
•如果生物批次的溶出度僅在45分鐘后大于或等于85%，則質(zhì)量標準可在45分鐘后設定為75%、80%或85%。如果45分鐘后生物批次的溶出度小于或等于85%，如果可能，應規(guī)定45分鐘時的最小溶出度為75%。否則，如果45分鐘后溶出度規(guī)格(Q)小于75%，則溶出度規(guī)格應基于一個以上的時間點(規(guī)格設定原則見附件:決策樹)。
Recommendation in case of BCS biowaiver BCS免除推薦
In case there is no biobatch the specification limit with a fixed Q value within 15 min (for BCS class I and III) or 30 minutes (applicable only for human BCS class I products) can be established. This Q value should be at least 80% using discriminatory test conditions (i.e. the QC method applied for), irrespective of the dissolution results of the test batch observed in the study used to claim the BCS biowaiver. The conditions for the dissolution test in the specification should be chosen as the most discriminatory between those used in the comparative dissolution study.
如果沒有生物批次，可以在15分鐘(BCS I類和III類)或30分鐘(僅適用于人BCS I類產(chǎn)品)內(nèi)建立固定Q值的質(zhì)量標準限值。無論在用于聲明BCS生物豁免的研究中觀察到的試驗批次的溶出度結(jié)果如何，使用歧視性試驗條件(即應用的QC方法)時，該Q值應至少為80%。質(zhì)量標準中的溶出度試驗條件應選擇在溶出度比較研究中使用的條件中最具鑒別性的條件。
3. Conclusion結(jié)論
This reflection paper should facilitate congruent decisions on setting specifications for in vitro dissolution of generic drug products with immediate release characteristics. The principle is to derive the specification of the drug product on the basis of the quality characteristics of the biobatch. Similar principles may be considered for deriving the specification for innovator products.
這份反思文件應該有助于在制定規(guī)范方面做出一致的決定具有速釋特性的仿制藥產(chǎn)品的體外溶出度。原則是根據(jù)生物批次的質(zhì)量特征得出藥品的質(zhì)量標準。類似的原則也可以用來推導創(chuàng)新產(chǎn)品的規(guī)格。
參考文件：
Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action， 2017.8
來源：文亮頻道
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