中文字幕一级黄色A级片|免费特级毛片。性欧美日本|偷拍亚洲欧美1级片|成人黄色中文小说网|A级片视频在线观看|老司机网址在线观看|免费一级无码激情黄所|欧美三级片区精品网站999|日韩av超碰日本青青草成人|一区二区亚洲AV婷婷

摘要：制劑生產(chǎn)工藝中過量灌裝（overfill）與過量投料（overage）不同，CDE對這兩種過量方式的審評尺度也存在較大差異，本文從相關(guān)概念、各國法規(guī)政策的相關(guān)要求入手，對其二者進(jìn)行區(qū)分，以便更好的明確制劑工藝的投藥量，不足和缺陷之處望批評指正。

一、定義：

過量投料（過量加入），如已知某一成分在生產(chǎn)或貯存期間含量會降低，生產(chǎn)時可適當(dāng)增加投料量，以保證在有效期內(nèi)含量能符合規(guī)定。"An overageis a fixed amount of the drug substance in the dosage form that is added inexcess of the label claim." FDA Guidance Drug Product Chemistry,Manufacturing, and Controls Information 2003 Draft EMA DevelopmentPharmaceutics.

過量灌裝（過量裝量），是指使用時因包材的粘附而損失需要過量灌裝的情況，特別是注射劑，需要考慮西林瓶/安瓿瓶，甚至針筒的粘附損失，目的是確保給藥劑量。Overfill is the volume or weight of the formulation filled in eachcontainer in sliaht excess of the labeled content. Allowable excess volume mayalso be referred to as overfill. FDA Guidance Allowable Excess Volume andLabeled Vial Fill Size in Injectable Drug and Biological Products、FDA Guidance Drug ProductChemistry, Manufacturing, and Controls Information 2003 Draft.

二、制劑工藝中的過量投料

過量投料中包括化學(xué)損耗和物料損耗，詳述如下：

化學(xué)損耗: 在樣品制備及儲存過程中引起藥物的降解，造成藥物有效含量下降。ICHQ8(R2)中指出，一般不提倡在藥品生產(chǎn)中過量使用原料藥，以補(bǔ)償藥品在生產(chǎn)或其有效期內(nèi)的降解。但是有些藥物穩(wěn)定性極差，目前的生產(chǎn)工藝水平不能完全抑制其降解且降解產(chǎn)物不會造成安全性風(fēng)險，故仍允許過量。如維生素A的制劑可允許過量20％。

物理損耗：在藥物制劑工藝中，固體制劑存在制粒、混合、整粒，壓片、分包裝等多個環(huán)節(jié)存在著原輔料損失的可能；在液體制劑的工藝中，存在著管道及鍍層的金屬對藥物的吸附等損耗；外用半固體軟膏劑的制備中，常需要適當(dāng)加溫以促進(jìn)脂質(zhì)原料的溶解，在半成品的不同容器間的轉(zhuǎn)移，和分裝工序中也都存在一定的死體積，造成物料的損失；特殊劑型如緩控釋功能的激光打孔滲透泵片劑，外層是堅硬的半透膜，內(nèi)部是雙層，一層為含藥層，另一層為吸水后具有高滲的驅(qū)動層，由于此類制劑本身的固有缺陷以及API本身的理化性質(zhì)特點，總要有極少部分在片劑有效的運(yùn)轉(zhuǎn)途徑的最終點不能完全被泵出或者藥物存在反滲透現(xiàn)象而使少部分藥物儲留于片殼內(nèi)，為了使藥品的有效性得以保持，所以需要過量投料。例如輝瑞公司生產(chǎn)的格列吡嗪緩釋片過量10%；甲磺酸多沙唑嗪控釋片過量5%；硝苯地平控釋片過量10%。大多數(shù)物理性損耗中，原輔料是等比例的，風(fēng)險較小?？傊壳皩徳u中可接受過量投料的唯一理由是參比中有相同的過量，并在生產(chǎn)處方中列明各組分過量的依據(jù)。

ICH Q8 PharmaceuticalDevelopment

In general,use of an overage of a drug substance to compensate fordegradation during manufacture or a product's shelf life, or to extend shelflife，isdiscouraged.Any overages in the manufacture of the drug product，whether they appear in the finalformulated product or not，should be justified considering the safety and efficacy of theproduct. Information should be provided on the 1) amount of overage，2) reason for the overage (e.g.，to compensate for expected anddocumented manufacturing losses),and 3) justification for the amount of overageThe overage should be included in the amount of drug substance listed in thebatch formula (3.2.P.3.2)."

不鼓勵過量加入來補(bǔ)償生產(chǎn)或者貨架期內(nèi)的產(chǎn)品降解，對于過量加入，應(yīng)提供依據(jù)并列明在生產(chǎn)處方中。

EMA Development Pharmaceutics

Overages are primarily employed to cover losses during manufactureof active substances or key excipients,i.e. manufacturing overage, and/orduring shelf-life i.e. stability overage. These can be distinguished since inthe former case there is unlikely to be increased dosage administered to thepatient， whereas thestability overage will result in overdosing where batches of product may reachthe patient soon after release.The inclusion of any overage should bejustified. Large overages (for example in excess of 10%) should not normally beused to cover up inherently unstable formulations it is better to reduce ashelf life rather than to risk exposing a patient to excessive doses of a drug.Similarly overages should not be used to cover up imprecise or inaccurateanalytical test procedures or sub-optimal manufacturing processes. Theintroduction of an overage of an active substance into a formulation shouldalways be justified on the grounds of safety and efficacy of the product. Itshould also be remembered that over dosage may be introduced by the mechanismof delivery, e.g. deposition of a metered-dose inhaled drug in the mouth.

應(yīng)以臨床安全，有效為出發(fā)點，區(qū)分是生產(chǎn)損失過量加入還是貨架期損失過量加入。

三、小容量注射劑的過量灌裝

液體藥物通常必須通過中介設(shè)備（例如注射器）進(jìn)行給藥，通常很難從小瓶中取出100％的內(nèi)容物。

2020版《中國藥典》0102注射劑中規(guī)定，注射劑的灌裝標(biāo)示裝量不大于50ml時，可參照下表適量增加裝量。

2017年CDE發(fā)布的《已上市化學(xué)仿制藥（注射劑）一致性評價技術(shù)要求》規(guī)定過量灌裝量要和原研一致。

FDA藥典相關(guān)規(guī)定，旨在“在沒有適當(dāng)理由的情況下，減少小瓶的過量灌裝，以期減少用藥錯誤、不良事件和液體藥物產(chǎn)品的濫用”但并未提出一個嚴(yán)格的框架來對產(chǎn)品進(jìn)行一刀切的監(jiān)管。如果企業(yè)確實需要過量灌裝，企業(yè)應(yīng)遵守美國藥典（USP）通用章節(jié)<1151>，該章節(jié)建議企業(yè)設(shè)計產(chǎn)品“以符合標(biāo)簽要求和可接受的過量灌裝，并允許正確的劑量”。需要通過使用“可提取的內(nèi)容測試數(shù)據(jù)”來證明偏差。此類數(shù)據(jù)應(yīng)包括在產(chǎn)品申請批準(zhǔn)中，并代表商業(yè)化過程。舉例：某無菌粉灌裝品種需達(dá)到100mg的劑量，灌裝107.5mg無菌粉，臨床使用時注入4.3ml配伍溶液，抽取4.0ml溶液，可確保臨床使用量（即0.3ml的死體積），該品種的過量灌裝為7.5%。

FDA的法規(guī)指南

Location Issues in Drug Product: 3.2.P,The use of an over-fillshould be indicated in 3.2.P.1. The rationale for an overfill should beincluded in 3.2.P.2.2.1.

FDA will RTR an ANDA whose subject is a parenteral drug product ifits fill volume deviates from the RLD drug product and the deviationis not permitted. ANDA parenteral drug products should contain the sameconcentration and total drug content per container as the RLD. Therefore, adeviation from the fill volume (total drug content) of the RLD parenteral drugproduct may constitute a change in strength. A change in strength mustfirst be approved via the suitability petition process before it can beproposed in an ANDA submission That is, alterations beyond overfill allowancesthat are within USP recommendations in a relevant drug product monograph.

注射劑裝量應(yīng)與RLD一致，如不一致(對于RLD的裝量改變，超出了藥典有關(guān)品種專論中建議的過量灌裝范圍)，應(yīng)事先經(jīng)適用性請愿程序批準(zhǔn)，否則會RTR。

EMA關(guān)于過量灌裝

1、250micrograms powder for solution for injection should be reconstituted with 0.72ml sterile water for injections, yielding a deliverable volume of 0.5 ml. An additionaloverfill is included in each vial to ensure that 250 µg of romiplostim can bedelivered. EMA Nplate.

2、For the 100mg vial, a 4.30 ml fill containing 107.5 mg bevacizumab (7,5% overfill)achieves delivery of 100 mg bevacizumab.EMA Avastin

小瓶包裝死體積及復(fù)溶損失導(dǎo)致的過量。

四、如何區(qū)分參比是過量灌裝還是過量投料

以某無菌粉灌裝為例，規(guī)格為500mg，原研說明書規(guī)定主成分與輔料比例為1:0.725，參比反向工程中，測定主成分含量為105%，輔料的含量為103.6%，不同配伍溶劑，可提取的內(nèi)容性損失最大約為4.5%，符合2020版《中國藥典》0102注射劑中規(guī)定，因此該品種為過量灌裝；對于過量投料，本人未經(jīng)歷過相關(guān)案例，根據(jù)ICHQ8相關(guān)要求，總體來說，不鼓勵加入過量原料藥以補(bǔ)償生產(chǎn)過程或產(chǎn)品存貯期中原料藥的降解，或用以延長保存期。

對于制劑生產(chǎn)過程中出現(xiàn)的過量現(xiàn)象，無論其是否是出現(xiàn)在最終制劑中，都應(yīng)當(dāng)要從產(chǎn)品的安全性和有效性方面對其進(jìn)行合理性說明。應(yīng)提供如下信息：1）過量的量；2）過量的原因（如，補(bǔ)償生產(chǎn)過程中出現(xiàn)的損失）；3）超出量的合理性說明應(yīng)分別在制劑處方組成2.3.P.1、3.2.P.1和制劑生產(chǎn)2.3.P.3、3.2.P.3部分討論過量加入的原因。

五、參考文獻(xiàn)

[1] 淺析藥物制備工藝中的“過量投料”現(xiàn)象—中國藥審.

[2]USP<1151>.

[3]Allowable-Excess-Volume-Labeled-Vial-Fill-Size-in-Injectable-Drug-and-Biological-Products

[4] ICH Q8 Pharmaceutical Development.

[ 5] FDA Guidance Allowable Excess Volume and Labeled Vial Fill Sizein Injectable Drug and Biological Products.

[6] EMA Avastin/ Nplate.