摘要：制劑生產工藝中過量灌裝（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，本文從相關概念、各國法規政策的相關要求入手，對其二者進行區分，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或貯存期間含量會降低，生產時可適當增加投料量，以保證在有效期內含量能符合規定。"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損耗和物料損耗，詳述如下：

化學損耗: 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中過量使用原料藥，以補償藥品在生產或其有效期內的降解。但是有些藥物穩定性極差，目前的生產工藝水平不能完全抑制其降解且降解產物不會造成安全性風險，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、分包裝等多個環節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，常需要適當加溫以促進脂質原料的溶解，在半成品的不同容器間的轉移，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，內部是雙層，一層為含藥層，另一層為吸水后具有高滲的驅動層，由于此類制劑本身的固有缺陷以及API本身的理化性質特點，總要有極少部分在片劑有效的運轉途徑的最終點不能完全被泵出或者藥物存在反滲透現象而使少部分藥物儲留于片殼內，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%。大多數物理性損耗中，原輔料是等比例的，風險較小。總之，目前審評中可接受過量投料的唯一理由是參比中有相同的過量，并在生產處方中列明各組分過量的依據。

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償生產或者貨架期內的產品降解，對于過量加入，應提供依據并列明在生產處方中。

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.

應以臨床安全，有效為出發點，區分是生產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備（例如注射器）進行給藥，通常很難從小瓶中取出100％的內容物。

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

2017年CDE發布的《已上市化學仿制藥（注射劑）一致性評價技術要求》規定過量灌裝量要和原研一致。

FDA藥典相關規定，旨在“在沒有適當理由的情況下，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品的濫用”但并未提出一個嚴格的框架來對產品進行一刀切的監管。如果企業確實需要過量灌裝，企業應遵守美國藥典（USP）通用章節<1151>，該章節建議企業設計產品“以符合標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“可提取的內容測試數據”來證明偏差。此類數據應包括在產品申請批準中，并代表商業化過程。舉例：某無菌粉灌裝品種需達到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.

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

EMA關于過量灌裝

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溶損失導致的過量。

四、如何區分參比是過量灌裝還是過量投料

以某無菌粉灌裝為例，規格為500mg，原研說明書規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，可提取的內容性損失最大約為4.5%，符合2020版《中國藥典》0102注射劑中規定，因此該品種為過量灌裝；對于過量投料，本人未經歷過相關案例，根據ICHQ8相關要求，總體來說，不鼓勵加入過量原料藥以補償生產過程或產品存貯期中原料藥的降解，或用以延長保存期。

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

五、參考文獻

[1] 淺析藥物制備工藝中的“過量投料”現象—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.