• 2023-06-02

    實用!美國藥典711溶出度實驗更新了,快來看看您的實驗過程合規性吧!

    本通則與《歐洲藥典》和/或《日本藥典》的相應文本相一致。這些藥典承諾不對本統一章節進行任何單方面更改。 本通用章文本中屬于USP國家文本的部分,因此不是協調組織文本的一部分,用符號(◆ ◆)來說明這一事實。 本試驗旨在確定是否符合溶出度要求◆ 個別專論中所述◆ 用于口服給藥的劑型。在本通用章中,劑量單位定義為1片或1粒或指定的量。◆在本文所述的器械設計類型中,請使用單獨專論中指定的器械設計。如果標簽上注明某物品是腸溶的,而溶出或崩解試驗沒有明確說明它將用于緩釋物品,并且包含在各論中,則適用緩釋劑型的程序和解釋,除非在各論中另有規定。◆ 如果含有明膠的劑型由于存在交聯的證據而不符合相應驗收表中的標準(見釋義、速釋制劑、緩釋制劑或延釋制劑),則應按照下文所述,在介質中加入酶,重復溶出過程,并從相應驗收表的第一階段開始評估溶出結果。如果在第一階段的測試中沒有達到標準,并且觀察到交聯的證據,則沒有必要繼續測試到最后階段(最多24個單位)。 明膠在某些化合物存在和/或在某些儲存條件下,包括但不限于高濕度和高溫度,可能存在交聯。明膠膠囊外殼的外表面和/或內表面或劑型上可能會形成薄膜,以防止藥物在溶出度測試過程中釋放(更多信息請參閱《膠囊-溶出度檢測和相關質量屬性》〈1094〉)。 [注意:所有對〈1000〉以上章節的引用僅用于提供信息,并作為一種有用的資源使用。這些章節并不是強制性的,除非明確要求用于此用途。] 組件由以下部分組成:有蓋或無蓋的溶出杯,由玻璃或其他惰性透明材料1制成;電動機;轉軸;轉籃。溶出杯部分浸沒在合適大小的水浴中,或通過合適的裝置(例如加熱套)加熱。水浴或加熱裝置允許在試驗期間將容器內的溫度保持在37±0.5°,并且容許杯內液體保持恒定、平穩的運動。整個儀器包括放置的環境,除了平穩轉動的攪拌部件,不得有明顯的運動、攪拌或振動。儀器最好能允許在檢測過程中能夠觀察到檢品和攪拌部件。溶出杯為圓柱形,底部為半球形◆具有以下尺寸和容量:◆ 容量為1L,高度為160–210 mm,內徑為98–106 mm;對于2L的容量,高度為280–300 mm,內徑為98–106 mm;和◆ 對于4 L的容量,高度為280–300 mm,內徑為145–155 mm◆. 它的側面在頂部有凸緣。安裝好的蓋子可以用來延緩蒸發。轉軸與溶出杯的垂直軸線在任何點處都不相差超過2 mm,并且轉動平穩,不會出現可能影響結果的明顯擺動。使用調速裝置,可選擇軸轉速并將其保持在規定的轉速上◆ 在個別專論中給出◆ 的±4%范圍以內。 轉軸和轉籃部件由316型不銹鋼或其他惰性材料制成,規格如圖1所示。可以使用具有約0.0001英寸(2.5μm)厚的鍍金籃子。在每次測試開始時,將一劑藥品放置在干燥的籃子中。試驗期間,溶出杯底部和籃子底部之間的距離保持在25±2 mm。       除了使用由葉片和軸形成的槳葉作為攪拌元件外,使用裝置1的組件。軸的位置應確保其軸線在任何點與溶出杯垂直軸線的距離不超過2 mm,并且旋轉平穩,不會出現可能影響結果的明顯擺動。葉片的垂直中心線穿過軸的軸線,使得葉片的底部與軸的底部齊平。槳葉符合圖2所示的規格。試驗期間,葉片底部和溶出杯底部之間的距離保持在25±2 mm。金屬或適當惰性的剛性葉片和軸組成一個整體。可以使用合適的兩部分可拆卸設計,前提是組件在測試過程中保持牢固接合。槳葉和軸可以涂上合適的涂層,以使兩者都是惰性的。在葉片開始旋轉之前,允許一劑藥品下沉到容器底部。一小塊松散的非反應性材料,例如不超過幾圈的螺旋線,可以連接到本來會漂浮的一劑藥品上。另一種下沉裝置如圖2a所示。也可以使用其他經過驗證的沉降片裝置。 ◆沉降藍的另一種選擇是吊籃。藥品被放置在一個由不銹鋼絲網制成的四邊形籃子中,焊接在其上窄邊之一,并連接到不銹鋼連桿的末端(見圖2b)。蓋子放置在籃子的水平對角線上。桿組件通過可調節螺紋鋼桿連接到溶解容器的蓋子上,并通過兩個聚四氟乙烯螺母固定,距離容器中心約3.2厘米,或通過其他適當的方式固定。將吊籃底部的下角調整到槳葉頂部上方約1cm處(見圖2c)。連接桿的軸線沿著連接桿的垂直長度平行于槳軸的軸線,并且吊籃的最大面位于垂直于溶出杯圓柱體半徑的垂直平面內。     該組件包括一組圓柱形平底玻璃容器;一組玻璃往復缸;惰性配件(316型不銹鋼或其他合適的材料),以及由合適的非吸收性和非反應材料制成并設計成適合往復缸的頂部和底部的篩網;以及馬達和驅動組件,使缸體在容器內垂直往復運動;如果需要,將往復缸水平地分度到另一排容器上。將容器部分浸入任何方便尺寸的合適水浴中,以便在試驗期間將溫度保持在37±0.5°。儀器的任何部分,包括儀器放置的環境,都不能產生顯著的運動、攪動或振動,而這些運動、攪動和振動是由于光滑的垂直往復氣缸造成的。使用一種裝置,允許選擇往復率并將其保持在個別專著中規定的浸透率◆的±5%范圍內。最好使用能夠觀察試樣和往復式圓筒的設備。容器配備有蒸發帽,在試驗期間保持在原位。除非另有規定,否則部件應符合圖3所示的尺寸◆在個別專論中◆。 該組件包含一個用于溶出介質的儲液器和相應的泵;流通池和將溶出介質保持在37±0.5°的水浴。使用◆如個別專論所述◆中規定的尺寸。 泵推動溶出介質向上通過流通池。該泵的輸送范圍在240至960毫升/小時之間,標準流速為4、8和16毫升/分鐘。泵必須提供恒定的流量(額定流量的±5%以內);流量分布為正弦曲線,脈動為120±10脈沖/min。也可以使用無脈沖的泵。使用流通池的溶出試驗程序必須在速率和任何脈動方面進行表征。     由透明和惰性材料制成的流通池(見圖4和圖5)垂直安裝有過濾系統(在個別專論中有規定),防止未溶解的顆粒從池頂部逸出;標準流通池直徑分別為12毫米和22.6毫米;底部錐體通常填充有直徑約為1mm的小玻璃珠,其中一個約為5mm的玻璃珠位于頂部以保護液體進入管;片劑支架(見圖4和圖5)可用于特殊劑型的定位,例如泡騰片。將流通池浸入溫度保持在37±0.5°的水浴中。     該裝置使用一個夾緊機構和兩個O形環來組裝測試池。泵與溶出單元分開,以保護溶出單元免受來自泵的任何振動的影響。泵的水平位置不應高于溶出介質容器。管線連接應盡可能短。使用適當的惰性管道,如聚四氟乙烯,內徑約為1.6毫米,用具有化學惰性的法蘭盤連接。 確定設備是否適合進行溶出度測試必須包括是否符合上述儀器的尺寸和公差。此外,在使用過程中必須定期監測的關鍵測試參數包括溶出介質的體積和溫度、轉速(第1法和第2法)、浸沒頻率(第3法)和介質的流速(第4法)。 定期確定溶出試驗設備的性能。◆性能驗證試驗證明了單個設備的適用性。 將◆在個別專論中給出◆ 的溶出介質(±1%)放入指定儀器的容器中, 組裝儀器,將溶出介質平衡到37±0.5°,然后取下溫度計。在儀器中放置1個單位劑量的藥品,注意避免表面產生氣泡,并立即以◆在個別專論中規定◆的速率操作儀器. 在規定的時間間隔內,或在規定的每個時間,從溶出介質表面以下的旋轉籃或葉片頂部之間的中間區域取出樣品,且距離容器壁不小于1cm。 [注:如果規定了多次取樣時間,則將取出進行分析的等分試樣更換為37°下等體積的新鮮溶出介質,或者,如果可以證明不需要更換介質,則校正計算中的體積變化。在試驗期間,將容器蓋上,并在適當的時間驗證試驗混合物的溫度] 進行◆如個別專著中所述◆分析使用合適的測定方法。4使用額外的劑型單位重新進行試驗。 如果使用自動化設備進行采樣或對儀器進行其他修改,則有必要驗證修改后的儀器將產生與本通用章所述標準儀器相同的結果。 溶出介質:使用合適的溶出介質。使用◆ 在個別專論中◆指定的溶劑。指定的體積是指在20°到25°之間進行的測量。如果溶出介質是緩沖溶液,則調整溶液,使其pH值在◆在各論中給出◆ 規定pH值的0.05以內。[注意:溶解氣體會導致氣泡形成,這可能會改變測試結果。如果溶解氣體影響溶出結果,則應在測試前清除溶解氣體。5] 時間:在給出了單一的時間規定的情況下,如果滿足最低溶解量的要求,則可以在更短的時間內完成測試。只能在規定的時間內,在±2%的時間誤差范圍內取出試樣。 ◆速釋劑型的合并樣品的程序:如果各論中規定了合并樣品的步驟,則使用該程序。按照程序部分第1法和第2法中的速釋制劑的指示進行操作。將取出的6個或12個單獨樣本的等體積過濾溶液合并,并將合并的樣本用作試樣。測定合并樣品中的活性成分的平均溶出量。◆ 按照速釋制劑的方法進行操作。 溶出介質:按照速釋制劑的方法進行制備。 時間:測試時間點,通常為三個,以小時為單位。     使用方法A程序或方法B程序以及◆個別專論中◆規定的儀器。除另有規定外所有試驗時間與規定時間相差不超過±2%。 在儀器的每個容器中放入規定體積的溶出介質,組裝儀器,將溶出介質平衡至37±0.5°,然后取下溫度計。在六個往復圓筒中的每個圓筒中放置一劑量藥品,注意將氣泡從每個藥品的表面排除,并立即按照◆在個別專論中◆ 的規定操作設備。在向上和向下的沖程中,往復式圓筒移動了9.9–10.1cm的總距離。在規定的時間間隔內,或在規定的每個時間,升起往復式圓筒,并從溶出介質液面至每個容器底部的中間區域提取一部分待測溶液。按照◆ 在個別專論中◆的規定進行分析。如有必要,使用更多的劑型單位重復測試。  溶出介質:按照第1法和第2法中速釋制劑的說明進行制備。 時間:按照第1法和第2法中速釋制劑的說明進行。 緩釋劑型 按照第3法中速釋制劑的說明進行操作。 溶出介質:按照第1法和第2法中緩釋劑型的說明進行制備。 時間:按照第1法和第2法中緩釋劑型的說明進行。 遲釋制劑 按照第1法和第2法中遲釋制劑方法B程序的說明進行操作,使用一排容器用于酸性階段介質,下一排容器用作緩沖液階段,并使用規定體積的介質(通常為300 mL)。 時間:按照第1法和第2法中速釋制劑的說明進行。 速釋制劑 根據◆在專著中◆的規定將玻璃珠放入流通池。將1單位劑量藥品放在珠子上,或者,如果◆ 在專著中◆另有規定, 也可置于載具上。組裝過濾頭,并使用合適的夾緊裝置將零件固定在一起。用泵將加熱至37±0.5°的溶出介質引入流通池,以獲得◆ 在個別專論中◆ 規定的流速并且流速精度為5%。在每個規定的時間收集浸出液。按照◆ 在個別專論中◆規定進行分析。使用額外的劑型單位重復測試。 溶出介質:按照第1法和第2法中的速釋制劑的說明進行制備。 時間:按照第1法和第2法中的速釋制劑的說明進行。 緩釋劑型 按照第4法中速釋制劑型的說明進行操作。 溶出介質:按照第4法中速釋制劑的說明進行制備。 時間:按照第4法中速釋制劑的說明進行操作。 遲釋制劑 按照第1法和第2法中遲釋制劑的說明,使用指定的介質進行操作。 時間:按照第1法和第2法中遲釋制劑的說明進行操作。 參考原文附件:uspnf711dissolutionpf482.pdf

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    2023-05-06

    收藏!法規 | 非無菌半固體劑型放大和批準后變更工業指南

    GUIDANCE FOR INDUSTRY Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence d0cumentation SUPAC-SS非無菌半固體劑型放大和批準后變更工業指南:化學、制造和控制;體外釋放測試和體內生物等效性文件SUPAC-SS This guidance provides recommendations to pharmaceutical sponsors of new drug applications (NDAs), abbreviated new drug applications (ANDAs), and abbreviated antibiotic drug applications (AADAs) who intend to change (1) the components or composition, (2) the manufacturing (process and equipment), (3) the scale-up/scale-down of manufacture, and/or (4) the site of manufacture of a semisolid formulation during the postapproval period. This guidance addresses nonsterile semisolid preparations (e.g., creams, gels, lotions, and ointments) intended for topical routes of administration. The guidance defines (1) the levels of change; (2) recommended chemistry, manufacturing, and controls (CMC) tests to support each level of change; (3) recommended in vitro release tests and/or in vivo bioequivalence tests to support each level of change; and (4) d0cumentation to support the change.本指南為新藥申請(NDA)、仿制藥申請(ANDA)和仿制抗生素藥物申請(AADA)的制藥發起人提供了建議,他們打算改變(1)成分或組成,(2)制造(工藝和設備),(3)制造批量的放大/縮小,和/或(4)批準后期間半固體制劑的生產地點。本指南涉及用于局部給藥途徑的非無菌半固體制劑(如乳膏、凝膠、乳液和軟膏)。該指南定義了(1)變化的程度;(2) 推薦的化學、制造和控制(CMC)測試,以支持每個級別的變更;(3) 推薦的體外釋放試驗和/或體內生物等效性試驗,以支持每一水平的變更;以及(4)支持變更所需提交的文件要求。 The guidance specifies the application information that should be provided to the Center for Drug eva1uation and Research (CDER) to ensure continuing product quality and performance chacteristics of the semisolid topical formulation for specified changes. The guidance does not comment on or otherwise affect compliance/inspection d0cumentation defined by the Office of Compliance in CDER or the Office of Regulatory Affairs at FDA.該指南規定了應向藥物評估與研究中心(CDER)提供的申報信息,以確保在特定變化下,半固體局部制劑能維持其產品質量和性能特征。該指南不對CDER合規辦公室或美國食品藥品監督管理局監管事務辦公室定義的合規/檢查文件發表評論或產生其他影響。 The guidance provides recommendations on application d0cumentation for the following multiple changes, provided appropriate test and filing d0cuments are submitted (1) multiple level 1 changes with level 1 test and filing d0cumentation; (2) multiple level 1 changes; one level 2 change with level 2 test and filing d0cumentation; (3) multiple level 2 changes with level 2 test d0cumentation and a prior approval supplement (PAS) and (4) level 3 manufacturing site change and any other level 1 change with level 3 manufacturing site change test and filing d0cumentation. The d0cumentation to support the changes varies depending on the type and the complexity of the semisolid dosage form. For those changes filed in a Changes Being Effected (CBE) Supplement (21 CFR 314.70(c)), the FDA may review the supplemental information and decide that the changes are not approvable. Sponsors should contact the appropriate CDER review division and staff for information about tests and application d0cumentation for changes not addressed in this guidance, or for successive level 2 or 3 changes submitted over a short period.該指南為以下多項變更的申請文件提供了建議,前提是提交了適當的測試和備案文件(1)具有1級測試和備案文檔的多項1級變更;(2) 多個1級變化;一個2級變更,帶有2級測試和歸檔文件;(3) 具有2級測試文件和prior approval supplement (PAS)的多個2級變更,以及(4)具有3級生產現場變更和具有3級制造現場變更測試和歸檔文件的任何其他1級變更。支持變更的文件因半固體劑型的類型和復雜性而異。對于在《Changes Being Effected(CBE)補編》(21 CFR 314.70(c))中提交的變更,美國食品藥品監督管理局可能會審查補充信息,并決定這些變更不可批準。發起人應聯系相應的CDER審查部門和工作人員,以獲取有關本指南中未提及的變更或短期內連續提交的2級或3級變更的測試和申請文件的信息。 The regulations provide that applicants may make changes to an approved application in accordance with a guidance, notice, or regulation published in the Federal Register that provides for a less burdensome notification of the change (e.g., by notification at the time a supplement is submitted or in the next annual report) (21 CFR 314.70(a)). This guidance permits less burdensome notice of certain postapproval changes within the meaning of § 314.70(a).條例規定,申請人可以根據指南、通知、或在《Federal Register》上發布的法規,該法規規定了較輕的變更通知(例如,在提交補充文件時或在下一份年度報告中發出通知)(《美國聯邦法規匯編》第21卷第314.70(a)節)。本指南允許對§314.70第(a)條所指的某些批準后變更進行較輕的通知。 In general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active ingredient is often dissolved in one phase, although occasionally the drug is not fully soluble in the system and is dispersed in one or both phases, thus creating a three-phase system. The physical properties of the dosage form depend upon various factors, including the size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology. These factors combine to determine the release characteristics of the drug, as well as other characteristics, such as viscosity. 一般來說,半固體劑型是具有復雜結構元素的復雜制劑。它們通常由兩相(油和水)組成,其中一個是連續(外部)相,另一個是分散(內部)相。活性成分通常溶解在一個相中,盡管有時藥物不能完全溶解在系統中,而是分散在一個或兩個相中,從而形成三相系統。劑型的物理特性取決于各種因素,包括分散顆粒的大小、相之間的界面張力、活性成分在相之間的分配系數以及產品流變性。這些因素結合起來決定了藥物的釋放特性,以及其他特性,例如粘度。 A.Critical Manufacturing Parameters關鍵制造參數 For a true solution, the order in which solutes are added to the solvent is usually unimportant. The same cannot be said for dispersed formulations, however, because dispersed matter can distribute differently depending on to which phase a particulate substance is added. In a typical manufacturing process, the critical points are generally the initial separation of a one-phase system into two phases and the point at which the active ingredient is added. Because the solubility of each added ingredient is important for determining whether a mixture is visually a single homogeneous phase, such data, possibly supported by optical microscopy, should usually be available for review. This is particularly important for solutes added to the formulation at a concentration near or exceeding that of their solubility at any temperature to which the product may be exposed. 對于真正的溶液,溶質加入溶劑的順序通常并不重要。然而,對于分散的制劑來說,情況并非如此,因為分散的物質可以根據顆粒物質添加到哪一相而分布不同。在典型的制造過程中,臨界點通常是將一個相系統初始分離為兩相,以及添加活性成分的點。由于每種添加成分的溶解度對于確定混合物在視覺上是否是單一的均相很重要,因此通常應該獲得這些數據,這些數據可能可以從光學顯微鏡獲取以供審查。這對于以接近或超過其在產品可能暴露的任何溫度下的溶解度的濃度,并被添加到制劑中的溶質來說尤其重要。 Variations in the manufacturing procedure that occur after either of these events are likely to be critical to the characteristics of the finished product. This is especially true of any process intended to increase the degree of dispersion through reducing droplet or particle size (e.g., homogenization). Aging of the finished bulk formulation prior to packaging is critical and should be specifically addressed in process validation studies. 在這些事件中的任何一個發生之后,制造程序的變化可能對成品的特性影響至關重要。這對于任何旨在通過減小液滴或顆粒尺寸(例如均化)來增加分散度的工藝來說尤其如此。在確定包裝方案前完成的主體配方的老化研究至關重要,應在工藝驗證研究中著重解決。 B.General Stability Considerations穩定性研究 The effect that SUPAC changes may have on the stability of the drug product should be eva1uated. For general guidance on conducting stability studies, see the FDA Guideline for Submitting d0cumentation for the Stability of Human Drugs and Biologics. For SUPAC submissions, the following points should also be considered: 應評估SUPAC變化可能對藥品穩定性產生的影響。有關進行穩定性研究的一般指導,請參閱美國食品藥品監督管理局提交人類藥物和生物制品穩定性文件的指南。對于SUPAC提交的文件,還應考慮以下幾點: 1.In most cases, except those involving scale-up, stability data from pilot scale batches will be acceptable to support the proposed change.  在大多數情況下,除了涉及放大的情況外,中試批次的穩定性數據將是可接受的,以支持擬討論的變更。 2.Where stability data show a trend towards potency loss or degradant increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative prechange batch be submitted for comparison. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. 如果穩定性數據顯示在加速條件下有效力損失或降解物增加的趨勢,建議提交代表性的變化發生前的批次的歷史加速穩定性數據進行比較。還建議在這些情況下,在補充資料中提供正在進行的研究中的所有可用的測試批次的長期數據。提交歷史加速和可用的長期數據將有助于審查和批準補充資料 3.A commitment should be included to conduct long-term stability studies through the expiration dating period, according to the approved protocol, on either the first or first three (see section III-VI for details) production batches, and to report the results in subsequent annual reports.應承諾根據批準的方案,在第一批或前三批(詳見第III-VI節)生產批次的有效期內進行長期穩定性研究,并在隨后的年度報告中報告結果。 C.The Role of In Vitro Release TestingIVRT測試的作用 The key parameter for any drug product is its efficacy as demonstrated in controlled clinical trials. The time and expense associated with such trials make them unsuitable as routine quality control methods. Therefore, in vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change. A variety of physical and chemical tests commonly performed on semisolid products and their components (e.g., solubility, particle size and crystalline form of the active component, viscosity, and homogeneity of the product) have historically provided reasonable evidence of consistent performance. More recently, in vitro release testing has shown promise as a means to comprehensively assure consistent delivery of the active component(s) from semisolid products.任何藥品的關鍵參數都是其療效,正如對照臨床試驗所證明的那樣。與此類試驗相關的時間和費用使其不適合作為常規質量控制方法。因此,通常使用體外替代測試來確保產品質量和性能在一段時間內保持不變。在歷史角度看,通常對半固體產品及其組分進行的各種物理和化學測試(如活性組分的溶解度、粒度和結晶形式、產品的粘度和均勻性)提供了一致性能的合理證據。最近,體外釋放測試(IVRT)已顯示出作為一種全面確保半固體產品中活性成分遞送一致性手段的前景。 An in vitro release rate can reflect the combined effect of several physical and chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. In most cases, in vitro release rate is a useful test to assess product sameness between prechange and postchange products. However, there may be instances where it is not suitable for this purpose. In such cases, other physical and chemical tests to be used as measures of sameness should be proposed and discussed with the Agency. With any test, the metrics and statistical approaches to d0cumentation of “sameness” in quality attributes should be considered.體外釋放率可以反映幾個物理和化學參數的綜合影響,包括活性成分的溶解度和粒徑以及劑型的流變學特性。在大多數情況下,體外釋放率是評估變更前和變更后產品之間產品相同性的有用測試。然而,在某些情況下,它可能不適合用于此目的。在這種情況下,申請人應提出并與機構討論其他用作確保相同性措施的物理和化學測試。對于任何測試,都應該考慮質量屬性中“相同性”的度量和統計方法。 The evidence available at this time for the in vitro-in vivo correlation of release tests for semisolid dosage forms is not as convincing as that for in vitro dissolution as a surrogate for in vivo bioavailability of solid oral dosage forms. Therefore, the Center’s current position concerning in vitro release testing is as follows:目前,半固體劑型的體外-體內釋放試驗相關性的證據不如體外溶出作為固體口服劑型體內生物利用度的替代品的證據令人信服。因此,中心目前關于體外釋放試驗的立場如下: 1.In vitro release testing is a useful test to assess product “sameness” under certain scale-up and postapproval changes for semisolid products.體外釋放測試是一種有用的測試,用于評估半固體產品在某些放大和批準后變化下的產品“相同性” 2.The development and validation of an in vitro release test are not required for approval of an NDA, ANDA or AADA nor is the in vitro release test required as a routine batch-to-batch quality control test.批準NDA、ANDA或AADA不需要體外釋放試驗的開發和驗證,也不需要將體外釋放試驗作為常規的逐批質量控制試驗。 3.In vitro release testing, alone, is not a surrogate test for in vivo bioavailability or bioequivalence.單獨的體外釋放試驗不是體內生物利用度或生物等效性的替代試驗 4.The in vitro release rate should not be used for comparing different formulations across manufacturers.體外釋放率不應用于比較不同制造商的不同配方。 This section of the guidance focuses on changes in excipients in the drug product. Qualitative changes in excipients should include only those excipients which are present in approved drug products for the specific route of administration. Quantitative changes in excipients should not exceed the amount previously approved in products with the same specific route of administration. The chronology of changes in components and composition should be provided. 2 Changes in components or composition that have the effect of adding a new excipient or deleting an existing excipient are defined as level 3 changes (see section III.C below), except as described below. These changes generally result in the need to change the labeling. 本節指南的重點是藥品中輔料的變化。輔料的定性變化應僅包括特定給藥途徑的批準藥品中存在的輔料。輔料的定量變化不應超過具有相同特定給藥途徑的產品中先前批準的量。應提供成分和組成變化的時間順序。2具有添加新輔料或刪除現有輔料效果的成分或組成的變化被定義為3級變化(見下文第III.C節),以下所述情況除外。這些變化通常導致需要更改標簽。 Compositional changes in preservatives are considered separately and are not included as part of the total additive effect under sections III.A, B and C.防腐劑的成分變化是單獨考慮的,不包括在第III.A、B和C節的總添加效應中。 A.Level 1 Change一級變更 1.Definition of Level定義 Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance1級變化是指不太可能對配方質量和性能產生任何可檢測影響的變化 Examples例如: Deletion or partial deletion of an ingredient intended to affect the color, fragrance, or flavor of the drug product.刪除或部分刪除旨在影響藥品顏色、香味或風味的成分 Any change in an excipient up to 5% of approved amount of that excipient. The total additive effect of all excipient changes should not be more than 5%. Changes in the composition should be based on the approved target composition and not on previous level 1 changes in the composition. A change in diluent (q.s. excipient) due to component and composition changes in excipient may be made and is excluded from the 5% change limit輔料的任何變化,最高可達該輔料批準量的5%。所有輔料變化的總添加效應不應超過5%。成分的變化應基于已批準的目標成分,而不是之前的1級成分變化。由于輔料的成分和組成變化,可能會導致稀釋劑發生變化,且不包括在5%的變化范圍內 Change in a supplier of a structure forming excipient that is primarily a single chemical entity (purity$95%) or change in a supplier or technical grade of any other excipient.主要為單一化學實體的結構形成輔料供應商的變更(純度為95%),或任何其他輔料的供應商或技術等級的變更 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Application/compendial product release requirements and stability testing.符合申報資料/藥典標準的放行要求和穩定性測試 Stability testing: First production batch on long-term stability reported in annual report.穩定性測試:年度報告中報告的第一批生產批的長期穩定性。 b.In Vitro Release d0cumentation體外釋放文件 None.不需要 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation灌裝文件 Annual report (all information including long-term stability data).年度報告(包括長期穩定性數據在內的所有信息)。 B.Level 2 Change二級變更 1.Definition of Level定義 Level 2 changes are those that could have a significant impact on formulation quality and performance.2級變化是指潛在可能對配方質量和性能產生重大影響的變化。 Examples:例如 Changes of >5% and≤10% of approved amount of an individual excipient. The total additive effect of all excipient changes should not be more than 10%. Changes in the composition should be based on the approved target composition and not on previous level 1 or level 2 changes in the composition. Changes in diluent (q.s. excipient) due to component and composition changes in excipients are acceptable and are excluded from the 10% change limit.單個輔料批準量的變化>5%和≤10%。所有輔料變化的總添加效應不應超過10%。成分的變化應基于已批準的目標成分,而不是之前的1級或2級成分變化。由于輔料的成分和組成變化而引起的稀釋劑的變化是可以接受的,并且不在10%的變化限制范圍內。 Change in supplier of a structure forming excipient not covered under level 1.1級未涵蓋的結構形成賦形劑的供應商變更。 Change in the technical grade of structure forming excipient.結構形成賦形劑技術等級的變化。 Change in particle size distribution of the drug substance, if the drug is in suspension.如果藥物處于混懸狀態,則原料藥粒度分布的變化。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Application/compendial product release requirements and executed batch records.符合申報資料/藥典標準的放行要求和執行的批次記錄。 Stability testing: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.穩定性測試:在CBE補充中報告一批三個月的加速穩定性數據,在年度報告中報告的第一批生產的長期穩定性數據。 b.In Vitro Release d0cumentation體外釋放文件 The in vitro release rate of a lot of the new/modified formulation should be compared with that of a recent lot of comparable age of the pre-change formulation of the product. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the two formulations should be demonstrated to be within acceptable limits using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.一批新的/改良的制劑的體外釋放率應與最近一批變化前產品的制劑的可比效期的產品的體外釋放速率進行比較。應使用以下第VII節(體外釋放試驗)中所述的試驗程序,證明兩種制劑的中位體外釋放率(通過每個擴散池的的斜率評估,見第VII節)在可接受的限度內。 c.In Vivo Bioequivalence d0cumentation體內生物等效性文件 None.不需要 3.Filing d0cumentation灌裝文件 Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE補充資料(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 C.Level 3 Change三級變更 1.Definition of Level定義 Level 3 changes are those that are likely to have a significant impact on formulation quality and performance.3級變化是指極可能對配方質量和性能產生重大影響的變化。 Examples:例如 Any qualitative and quantitative changes in an excipient beyond the ranges noted in level 2 change.輔料的任何定性和定量變化超出2級變化中注明的范圍。 Change in crystalline form of the drug substance, if the drug is in suspension.如果藥物處于混懸狀態,則藥物結晶形式的變化。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Application/compendial product release requirements and executed batch records.符合申報資料/藥典標準的放行要求和執行的批次記錄。 Significant body of information available: One batch with three months accelerated stability data reported in prior approval supplement and long-term stability data of first three production batches reported in annual report可獲取Significant body of information(見名詞解釋,下同):prior approval supplemen中報告的一個批次的三個月加速穩定性數據和年度報告中報告的前三個生產批次的長期穩定性數據 Significant body of information not available: Three batches with three months accelerated stability data reported in prior approval supplement and long-term stability data of first three production batches reported in annual report.不可獲取Significant body of information:prior approval supplement中報告三個批次的三個月加速穩定性數據和年度報告中報告的前三個生產批次的長期穩定性數據。 b.In Vitro Release d0cumentation體外釋放數據 The in vitro release rate of the new/modified formulation should be established as a point of reference. Under this level 3 change, in vitro release d0cumentation is not required, but sponsors are encouraged to develop this information for use in subsequent changes under this guidance. 新配方/改良配方的體外釋放率應作為參考點。根據這一3級變更,不需要體外釋放文件,但鼓勵申請人開發這些信息,以便在本指南下的后續變更中使用。 c.In Vivo Bioequivalence d0cumentation體內生物等效性文件 Full bioequivalence study on the highest strength, with in vitro release/other approach on the lower strength(s).最高劑量的完全生物等效性研究,較低劑量的體外釋放/其他方法。 3.Filing d0cumentation灌裝文件 Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).Prior Approval Supplement (PAS)(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 D.Preservative防腐劑 For semisolid products, any change in the preservative may affect the quality of the product. If any quantitative or qualitative changes are made in the formulation, additional testing should be performed. No in vitro release d0cumentation or in vivo bioequivalence d0cumentation is needed for preservative changes.對于半固體產品,防腐劑的任何變化都可能影響產品的質量。如果配方發生任何定量或定性變化,則應進行額外的測試。防腐劑變更不需要體外釋放文件或體內生物等效性文件。 1.Level 1 Change一級變更 a.Definition of Level定義 Quantitatively 10% or less change in the approved amount of preservative. 防腐劑批準量的定量變化為10%或更少。 b.Test d0cumentation測試文件 Application/compendial product release requirements.符合申報資料/藥典標準的放行要求 Preservative Effectiveness Test carried out at lowest specified preservative level.在最低規定防腐劑水平下進行的防腐劑有效性測試。 c.Filing d0cumentation灌裝文件 Annual report年度報告 2.Level 2 Change二級變更 a.Definition of Level定義 Quantitatively greater than 10% and up to 20% change in the approved amount of preservative.防腐劑批準量的定量變化大于10%,最高可達20%。 b.Test d0cumentation測試文件 Application/compendial product release requirements符合申報資料/藥典標準的放行要求 Preservative Effectiveness Test at lowest specified preservative level.最低規定防腐劑水平下的防腐劑有效性測試。 c.Filing d0cumentation灌裝文件 Changes being effected supplement.CBE補充。 3.Level 3 change三級變更 a.Definition of Level定義 Quantitatively greater than 20% change in the approved amount of preservative (including deletion) or use of a different preservative.防腐劑批準量(包括刪除)或使用不同防腐劑的定量變化超過20%。 b.Test d0cumentation Application/compendial product release requirements.符合申報資料/藥典標準的放行要求。 Preservative Effectiveness Test at lowest specified preservative level.最低規定防腐劑水平下的防腐劑有效性測試。 Analytical method for identification and assay for new preservative.新防腐劑的鑒別和分析方法。 Validation studies to show that the new preservative does not interfere with application/compendial test.驗證研究表明,新防腐劑不會干擾申報資料/藥典標準測試。 Executed batch records執行的批次記錄 Stability testing: One batch with three months accelerated stability data reported in prior approval supplement and long-term stability data of first production batch reported in annual report.穩定性測試:prior approval supplement中報告的一批三個月加速穩定性數據和年度報告中報告的第一批生產的長期穩定性數據。 c.Filing d0cumentation灌裝文件 Prior approval supplement (all information including accelerated stability data); annual report (long-term stability data).Prior approval supplement(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 Manufacturing changes may affect both equipment used in the manufacturing process and the process itself.制造變更可能會影響制造過程中使用的設備和過程本身。 A.Equipment設備 1.Level 1 Change一級變更 a.Definition of Level定義 Change from nonautomated or nonmechanical equipment to automated or mechanical equipment to transfer ingredients. Change to alternative equipment of the same design and operating principles.將非自動化或非機械設備改為自動化或機械設備以轉移配料。更改為具有相同設計和操作原理的替代設備。 b.Test d0cumentation測試文件 i.Chemistry d0cumentation化學文件 Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申報資料/藥典標準的放行要求。變更通知和更新的已執行批次記錄的提交。 Stability testing: First production batch on long-term stability reported in annual report.穩定性測試:年度報告中報告的第一批長期穩定性生產。 ii.In Vitro Release d0cumentation體外釋放文件 None.不需要 iii.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 c.Filing d0cumentation Annual report (all information including long-term stability data).年度報告(包括長期穩定性數據在內的所有信息)。 2.Level 2 Change二級變更 a.Definition of Level定義 Change in equipment to a different design or different operating principles. Change in type of mixing equipment, such as high shear to low shear and vice versa.將設備變更為不同的設計或不同的操作原理。混合設備類型變化,如高剪切到低剪切,反之亦然。 b.Test d0cumentation測試文件 i.Chemistry d0cumentation化學文件 Application/compendial product release requirements. Notification of change and submission of updated executed batch records符合申報資料/藥典標準的放行要求。變更通知和提交更新的已執行批次記錄 Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.可獲得Significant body of information:在CBE報告補充一批三個月的加速穩定性數據,在年度報告中報告第一批生產批的長期穩定性數據。 Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可獲得Significant body of information:年度報告中報告三個月加速穩定性數據的三個批次的CBE補充和前三個生產批次的長期穩定性數據。 ii.In Vitro Release d0cumentation體外釋放文件 The in vitro release rate of a lot of the dosage form prepared in new equipment should be compared with the release rate of a recent lot of comparable age of the product prepared using original equipment. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the two formulations should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.在新設備中制備的批次的體外釋放率應與使用原始設備制備的最近一批可比效期的產品的釋放率進行比較。應使用以下第VII節(體外釋放試驗)中所述的試驗程序,證明兩種制劑的中位體外釋放率(通過每個擴散池的斜率估計,見第VII節)在可接受的限度內。 iii.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 c.Filing d0cumentation灌裝文件 Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data). CBE補充(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 3.Level 3 Change No level 3 changes are anticipated in this category.預計這一類別不會發生3級變化。 B.Process工藝 1.Level 1 Change一級變更 a.Definition of Level定義 Process changes, including changes such as rate of mixing, mixing times, operating speeds, and holding times within approved application ranges. Also, order of addition of components (excluding actives) to either oil or water phase.工藝變化,包括在批準的應用范圍內的混合速率、混合時間、操作速度和保持時間等變化。此外,也包括油相或水相中成分(不包括活性物質)的添加順序。 b.Test d0cumentation測試文件 i.Chemistry d0cumentation化學文件 None beyond application/compendial product release requirements.沒有超出符合申報資料/藥典標準的放行要求。 ii.In Vitro Release d0cumentation體外釋放文件 None.不需要 iii.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 c.Filing d0cumentation灌裝文件 Annual report年度報告 2.Level 2 Change二級變更 a.Definition of Level定義 Process changes, including changes such as rate of mixing, mixing times, rate of cooling, operating speeds, and holding times outside approved application ranges for all dosage forms. Also, any changes in the process of combining the phases.工藝變化,包括混合速率、混合時間、冷卻速率、操作速度和保持時間等超出所有劑型批準應用范圍的變化。此外,合并階段過程中的任何變化。 b.Test d0cumentation測試文件 i.Chemistry d0cumentation化學文件 Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申報資料/藥典標準的放行要求。變更通知和提交更新的已執行批次記錄。 Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report.可獲得Significant body of information:在CBE補充中報告一批三個月的加速穩定性數據,在年度報告中報告第一批生產批的長期穩定性數據。 Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可獲得Significant body of information:年度報告中報告了三個月加速穩定性數據的三個批次的CBE補充和前三個生產批次的長期穩定性數據。 ii.In Vitro Release d0cumentation體外釋放文件 The in vitro release rate of a lot of the dosage form prepared by the new/modified process should be compared with the in vitro release rate of a recent lot of comparable age of the dosage form prepared by the prechange process. The median in vitro release rates (as estimated by the estimated slope from each cell, see VII) of the lots prepared by the two processes should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.通過新的/改良的工藝制備的批次劑型的體外釋放率應與變更前工藝制備的最近生產的可比效期的批次的體外釋放速率進行比較。應使用以下第VII節(體外釋放試驗)中所述的試驗程序,證明通過兩種工藝制備的批次的體外釋放率中位數(通過每個擴散池的斜率估計,見VII)在可接受的限度內。 iii.In Vivo Bioequivalence d0cumentation體內生物等效性文件 None.不需要 c.Filing d0cumentation灌裝文件 Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE補充(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 3.Level 3 Change三級變更 No level 3 changes are anticipated in this category.預計這一類別不會發生3級變化。 This guidance recommends that the minimum batch size for the NDA pivotal clinical trial batch or the ANDA/AADA biobatch be at least 100 kg or 10% of a production batch, whichever is larger. Deviations from this recommendation should be discussed with the appropriate agency review division. All scale changes should be properly validated and may be inspected by appropriate agency personnel.本指南建議NDA關鍵臨床試驗批次或ANDA/AADA生物批次的最小批量至少為100 kg或生產批次的10%,以較大者為準。與本建議的偏差應與相應的機構審查部門進行討論。所有規模變化都應經過適當驗證,并可由適當的機構人員進行檢查。 A.Level 1 Change一級變更 1.Definition of Level定義 Change in batch size, up to and including a factor of ten times the size of the pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es) are of the same design and operating principles; (2) the batch(es) is manufactured in full compliance with cGMPs; and (3) the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es).批次大小的變化,最大為關鍵臨床試驗/生物批次大小的十倍,其中:(1)用于生產試驗批次的設備具有相同的設計和操作原理;(2) 該批次的生產完全符合cGMP;以及(3)在試驗批次和全量生產批次上使用相同的標準操作程序和控制,以及相同的配方和制造程序。 2.Test d0cumentation a.Chemistry d0cumentation化學文件 Application/compendial product release requirements. Notification of change and submission of updated executed batch records in annual report. Stability testing: First production batch on long-term stability reported in annual report.符合申報資料/藥典標準的放行要求。變更通知和年度報告中提交更新的已執行批次記錄。穩定性測試:年度報告中報告的第一批長期穩定性生產。 b.In Vitro Release d0cumentation體外釋放文件 None.不需要 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation灌裝文件 Annual report (all information including long-term stability data)年度報告(包括長期穩定性數據在內的所有信息) B.Level 2 Change二級變更 1.Definition of Level定義 Changes in batch size from beyond a factor of ten times the size of the pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es) are of the same design and operating principles; (2) the batch(es) is manufactured in full compliance with cGMPs; and (3) the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es).批次大小的變化超過關鍵臨床試驗/生物批次大小的十倍,其中:(1)用于生產試驗批次的設備具有相同的設計和操作原理;(2) 該批次的生產完全符合cGMP;以及(3)在試驗批次和全量生產批次上使用相同的標準操作程序和控制,以及相同的配方和制造程序。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Application/compendial product release requirements. Notification of change and submission of updated executed batch records.符合申報資料/藥典標準的放行要求。變更通知和提交更新的已執行批次的記錄。 Stability testing: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first production batch reported in annual report穩定性測試:在CBE補充中報告一批三個月的加速穩定性數據,在年度報告中報告第一批生產的長期穩定性數據 b.In Vitro Release d0cumentation體外釋放文件 The in vitro release rate of a lot of the scaled-up batch should be compared with the in vitro release rate of a recent lot, of comparable age, of the prechange scale. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the lots of the two scales should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.應將一批放大批次的體外釋放率與最近一批具有可比效期的變化前的產品的體外釋放速率進行比較。應使用以下第VII節(體外釋放試驗)中所述的試驗程序,證明兩種量表批次的體外釋放率中位數(通過每個擴散池的斜率評估,見第VII節)在可接受的范圍內。 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data)CBE補充(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據) C.Level 3 Change三級變更 No level 3 changes are anticipated in this category.預計這一類別不會發生3級變化。 I.MANUFACTURING SITE制造場所 Manufacturing site changes consist of changes in location in the site of manufacture, packaging/filling operations, and/or testing for both company owned and contract manufacturing facilities and do not include any other level 2 or 3 changes, e.g., changes in scale, manufacturing (including process and/or equipment), and components or composition. New manufacturing locations should have had a satisfactory cGMP inspection within the past two years.制造現場變更包括公司自身和協議制造商的制造現場位置、包裝/灌裝操作和/或測試的變更,不包括任何其他2級或3級變更,例如規模、制造(包括工藝和/或設備)以及組件或組成的變更。新的生產地點應該在過去兩年內通過了令人滿意的cGMP檢查。 A stand-alone analytical testing laboratory site change may be submitted as a changes being effected supplement if the new facility has a current and satisfactory cGMP compliance profile with FDA for the type of testing operation in question. The supplement should contain a commitment to use the same test methods employed in the approved application, written certification from the testing laboratory stating that they are in conformance with cGMPs, and a full descr1ption of the testing to be performed by the testing lab. If the facility has not received a satisfactory cGMP inspection for the type of testing involved, a prior approval supplement is recommended. No stability data are needed for a change in a stand alone analytical facility.如果新檢測實驗相關檢測操作具有令人滿意的cGMP合規性,達到FDA要求,則可提交獨立分析檢測實驗室場地變更,作為CBE補充。補充文件應包含使用批準申請中使用的相同測試方法的承諾、測試實驗室的書面證明,說明這些方法符合cGMP,以及測試實驗室將進行的測試的完整描述。如果實驗室未收到令人滿意的cGMP檢查,建議進行prior approval supplement。獨立分析設施的變化不需要穩定性數據。 A.Level 1 Change一級變更 1.Definition of Level定義 Level 1 changes consist of site changes within a single facility where the same equipment, standard operating procedures (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility. Common is defined as employees already working on the campus who have suitable experience with the manufacturing process.一級變更包括單個設施內的現場變更,其中使用了相同的設備、標準操作程序(SOP)、環境條件(如溫度和濕度)和控制裝置,以及兩個制造現場共用的人員,并且除了管理信息和設施位置外,不對制造批次記錄進行任何變更。通常被定義為已經在工廠工作的員工,他們在制造過程中有適當的經驗。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 None beyond application/compendial product release requirements.沒有超出符合申報資料/藥典標準的放行要求。 b.In Vitro Release d0cumentation體外釋放文件 None.不需要 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation灌裝文件 Annual report.年度報告 B.Level 2 Change二級變更 1.Definition of Level定義 Level 2 changes consist of site changes within a contiguous campus, or between facilities in adjacent city blocks, where similar equipment, standard operating procedures, (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used, and where no changes are made to the manufacturing batch records, except for administrative information and the location of the facility. 2級變更包括相鄰園區內或相鄰城市街區設施之間的現場變更,使用類似的設備、標準操作程序(SOP)、環境條件(如溫度和濕度)和控制措施,以及兩個制造現場共用的人員,并且不更改制造批記錄,除了管理信息和設施的位置。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Location of new site and updated executed batch records. None beyond application/compendial product release requirements.新設施的位置和更新的已執行批次記錄。沒有超出符合申報資料/藥典標準的放行要求。 Stability testing: First production batch on long-term stability reported in annual report.穩定性測試:年度報告中報告的第一批長期穩定性生產。 b.In Vitro Release d0cumentation體外釋放文件 None.不需要 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation灌裝文件 Changes being effected supplement; annual report (long-term stability data).CBE補充;年度報告(長期穩定性數據)。 C.Level 3 Change三級變更 1.Definition of Level定義 Level 3 changes consist of a site change in manufacturing site to a different campus. A different campus is defined as one that is not on the same original contiguous site or where the facilities are not in adjacent city blocks. To qualify as a Level 3 change, similar equipment, SOPs, environmental conditions, and controls should be used in the manufacturing process at the new site. Changes should not be made to the manufacturing batch records except when consistent with other level 1 changes. Administrative information, location, and language translation may be revised as needed. 第3級變更包括將生產現場變更為不同的園區。不同的園區被定義為不在同一原始相鄰場地上,或者設施不在相鄰的城市街區。為了符合3級變更的資格,在新工廠的制造過程中應使用類似的設備、SOP、環境條件和控制措施。除非與其他1級更改一致,否則不應對生產批次記錄進行更改。行政信息、地點和語言翻譯可能會根據需要進行修訂。 Any change to a new contract manufacturer also constitutes a level 3 change.對新協議制造商的任何變更也構成3級變更。 2.Test d0cumentation測試文件 a.Chemistry d0cumentation化學文件 Location of new site and updated executed batch records.新設施的位置和更新的已執行批次記錄。 Application/compendial product release requirements.符合申報資料/藥典標準的放行要求。 Significant body of information available: One batch with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report可獲得Significant body of information:年度報告中報告的一批具有三個月加速穩定性數據的CBE補充和前三個生產批次的長期穩定性數據 Significant body of information not available: Three batches with three months accelerated stability data reported in changes being effected supplement and long-term stability data of first three production batches reported in annual report.不可獲得Significant body of information:年度報告中報告三個月加速穩定性數據的三個批次的CBE補充和前三個生產批次的長期穩定性數據。 b.In Vitro Release d0cumentation體外釋放文件 The in vitro release rate of a lot of the dosage form from the new manufacturing site should be compared with the in vitro release rate of a recent lot of comparable age of the dosage form manufactured at the prior site. The median in vitro release rates (as estimated by the estimated slope from each cell, see section VII) of the lots from the two sites should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below.從新的生產地點的批次體外釋放速率應與在先前生產地點最近生產的可比效期的批次的體外釋放率進行比較。應使用以下第VII節(體外釋放試驗)中所述的試驗程序,證明兩個部位批次的體外釋放率中位數(通過每個擴散池的斜率評估,見第VII節)在可接受的范圍內。 c.In Vivo Bioequivalence d0cumentation體內生物等效文件 None.不需要 3.Filing d0cumentation灌裝文件 Changes being effected supplement (all information including accelerated stability data); annual report (long-term stability data).CBE補充(包括加速穩定性數據在內的所有信息);年度報告(長期穩定性數據)。 原文內容已經過時,建議參考最新的《In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry》(超鏈接) The design of in vivo bioequivalence studies for semisolid dosage forms varies depending on the pharmacological activity of the drug and dosage form. A brief general discussion of such tests follows.半固體劑型的體內生物等效性研究的設計因藥物和劑型的藥理活性而異。以下是對此類試驗的簡要概述。 Objective:目標 To d0cument the bioequivalence of the drug product for which the manufacture has been changed, as defined in this guidance, compared to the drug product manufactured prior to the change or compared to the reference listed drug (RLD).記錄本指南中定義的變更生產的藥品與變更前生產的藥品相比或與參比藥物(RLD)相比的生物等效性。 Design:設計 The study design is dependent on the nature of the active drug. The bioequivalence study can be a comparative skin blanching study as in glucocorticoids (FDA, Topical Dermatological Corticosteroids: In Vivo Bioequivalence, June 2, 1995.) or a comparative clinical trial or any other appropriate validated bioequivalence study (e.g., dermatopharmacokinetic study) for the topical dermatological drug product.研究設計取決于活性藥物的性質。生物等效性研究可以是與糖皮質激素類似的比較性皮膚漂白研究(美國食品藥品監督管理局,局部皮膚科皮質類固醇:體內生物等效性,1995年6月2日)。 Analytical Method:分析方法 The assay methodology selected should ensure specificity, accuracy, interday and intraday precision, linearity of standard curves, and adequate sensitivity, recovery, and stability of the samples under the storage and handling conditions associated with the analytical method. 所選的分析方法應確保樣品在與分析方法相關的儲存和處理條件下的特異性、準確性、日間和日間精密度、標準曲線的線性以及足夠的靈敏度、回收率和穩定性。 GLOSSARY OF TERMS術語表 Approved Target Composition: The components and amount of each ingredient for a drug product used in an approved pivotal clinical study or bioequivalence study. Batch: A specific quantity of a drug or other material produced according to a single manufacturing order during the same cycle of manufacture and intended to have uniform character and quality, within specified limits. (21 CFR 210.3(b)(2)). Contiguous Campus: Contiguous or unbroken site or a set of buildings in adjacent city blocks. Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended drug substances for external application. Lotions are generally of lower viscosity. Diluent: A vehicle in a pharmaceutical formulation commonly used for making up volume and/or weight (e.g., water, paraffin base). Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or ointment) in its marketed package. It also can be a finished dosage form (e.g., tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)). Drug Release: The disassociation of a drug from its formulation thereby allowing the drug to be distributed into the skin or be absorbed into the body where it may exert its pharmacological effect Drug Substance: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3(b)) Emulsion: Emulsions are two phase systems in which an immiscible liquid (dispersed phase) is dispersed throughout another liquid (continuous phase or external phase) as small droplets. Where oil is the dispersed phase and an aqueous solution is the continuous phase, the system is designated as an oil-in-water emulsion. Conversely, where water or an aqueous solution is the dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as a water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent coalescence, the merging of small droplets into larger droplets and, ultimately, into a single separated phase. Emulsifying agents (surfactants) do this by concentration in the interface between the droplet and external phase and by providing a physical barrier around the particle to coalesce. Surfactants also reduce the interfacial tension between the phases, thus increasing the ease of emulsification upon mixing. Emulsifying agents substantially prevent or delay the time needed for emulsion droplets to coalesce. Emulsification is the act of forming an emulsion. Emulsification can involve the incorporation of a liquid within another liquid to form an emulsion or a gas in a liquid to form a foam Formulation: A listing of the ingredients and quantitative composition of the dosage form. Gel: A semisolid system in which a liquid phase is constrained within a three dimensional, crosslinked matrix. The drug substance may be either dissolved or suspended within the liquid phase Homogenization: A method of atomization and thereby emulsification of one liquid in another in which the liquids are pressed between a finely ground valve and seat under high pressure (e.g., up to 5,000 psi). Internal phase: The internal phase or the dispersed phase of an emulsion comprises the droplets that are found in the emulsion. In Vitro Release Rate: Rate of release of the active drug from its formulation, generally expressed as amount/unit area/time 0.5. Ointment: An unctuous semisolid for topical application. Typical ointments are based on petrolatum. An ointment does not contain sufficient water to separate into a second phase at room temperature. Water soluble ointments may be formulated with polyethylene glycol. Pilot Scale Batch: The manufacture of drug product by a procedure fully representative of and simulating that intended to be used for full manufacturing scale. Preservative: An agent that prevents or inhibits microbial growth in a formulation to which it has been added. Process: A series of operations, actions and controls used to manufacture a drug product. Scale-up: The process of increasing the batch size Scale-down: The process of decreasing the batch size. Shear: A strain resulting from applied forces that cause or tend to cause contiguous parts of a body to slide relative to one another in direction parallel to their plane of contact. In emulsification and suspensions, the strain produced upon passing a system through a homogenizer or other milling device. Low shear: Processing in which the strain produced through mixing and/or emulsifying shear is modest. High shear: Forceful processes which, at point of mixing or emulsification place a great strain on the product. Homogenization, by its very nature, is a high shear process which leads to a small and relatively uniform emulsion droplet size. Depending on their operation, mills and mixers are categorized as either high shear or low shear devices. Significant Body of Information: A significant body of information on the stability of the product is likely to exist after five years of commercial experience for new molecular entities , or three years of commercial experience for new dosage forms. Structure Forming Excipient: An excipient which participates in the formation of the structural matrix which gives an ointment, cream or gel etc., its semisolid character. Examples are gel forming polymers, petrolatum, certain colloidal inorganic solids (e.g., bentonite), waxy solids (e.g., cetyl alcohol, stearic acid), and emulsifiers used in creams. Strength: Strength is the concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard) (21 CFR 210.3(b)(16)). For semisolid dosage forms the strength is usually stated as a weight/weight (w/w) or weight/volume (w/v) percentage. Suspending agent: An excipient added to a suspension to control the rate of sedimentation of the active ingredients. Technical grade: Technical grades of excipients differ in their specifications and intended use. Technical grades may differ in: (1) specifications and/or functionality, (2) impurities, and (3) impurity profiles. Validation: A procedure to establish d0cumented evidence that provides a high degree of assurance that a specific process or test will consistently produce a product or test outcome meeting its predetermined specifications and quality attributes. A validated manufacturing process or test is one that has been proven to do what it purports or is represented to do. The proof of process validation is obtained through collection and eva1uation of data, preferably beginning with the process development phase and continuing through the production phase. Process validation necessarily includes process qualification (the qualification of materials, equipment, systems, building, personnel), but it also includes the control of the entire processes for repeated batches or runs. 參考文獻:《GUIDANCE FOR INDUSTRY Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence d0cumentation SUPAC-SS》 GuidanceforIndustry NonsterileSemisolidDosageForms Scale UpandPostapprovalChanges  Chemistry,Manufacturing,andControls InVitroReleaseTestingandInVivo Bioequivalenced0cumentation.pdf

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    2023-04-28

    銳拓RT7流池法溶出系統應用案例—雙相釋藥系統中速釋組分的體外釋放度研究

    雙相釋藥系統具有兩個不同的釋放相,根據其釋放特點可分為速釋-緩釋型、速釋-控釋型、速釋-定時釋放型制劑。雙相釋藥系統可調節藥物的釋藥速率、降低毒副作用、減輕胃腸道刺激、提高生物利用度等,為臨床提供更靈活的給藥方案。 本次研究案例的雙相釋藥制劑為速釋-緩釋型,其緩釋組分已經由客戶使用傳統溶出方法完成了體外釋放度研究,其與參比制劑的體外釋放結果相似性良好。 而對于速釋組分,由于在傳統溶出方法的測試條件下釋放過于快速,其體外釋放測試結果無法有效評估待測樣品與參比制劑的相似性。 根據我們以往的應用開發經驗,流池法在進行速釋組分的體外釋放度研究時,比傳統溶出方法更有優勢。故本次研究將使用流池法溶出系統進行相關體外釋放度測定,目標是獲得有區分力的測試結果。 20世紀50年代,流池法開始應用于口服制劑的藥物釋放度試驗。20世紀90年代,流池法正式被收載入美國藥典,成為USP<711>Apparatus 4。隨后,流池法被陸續收載入歐洲藥典、日本藥典等重要藥典中。中國藥典2020版亦正式收載流池法。 流池法溶出系統一般包括:用于儲存溶出介質的容器,輸送溶出介質的恒流泵,流通池,保持溶出介質溫度的恒溫水浴,以及自動取樣工作站。 流池法主要有兩種運行模式,分別是: 開環模式:進入流通池的溶出介質一直是空白不含API,溶出介質的體積由流速和實驗時長決定。流出流通池的樣品溶液不回到溶出介質儲存容器,而是進入自動取樣工作站。樣品溶液可以全部收集、分時間段收集或按照分流比收集。 閉環模式:流出流通池的樣品溶液將返回到溶出介質儲存容器中并充分攪拌均勻,自動取樣工作站從溶出介質儲存容器中進行取樣。 本研究將使用流池法的開環模式。在開環模式下,流池法溶出系統的取樣時間間隔可以比傳統溶出方法更小(例如:銳拓RT7的開環模式下最小取樣時間間隔可以達到30秒),從而更加精準地測定速釋組分的體外釋放度。 使用流池法進行片劑的體外釋放度測定時,一般可以選用大池(Large Cell)裝置或小池(Small Cell)裝置。大池和小池的主要區別在于兩者的池體內徑不同,在相同流速情況下小池內的流體剪切力會大于大池內的流體剪切力。 根據本次測試樣品的大小和速釋組分的釋放特點,我們選擇大池裝置進行流池法測試。大池裝置的錐體底部會放置一顆5mm直徑的紅寶石球,并在錐體部分填充指定質量的1mm直徑的玻璃珠。 在進行流通池溶出方法的開發過程中,應該充分評估關鍵測試參數對樣品溶出釋放結果的影響。本案例將探討溶出介質和流速對樣品速釋組分體外釋放度的影響。 溶出介質中的緩沖體系、pH值、表面活性劑,是影響樣品溶出釋放的關鍵因素。方法開發時應該充分考察溶出介質對樣品釋放的影響。 典型的溶出介質一般包括:鹽酸溶液、pH范圍為1.2~7.5的緩沖液(磷酸鹽或醋酸鹽)、模擬胃液或腸液(含酶或不含酶)和水。對于某些藥物,其自身與某些緩沖液或緩沖鹽的不相容性可能會影響溶出介質中緩沖體系的選擇。另外,所用緩沖液和酸的摩爾濃度可能會影響溶出介質的增溶效果。 在本次研究案例中,我們評估了不同pH值和緩沖體系的溶出介質對樣品速釋組分的釋放度的影響。下圖呈現的是其中三種溶出介質的測試結果: 溶出介質中一般會添加一定比例的表面活性劑以提高藥物的溶解度。表面活性劑的濃度、種類、等級和純度都會影響其增溶效果。另外需要注意的是,藥典不建議使用含水-有機溶劑的混合物作為溶出介質,除非有合適的理由。 在本次研究案例中,我們評估了在相同pH緩沖體系下,不同表面活性劑的不同濃度對樣品速釋組分的釋放度的影響。下圖呈現的是其中三種表面活性劑濃度的測試結果(表面活性劑濃度:Medium A < Medium B < Medium C): 測試結果顯示,隨著溶出介質中表面活性劑濃度的上升,樣品速釋組分的釋放速度明顯加快。 溶出介質的流速是流通池溶出方法的關鍵測試參數,方法開發時應該充分考察流速對樣品釋放的影響。 在本研究過程中,我們評估了在相同溶出介質的情況下,不同流速對樣品釋放度的影響。為了更直觀地呈現測試結果,我們將開環模式下測得的濃度-時間微分曲線換算為常見的累積溶出率-時間曲線: 測試結果顯示:溶出介質的流速越高,速釋組分的釋放速率越快。 流通池內的流體剪切力會隨著流速上升而增大,速釋組分更快被溶蝕,其中的原料藥更快地溶出進入介質中。 另外,根據Nernst & Brunner的擴散層模型,溶出率與擴散層兩邊的濃度差(Cs-C)成正比,與擴散層的厚度(h)成反比。 由于在開環模式下流入流通池內的介質都是新鮮的。更快的流速意味著本體溶液中原料藥的濃度更低,擴散層兩邊的濃度差更大,溶出速率更快。此外,更快的流速也會一定程度上減少擴散層的厚度,使得溶出速率加快。 為了確定釋放度測定方法的區分力,我們采用具有不同質量屬性的自研樣品與參比制劑進行對比研究。本文選取了參比制劑和其中兩種自研樣品,在合適測定條件下的體外釋放度結果,并以濃度-時間微分曲線呈現: 評價生物等效性的主要藥動學參數為AUC和Cmax,如果在AUC基本一致的情況下,Cmax 可以部分反映藥物體內吸收的快慢。同理,我們可以根據體外釋放度測試獲得的濃度-時間微分曲線的Cmax 來預測自研樣品和參比制劑在體內吸收速度的差異。 根據上圖的測試結果,我們不難發現: (1)對于兩種不同質量屬性的自研樣品:雖然兩者的Cmax基本一致,但是達到Cmax的時間(Tmax)是有區別的,自研樣品A的速釋組分釋放速度比自研樣品B快。本流通池測定方法能夠有效區分不同質量屬性自研樣品的體外釋放度差異。 (2)對于參比制劑和自研樣品:參比制劑的Cmax小于兩種自研樣品,且參比制劑到達Cmax的時間(Tmax)比兩種自研樣品都慢。我們有理由預測,自研樣品速釋組分的體內吸收速度會較參比制劑快,并有可能影響其生物等效性。此測試結果為后續的處方和工藝參數優化提供了很好的數據支持。 在藥物研發過程中,我們都希望建立有效的溶出釋放度測定方法,該方法能區分不同批次產品的質量,最理想的情況就是所有生物不等效的批次都能被檢測發現,從而將生物等效性試驗批的生物等效性研究結果外推至商業批。 相比于傳統溶出方法,流池法在方法區分力和生物等效性預測方面具有明顯優勢,更能夠滿足我們在藥物研發過程中對樣品體外釋放度測試的需求,其測試結果對處方和工藝參數優化也更有指導意義。 進一步地,得益于銳拓RT7流池法溶出系統更先進的開環取樣模式,使我們能夠快速且準確地收集到樣品速釋組分在快速釋放時間段內的溶出數據(前10分鐘的取樣間隔為1分鐘),并有效地區分不同質量屬性的自研樣品以及自研樣品與參比制劑之間的差異,成功達到本次研究的目標。

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