尼日利亞藥品註冊指南喺尼日利亞藥品註冊質量指南尼日利亞莱克斯·阿蒂菲克斯LLP, 尼日利亞律師樓, 有引入 f&d 幫助協助參與製造嘅人同公司, 分布, 出口和進口受管制食品和藥品,以滿足尼日利亞國家食品藥品監督管理局規定嘅要求 ("NAFDAC"). 本出版物提供咗尼日利亞藥品註冊嘅質量準則. 確認原子能機構承認世界衛生組織嘅技術支持 (边个), 西非世界衛生組織 (WAHO) 同協調國際會議 (ICH) 在制定本準則時. 目的本文為根據國際協調理事會通過程序實現嘅廣泛接受嘅形式同共同要求,為尼日利亞人類用藥註冊編寫監管報告提供了指導。 (ICH) 人類用藥登記嘅監管要求. 特別是, 該文件旨在令原子能機構關於為人類使用的藥物登記提交監Ich求與西非國家共同體由西非國家世界衛生組織錨定嘅統一努力保持一致 (WAHO). Therefore, 本文件嘅介紹將最終有助於以下; 透過就產品檔案嘅組織同格式提供指導,為藥品準備監管提交. 共同技術文件嘅透過 (CTD) 透過國際衞生中心進程制定,世界衛生組織喺世衛組織資格預審方案同西非衛生瓦霍中採用,促進統一人類使用註冊醫藥產品的監管要求· 在西非經共體成員國促進監管協調; 藥品監管機構之間嘅拍檔同信息共享就其他技術同一般要求提供指導詳細說明對活性藥物成分嘅要求 (Api) 同成品藥品; 便於提交和評估; 增加獲得優質基本藥物的機會; 促進一個更透明嘅監管系統列表嘅縮寫爱滋病獲得免疫缺陷綜合征API活性藥物成分APIMF活性藥物成分主文件。 ATC歐洲藥品和醫療保健質量局頒發嘅ATC解剖治療和化學分類CEP適宜性證書 (埃德QM) CPP藥品CTD紙通用技術文件DMF藥物主文件西非國家西非國家FPP成品藥品GMP良好製造做法愛滋病毒人體免疫缺陷病毒ICH國際協調技術要求理事會註冊供人使用嘅藥品INN國際非專有名稱MA市場授權NCE新化學實體NMRA國家藥品監督管理局OTC關於處方藥PIL患者信息傳單POM處方專用藥品SMPC產品摘要 西非衛生組織世衛組織世界衛生組織關於尼日利亞提出藥品註冊申請緊嘅一般原則,申請銷售許可的產品應以英文提交. 如果需要把文檔由原始語言翻譯為英文, 翻譯嘅準確性由申請人負責,翻譯應由原產国認證專家認證。.  數據演示文集應以電子形式提交,並應遵循CTD格式. 應為每個糢塊中嘅CTD嘅不同部分為不同嘅糢塊創建單獨嘅文件夾和子文件夾. 文檔應以可搜索嘅PDF格式提交,但QIS除外,該QIS應採用MS Word格式.  參考文獻和文本 ·         必須遵循檔案任何部分引用引用嘅國際標準. 任何參考源嘅最新版本, 指定必須使用出版年. ·         應根據本版《提交生物醫學期刊的手稿統一要求》引用文獻參考, 國際醫學期刊編輯委員會 (伊姆杰). ·         首字母縮略詞和縮寫應在每個模塊中首次使用.  必要時, 特別是用于分析方法, 規範和程序, 參考源相關部分嘅副本(s) 必須包括. ·         文檔中引用嘅所有內部流程必須經過驗證並引用適當嘅引用.  促進PD嘅編制, 呢啲準則係按照ICH通用技術文檔嘅結構組織嘅 (M4Q) guideline. M4Q嘅文本 (CTD-Q) 準則喺呢啲準則中逐字逐句地以粗躰文本重申, 稍作修改,以適應NAFDAC術語,並包括適用於藥品嘅某些文本, 尤其係: a)        "藥物物質"被替換為"活性藥物成分"或"API"b)        "藥品"被替換為"成品"或"FPP". c)        "應用"替換為"產品檔案"或"PD". d)        "組合產品"替換為"固定劑量組合"或"FDC". nafdac 根據世衛組織關於提交多源文件嘅準則提供嘅補充指導 (generic) finished product, 以下由M4Q轉載嘅粗體文本 (CTD-Q) guideline (2), 以普通文本打印,使其易於與ICH文本區分,並包含以進一步澄清NAFDAC對PD內容嘅期望. 呢種方法嘅目的係便利指引中案文嘅肯定同來源 (i.e. 從Ich或世衛組織). 呢啲準則嘅內容應與世衛組織或國際信息委員會其他現有參考文件和指南中描述嘅相關信息一起閱讀. 現有API同相應多源產品嘅質素不應低於新嘅API同創新者 (comparator) FFP. Therefore, 本文件同其他世衛組織指南中提及嘅ICH指南原則可能同樣適用於現有API同多源產品. 科學文獻可能適合滿足呢啲準則中概述嘅一些信息或參數嘅要求 (e.g. 指定識別嘅雜質嘅資格). Furthermore, 某些部分中列出嘅要求可能不適用於建議嘅API或FPP. 喺呢啲情況下, 應提供摘要或對科學文獻嘅完整參考, 或所要求嘅信息唔適用,應明確註明隨附嘅解釋性說明. 關於格式嘅指導世衛組織關於多來源提交文件嘅一般性文件準則中概述嘅建議 (generic) finished product: 一般格式: 在PD的格式和演示中,應遵循以共同技術文檔格式編製產品檔案. 喺好多情況下,重複節可以被認為係適當嘅. 每當重複一節時, 應該透過喺M4Q之後喺括號中創建一個區分標題嚟明確該節所指嘅 (CTD-Q) 指南標題, e.g. 3.2.S藥物物質 (或Api) (name, 製造商A). 以下係喺質素糢塊中介紹可能遇到嘅不同方案嘅信息嘅建議:  開放部分 (non-proprietar成品個APIMF應始終將其全部納入PD中, 作為3.2. s嘅附件. 對於包含多個API嘅FPP, 一個完整嘅"3.2.S"部分應為一個API提供, 然後係其他API嘅另一個完整"3.2.S"部分.  來自多個製造商嘅API, 一個製造商應為API提供一個完整嘅"3.2.S"部分, 然後係來自其他API製造商嘅API嘅另一個完整"3.2.S"部分. 對於具有多種優勢嘅FPP (e.g. 10, 50, 100 mg) 應提供一個完整嘅"3.2.P"部分,其中應提供分節內提供嘅不同CTD-Q嘅信息. 應為每種FPP強度提供一份完整嘅PD副本.  對於具有多個容器關閉系統嘅FPP (e.g. 瓶子和單位劑量水泡) 應提供一個完整嘅"3.2.P"部分,其中應提供分節內提供嘅不同演示文稿嘅信息. 用于多個FFP (e.g. 片劑和母產品) 每個Fpp都需要單獨嘅檔案.  對於提供重組二噁英嘅Fpp(s) 應為FPP提供一個完整嘅"3.2. p"部分, 然後係天拿水上嘅信息(s) 喺單獨嘅部分"3.2. p", as appropriate. 對於共起泡嘅FPP,應為每種產品提供完整嘅"3.2.P"部分.  CTD格式信息結構組織成一系列結構化文檔,然後組織成糢塊. 通用技術文檔同ICH一般問答嘅M4指導組織提供咗文檔嘅定義同內容表指南 (ToC) 格式, CTD內嘅交叉引用同文檔分頁, 隔離同分區編號.  表 1: 共同技術文件中嘅主要章節標題 (CTD) 格式編號標題同主部分標題     1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.A Module 1: 行政和產品信息求職信表內容 (Modules 1 to 5) 應用信息產品信息區域摘要電子審查文檔產品樣本(s) (如果在提交時可用) Appendix   2.1 2.2 2.3 2.4 2.5 2.6 2.7 Module 2: Common Technical Document (CTD) 摘要CTD內容表 (Modules 2 to 5) CTD介紹質素總體摘要非臨床概述臨床概述非臨床書面和製表摘要臨床摘要 3.1 3.2 3.3 Module 3: 糢塊內容質素表 3 數據文獻參考体 4.1 4.2 4.3 Module 4: 糢塊內容表不需要非周期性研究報告 4    通用產品研究報告文獻參考 5.1 5.2 5.3 5.4 Module 5: 臨床研究報告生物等價性或糢塊內容表 5    仿製藥所需嘅生物豁免器作為適用於所有臨床研究嘅表格列表臨床研究報告文獻參考糢塊 1 (行政和產品信息) 1.0     求職信: ·         向監管機構提交嘅任何數據應附上求職信.  求職信應清楚地說明提交緊嘅内容, 包括提及請求書 (if applicable) 同包裝嘅簡要說明. ·         求職信不應包含任何科學信息. ·         任何相互引用嘅監管文件都應喺求職信中明確說明, 以及以下信息應包含在內: ·應用類型, 指定是否新, 續約或變更; ·NMRA申請號 (由NMRA發佈); ·如果適用,則監管授權日期. ·品牌名稱, Dci, 劑量, 表示, dosage form; ·製造商名稱·申請人姓名·提交嘅樣本數量附件B中提供了樣本求職信: 形式 1.1    包括糢塊在內嘅應用程序內容表 1 (module 1-5) The Table of Contents (ToC) 成個監管檔案應該放喺一節.  它應該列出糢塊中包含嘅所有文檔 1-5.  每個糢塊都包含糢塊特定嘅ToC. 1.2    應用程序信息 1.2.1   申請信 1.2.2   報名表 1.2.3   公司成立證書 1.2.4   授權書 1.2.5   申請人公證申報. (申請人應聲明提交嘅信息真實且正確. 有關名稱嘅信息, 申請人嘅地位同簽名, 產品細節應在公證的申報中提供,並且應註明日期, 由公證人簽名和蓋章) 1.2.6   委託書/合同製造協議 1.2.7   醫藥產品證書 1.2.8   良好製造實踐證書 1.2.9   製造授權 1.2.10                商標註Toc證據 1.2.11                藥劑師年度執業執照 1.2.12                房地登記和保留證書 1.2.13                以前營銷授權嘅证据 (If applicable) 1.2.14                GMP檢查邀請函 1.2.15                歐洲藥典適宜性證書副本 (where applicable) 1.2.16                Letter of Access for APIMF(s) (where applicable) 1.2.17                與開展基於BCS嘅生物可用性研究有關嘅生物豁免請求 1.2.18                與開展額外強度生物可用性研究相關嘅生物豁免請求 1.3.    產品信息 1.3.1. Summary of Product Characteristics (SmPC) 產品特徵摘要副本 (SmPC) is to be placed in this section. 在評估過程中請求修訂時, 需要修訂後的SMPC的注釋版本.  註釋應識別所有更改, 或與上一次批准嘅 smpc 有關嘅, 或應監管當局的要求提出的要求. 1.3.2.      Labelling (外 & 內部標籤) ·         所有容器標籤, 包括內部和外部標籤, 應在本節中提供. ·         應該包括所有優勢嘅標籤, 劑型和重組天拿水. ·         在審查過程中請求進一步修訂時, 修改後的標籤的附加說明嘅版本可能會要求, 並應放置在節中. 1.3.3.      包裝插入 (都稱為患者信息PIL) ·         患者信息傳單副本 (PIL) is to be placed in this section. 1.4.    區域摘要 1.4.1.  Bioequivalence Trial Information Form (BTIF) 1.4.2.  質量信息摘要 (QIS) 1.5.        電子審查文檔電子版本嘅應用程序鼓勵喺可搜索嘅便將放在本節中子文檔應保存到光盤中. 所有提交支持藥品監管文件嘅電子媒體都應放在本節中 1.6.    樣品 ·         應隨申請一起提交用于商業目的嘅相同包裝中產品嘅樣品. 請注意,当最終產品包裝不可用時,可以使用模型包裝. Module 2: Common Technical Document (CTD) 摘要糢塊 2 包括以下內容 7 sections.   對於多源 (generic) pharmaceutical products, Modules 2.4-2.7 通常不需要. 2.1  CTD Table of Contents (Modules 2-5) 2.2  CTD簡介 2.3  質量總體摘要 2.4  非臨床概述 2.5  臨床概述 2.6  非臨床書面和表格摘要 2.7  臨床總結 2.1          CTD Table of Contents (Module 2-5)     CTD目錄2 to 5 should be provided. 2.2              CTD介紹介紹應包括專有名稱, 非專有名稱或藥物物質的通用名稱, 公司名稱, dosage form(s), strength(s), 管理路線, 同建議嘅指示(s). 它應該簡要描述糢塊嘅内容 2 to 5 與適當嘅交叉引用佢哋. 2.3              質量總體總結質素總體總結 (Qos) 係遵循糢塊中數據主體嘅範圍同大綱嘅摘要 3. QOS包含API部分 (2.3.S), Fpp部分 (2.3.P), Appendices (2.3.A) 同區域信息 (2.3.R). QOS不應包含信息, 糢塊中尚未包含嘅數據或理由 3 或喺CTD嘅其他部分. QOS-PD糢闆應按照本節中嘅指南完成. 請參閱ICH M4Q (R1). 2.3. S藥物對於含有多種藥物的藥物產品, 糢塊2.3.S.1至2.3.S.7中嘅信息應提交每種藥物物質, 明確識別每個糢塊標題中嘅物質名稱同製造商.  2.3. S.1 General Information (name, manufacturer) 包括糢塊3.2.S.1中嘅信息  2.3. S.2 Ma通用技術文檔址, i.e., 網站)  包括來自糢塊3.2.S.2有關製造商嘅信息, ·提供名稱, 每個製造商嘅地址同責任, including contractors, 以及每個提議嘅生產場地或設施,涉及製造和測試. ·製造過程簡要描述 (including, for example, 參考起始材料, critical steps, 和後處理) 以及旨在導致材料嘅常規同一致生產嘅控制(s) 適當質素; 可以呈現為流程圖. •              A flow diagram, 如3.2.S.2.2中提供; ·用于制造API嘅生物來源同起始材料和原材料嘅說明, 如3.2.S.2.3中所述; ·突出顯示關鍵工藝中間體, 如3.2.S.2.4中所述; ·過程驗證和/或評估嘅描述, 如3.2.S.2.5中所述. 2.3. S.3特徵 (name, manufacturer) 結構和異構體證據解釋嘅摘要, 如3.2.S.3.1所述, should be included. 3.2.S.3.2中提供嘅數據嘅表格摘要, 具有圖形表示, 在適當時應包括. 2.3. S.4藥物物質控制 (name, manufacturer) A brief summary of the justification of the specification(s), the analytical procedures, 和驗證應包括. 應提供3.2.S.4.1嘅規格. 3.2.S.4.4嘅批處理分析嘅表格摘要, with graphical representation where appropriate, should be provided. 2.3. S.5 Reference Standards or Materials (name, manufacturer) 來自3.2.S.5嘅信息 (tabulated presentation, where appropriate) should be included.  2.3. S.6集裝箱封閉系統 (name, manufacturer) 簡要說明和討論信息, 從3.2.S.6應包括在內.  2.3. S.7 Stability (name, manufacturer) 本節應包括所進行研究嘅摘要 (conditions, batches, analytical procedures) 簡要討論結果和結論, 建議嘅存儲條件, 複試日期或保質期, where relevant, as described in 3.2. S.7.1. The post-approval stability protocol, 如3.2.S.7.2中所述, should be included. 穩定性嘅表格摘要來自3.2.S.7.3, with graphical representation where appropriate, should be provided. 2.3. P成品藥品 2.3. P.1藥品嘅描述同成分 (name, dosage form) 應提供3.2.P.1嘅信息. 應提供3.2.P.1嘅組成. 2.3. P.2藥物開發 (name, dosage form) 應討論3.2.P.2嘅信息同數據. 應提供臨床試驗中使用嘅配方成分嘅表格摘要同溶解圖嘅介紹, where relevant. 2.3. P.3 Manufacture (name, dosage form) 3.2.P.3嘅信息應包括: ·製造商信息. ·簡要描述製造工藝和控制,旨在導致適當質量產品嘅常規同一致生產. •              A flow diagram, 根據以下規定 3.2. P.3.3. ·過程驗證和/或評估嘅簡要描述, as described in 3.2. P.3.5.  2.3. P.4輔料控制 (name, dosage form)  關於輔料質素嘅簡要總結, 如3.2.P.4中所述, should be included.  2.3. P.5藥品控制 (name, dosage form)  A brief summary of the justification of the specification(s), 分析程序和驗證摘要, 和雜質的特徵應提供. 規範(s) 應提供3.2.P.5.1起. 3.2.P.5.4下提供嘅批次分析嘅表格摘要, 在如中所述含圖形表示. 2.3. P.6 參考標準或材料 (name, dosage form)  來自3.2.P.6嘅信息 (tabulated presentation, where appropriate) should be included.  2.3. P.7集裝箱封閉系統 (name, dosage form)  應包括3.2.P.7中·流程圖 2.3. P.8 Stability (name, dosage form)  所進行的研究摘要 (conditions, batches, analytical proce規範理由嘅簡要摘要包括數據分析. 關於儲存條件同保質期嘅結論,, if applicable, 應給予使用中嘅存儲條件同保質期. 穩定性嘅表格摘要來自3.2.P.8.3, with graphical representation where appropriate, should be included. The post-approval stability protocol, 如3.2.P.8.2中所述, should be provided. 2.3. Appendices 2.3.  表格演示文稿床概述非臨床概述應提供糢塊中信息嘅綜合整體分析 4. In general, 非臨床概述不應超過約 30 頁面. 非臨床概述應按以下順序顯示: ·非藥物測試策略概述·藥理學·批次·毒理學·綜合概述同結論·文獻參考列表綜合概述和結論應明確定義非處方藥研究所證分析程序,並得出合乎邏輯嘅結論, 支持產品用于預期臨床用途嘅充分結論. 服用藥理學, 藥代動力學, 同毒理學結果考慮在內, 應討論非臨床性發現對人類安全使用藥物的影響 (i.e., 適用於批准後穩定性協議臨床概述在適當時用圖形表示息 2.4 同糢塊 4 通常唔需要多源 (generic) 藥品. 但是,在某些情況下,例如安全雜質配置文件嘅變化, 應進行安全評估研究.  2.5 臨床概述臨床概述旨在對《共同技術文件》中嘅臨床數據進行批判性分析. 臨床概述必須參考綜合臨床摘要中提供的應用數據, 個別臨床研究報告 (ICH E3), 同其他相關報告; 但它應該主要提出呢啲數據嘅結論同影響, 唔應該重述佢哋. 特別, 臨床摘要應提供CTD臨床信息嘅詳細事實匯總, 臨床概述應提供呢啲發現以及任何其他相關信息嘅簡明討論同解釋 (e.g., 可能具有臨床影響嘅相關動物數據或產品質量問題). 臨床概述應按以下順序顯示: Table of Contents 2.5.1 產品開發理念 2.5.2 生物製藥概述 2.5.3 臨床藥理學概述 2.5.4 效率概述 2.5.5 安全概述 2.5.6 收益和風險結論 2.5.7 文獻參考ICH M4E (R1) Module 2.5 為臨床概述嘅內容提供指導.  Module 3: 質素質素糢塊遵循ICH M4Q中概述嘅結構同說明性解釋 (R1).  文本僅在需要強調的情況下由文檔中複製. 3.1 Table of Contents (Module 3) 目錄應畀出糢塊中每個研究報告嘅位置 3 3.2. S數據主體 - 藥物物質下列信息可作為適用嘅API信息提交: Option 1 - 確認API資格預審文檔選項 2-  歐洲藥典適用性證書 (CEP) Option 3 - Active Pharmaceutical Ingredient Master File (APIMF) 程序選項 4 – 產品檔案中包含多種藥物的藥物產品的完整詳細信息, 應提交每種藥物物質嘅信息. 其中提到CEP, 申請人必須提供CEP持有人嘅出(訪問信). 訪問信應喺糢塊中提供 1.2.16. 世衛組織資格預審的證據也應在本節下提供(如適用). 申請人應喺API部分嘅開頭明確說明 (喺Pd同Qos - pd中) 如何提交每個API製造商嘅API信息. 申請人或FPP製造商提交嘅API信息應包括以下選項,根據使用嘅選項. Option 1: 確認API資格預審文件. 糢塊中應提供API資格預審文件確認嘅完整副本 1, 以及以FPP製造商或申請人嘅名義正式填寫嘅授權箱. The applicant should supply the following information in the dossier, with data summarized in the QOS-PD. -       3.2. S.1.3一般屬性–討論不受API製造商規範控制嘅其他適用物理化學品同其他相關API屬性, e.g. solubilities and polymorphs according to the guidance in this section. -       3.2. S.2 =如果FPP嘅無菌性基於API嘅無菌製造,則應提供滅菌過程嘅數據以及完整嘅驗證數據. -       3.2. S.3.1結構同其他特徵嘅闡明–用于識別多態和顆粒大小分布嘅研究, where applicable, according to the guidance in this section. -       3.2.S.4.1規格- FPP製造商嘅規格,包括API製造商規格嘅所有測試和限制,以及API製造商嘅規格(如多態性同/或顆粒大小分布)無法控制嘅任何附加測試和驗收標準. -       3.2. S.4.2/3.2.S.4.3分析程序和驗證–FPP製造商使用嘅任何方法,以及API製造商規範中嘅方法. -       3.2. S.4.4 Batch analysis – results from two batches of at least pilot scale, demonstrating compliance with the FPP manufacturer’s API specifications. -       3.2. S.5 Reference standards or materials – information on the FPP manufacturer’s reference standards. -       3.2.S.7穩定性–支持重新測試期嘅數據,如果提議嘅重試期較長,抑或建議嘅存儲條件溫度或濕度高於資格預審API. ·選項 2: 歐洲藥典嘅適用性證書 (CEP) A complete copy of the CEP (including any annexes) should be provided in Module 1. CEP嘅准入聲明應由CEP持有人代表FPP製造商或申請人向WHO藥品資格預審方案(參考CEP )正式填寫,. In addition, 應包括書面承諾,如果CEP被撤銷,申請人將通知NAFDAC. 申請人仲應承認,退出CEP將需要額外考慮API數據要求以支持PD. 書面承諾應隨糢塊中嘅CEP副本一起附 1. 與CEP一起, the applicant should supply the following information in the dossier, with data summarized in the QOS-PD.  3.2. S.1.3一般屬性–討論不受CEP同Ph.Eur控制嘅API任何其他適用物理化學品同其他相關屬性. Monograph, e.g. solubilities and polymorphs according to thCepuidance in this section.   3.2. S.3.1結構同其他特徵嘅闡明–識別多態性嘅研究 (除非CEP指定多態形式) 同顆粒大小分佈, where applicable, according to the guidance in this section.  3.2. S.4.1規範–FPP製造商嘅規格,包括CEP同Ph.Eur嘅所有測試和限制. 專著同CEP同Ph.Eur中未控制嘅任何附加測試和驗收標申請人應在檔案中提供以下信息2.數據匯總喺QOS-PD中EP同Ph.Eur中嘅方法外,FPP製造商使用嘅任何方法. Monograph. 3.2. S.4.4 Batch analysis – results from two 根據本節中嘅指南,溶解性同多態性P manufacturer’s API specifications. 3.2. S.5 Reference sta專著 materials – information on the FP根據本節中嘅指南3.2.S.6集裝箱封口系統-規格包括主要包裝部件嘅說明同識別,除非CEP指定咗集裝箱關閉系統,申請人聲明有意使用相同嘅容器閉合系統. 3.2.S.7穩定性–除非CEP指定與申請人提議嘅相同或更長嘅測試周期番, 和存儲條件相同或溫度和濕度高於S.4.4批量分析–至少兩批試點比例嘅結果證明符合FPP製造商嘅API規範ve pharS.5參考標準或材料–有關FPP製造商參考標準嘅信息造商可把API製造和流程驗證期間嘅質素控制作為APIMF提交。, 打開部分 (non-proprietary information) 需要作為3.2. s嘅附件完整地納入Pd. In addition, 申請人或FPP製造商應完全按照所提供的指導完成PD同QOS-PD中嘅以下部分,除非相關部分另有說明: 一般信息S.1.1-S.1.3製造S.2製造商(s) S.2.1制造工藝和工藝的描述控制S.2.2關鍵步驟和中間體的控制S.2.4結構的闡明和其他特征S.3.1雜質S.3.2 A 控制S.4.1-S.4.5參考標準或材料S.5集裝箱關閉系統S.6穩定S.7.1-S.7.3申請人有責任確保完整嘅APIMF (i.e. 申請人嘅開放部件同API製造商嘅受限部件) 由API製造商直接提供畀NAFDAC,並且申請人有權訪問APIMF中有關API當前製造嘅相關信息. PDF糢塊中應提供訪問信嘅副本 1. APIMF持有人可以使用為選項"PD中嘅全部詳細信息"提供嘅指南嚟準備其APIMF嘅開放同受限部分嘅相關部分. 仲應參考世衛組織技術報告系列中嘅亞太基金基金準則, No. 948, Annex 4 (4). Option 4: PD信息中關於3.2.S活性藥物成分部分嘅完整詳細信息, 包括化學嘅全部細節, manufacturing process, API製造和流程驗證期間嘅質素控制, 應如本準則後續部分所述,PD中提交緊. QOS-PD應按節完成 3.1 呢啲準則. 3.2. S.1      General Information (name, manufacturer) 3.2. S.1.1命名 (name, manufacturer) 應提供有關藥物物質名稱的信息活性藥物成分主文件 阿普伊姆.); ·簡稱(如果相關); ·化學名稱(s); ·公司或實驗室代碼; ·其他非專有名稱(s), e.g., 國家名稱, 美國採用名稱 (蘇桑), 日語接受名稱 (1月); 英國批准名稱 (禁止), 同化學文摘服務 (Cas) 註冊表編號.  所列化學名稱應與科學文獻中出現嘅化學品名稱同產品標籤信息中出現嘅名稱一致 (e.g. 在產品特性摘要中 (SmPC) 同包裝傳單, 都稱為患者信息單張 (PIL)). 如果存在多個名稱,應指示首選名稱. 3.2. S.1.2結構 (name, manufacturer) 結構公式, 包括相對同絕對嘅立體化學, the molecular formula, 同相對分子質素應提供.  此信息應與第一節中提供嘅信息一致 3.2. S.1.1. 對於作為鹽存在嘅API,仲應提供自由堿或酸嘅分子質素. 3.2. S.1.3一般屬性 (name, manufacturer) 結構, molecular formula, 分子量和結構公式指定. 人性中心,如果發分子公式息可用于開發規範, 在制定FP和測試以釋放和穩定性目的. 應討論API嘅物理同化學性質, 包括物理描述, 普通溶劑中嘅溶解性 (e.g. 水, alcohols, dichloromethane and acetone), 定量水性pH溶解性剖面 (e.g. pH 1.2–6.8, 劑量/溶解度體積), polymorphism, pH同pKa值, ultraviolet (UV) 吸收最大值和摩爾吸收率, melting point, 折射 (for a liquid), 吸濕性和分區系數 (請參閱QOS - pd中嘅表格). 此列表並非詳盡無遺,但會說明可包含的信息類型. 下面將更詳細地討論API需要考慮的一些最相關嘅屬性.  物理描述物理描述應包括外觀, 顏色同物理狀態. 固體形式應確定為晶體或無定形 (有關API實體窗體嘅更多信息,請參閱3.2.S.3.1).  選項供提交API數據嘅所有選項嘅可溶性和定量下列pH溶解性配置文件. 應提供一些常見溶劑中的溶解性 (e.g. 在水中, alcohols, dichloromethane and acetone). 生理pH範圍內嘅溶解性 (pH 1.2–6.8) 在幾個緩衝介質中應提供毫克/毫升. 如果此信息不易獲得 (e.g. 從文獻參考), 它應該喺內部生成. For solid oral dosage forms, 劑量/溶解度應根據醇二氯甲烷和丙酮 (mg) 劑量/溶解量=藥物的最小濃度 (毫克/毫升) * * 對應於喺生理pH範圍內確定嘅最低溶解度 (pH 1.2–6.8) 同溫度 (37 ± 0.5 °C). 根據生物製藥分類系統 (Bcs), 高溶性 (或高水溶性) API係嗰啲劑量/溶解度≤ 250 ml. For example, 化合物A具有其最低的溶解度 37 ±0.5°C, 1.0 毫克/毫升在pH 6.8 並喺 100 mg, 200 毫克和 400 毫克強度. 此API唔會被視為BCS高可溶性API,因為它的劑量/溶解度大於 250 ml (400 毫克/1.0毫克/毫升| 400 ml). ICH嘅CTD-Q問題同毫升案/位置問題文pH 1.2~6.8多態性 (5) 以下列表說明特定數據應位於PD中嘅位置: ·多態形式(s) 建議嘅API中應列喺第一節中 3.2. S.1.3. ·製造工藝和工藝控制嘅描述 (3.2.S.2.2) 應指示製造哪種多態形式, where relevant. ·為識別API嘅潛在多態形式而執行嘅文獻參考或研究, 包括研究結果, 應在第一節中提供 3.2. S.3.1. ·如果要定義或限制多態形式 (e.g. 對於非BCS高可溶性和/或多態性已被確定為問題嘅API), 詳細信息應包含喺3.2.S.4.1中– 3.2. S.4.5. 呢啲準則嘅參考部分包含其他信息.  ICH嘅CTD-Q問題同答案/位置問題文檔中建議嘅粒子大小分布 (5), 為確定API嘅粒徑分布而進行的研究應喺第3.2.S.3.1節中提供 (有關更多信息,請參閱本指南嘅一部分).  來自文獻支持數據嘅信息同特定研究或已發表嘅文獻嘅結果可以包含喺本節中或附件中. 請參閱ICH指南: Q6A同Q6B 3.2. S.2     Manufacture (name, manufacturer) 3.2. S.2.1製造商(s) (name, manufacturer) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. The facilities involved in the manufacturing, packaging, labelling, 應列出API嘅測試同存儲. If certain companies are responsible only for specific steps (e.g. API嘅銑削) this should be clearly indicated. 製造商或公司名單應指定生產或製造站點的實際地址(s) involved (including block(s) 同單位(s)), rather than the administrative offices. 電話號碼(s), 傳真號碼(s) 同電子郵件地址 (es) should be provided. 應為API嘅生產提供有效的製造授權. If available, 糢塊中嘅PD中應提S.1一般信息2.2製造工藝和工藝控制說明 (name,                  Manufacturer) API製造流程嘅描述代表申請人對API製造嘅承諾. 應提供信息,以充分描述製造流程和工藝控制. For example:  合成過程嘅流程圖(es) 應提供包括分子公式, 權重, 屈服範圍, 起始材料嘅化學結構, intermediates, 反映立體化學的試劑和API, 並確定工作條件和溶劑.  應提交製造過程嘅順非專有信息括, for example, 原材料數量, solvents, 反映商業製造嘅代表性批次規模嘅催化劑和試劑, 確定關鍵步驟, 過程控制, 設備和操作條件 (e.g. temperature, 壓力, pH, 和時間).  應以與主要流程相同嘅細節嚟解釋同描述替代過程. 應確定後處理步驟並證明其合理性. 任何支持理由嘅數據都應引用或以3.2.S.2.5提交. Where the APIMF procedure is used, 可指示對APIMF受限部分嘅交叉引用以提供機密信息. 喺呢種情況下, 如果詳細信息在"受限"部件中顯示, 為PD嘅一部分提供嘅信息包括流程圖 (包括分子結構和所有試劑和溶劑) 以及製造過程嘅簡要概述, 特別強調最後嘅步驟, 包括淨化程序. However, 用于無菌API, 應於"打開"部分提供滅菌過程嘅完整驗證數據 (如果冇對最終產品進行進一步滅菌). The following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier. 如ICH Q7同世衛組織技術報告系列所討論, No. 957, Annex 2, 把API起始材料引入製造流程嘅啲係應用GMP要求嘅起點. API起始材料本身需要提出,其選擇需要製造商證明其合理性,並由評估員接受。. 考慮到分子嘅複雜性,應提出API起始材料, API起始材料與最終API嘅接近性, API起始材料作為商用化學品嘅可用性以及對API起始材料嘅質素控制. 理由應記錄在檔案中,並可供NAFDAC GMP檢查員審查. 喺API起始材料係一個複雜嘅分子,並且只有最少數量嘅合成步驟由最終API, 應提出另一個稱為合成起始材料的分子,申請人有理由選擇. 合成起始材料定義製造過程中要喺應用程序中描述API嘅起點. 申請人應提出並證明哪些物質應被視為合成的起始材料 (有關進一步指導,請參閱第3.2.S.2.3節). 喺透過發酵獲得API嘅前體嘅情況下, 或植物或動物起源, 呢種分子可以被認為係API起始材料,無論複雜性如何. 在特殊情況下,可接受一步合成, for example, 其中API起始材料由CEP覆蓋, 或API起始材料係透過喺世衛組織規劃嘅藥物資格預審程序中透過APIMF或API資格預審程序接受嘅API, 抑或当API嘅結構如此簡單,一步合成可以合理, e.g. 埃瑟姆丁醇或乙酰胺. 除了根據ICH M4Q對製造流程嘅詳細說明, 材料回收, if any, 應詳細描述它們被引入到流程中嘅步驟. 應充分控制恢復操作,使雜質水平不會隨著時間的推移而增加. 用于溶劑嘅恢復, 任何加工,以提高回收溶劑嘅質素應描述. 關於過濾嘅回收 (母親酒) 獲得第二作物, 應提供母酒最大持有時間嘅信息,以及可回收材料嘅最大次數. 應提供雜質水平數據,以證明過濾油的回收合理性. 如果一個API製造商正在使用多個製造站點, 應提供表格形式嘅綜合列表,比較每個站點嘅流程並突出顯示任何差異. 製造中使用嘅所有溶劑 (包括淨化和/或結晶步驟(s)) 應明確識別. 最後步驟中使用的溶劑應是高純度. 不建議在淨化和/或結晶的最後步驟中使用回收溶劑; however, 提供足夠緊嘅數據以證明回收嘅溶劑符合ICH Q7中概述嘅適當標準時,其使用係合理嘅。. 已識別多態性或無定形形式嘅地方, 應說明合成產生嘅表單. 粒子大小被視為關鍵屬性嘅地方 (詳情請參閱3.2.S.3.1) 粒子大小縮小方法(s) (e.g. 銑削或微化) 應描述. 應為使用替代製造工藝提供理由. 替代流程嘅解釋應與主要流程嘅詳細程度相同. 應證明,替代流程獲得嘅批次與主要流程獲得嘅雜質配置文件相同. 如果獲得嘅雜質配置文件不同,則應根據S.3.2中描述嘅要求證明該配置文件係可以接受嘅. 提供試點規模製造嘅信息係可以接受嘅, 只要它代表生產規模,並根據NAFDAC變異指南嘅要求立即向NAFDAC報告規模. 3.2. S.2.3材料控制 (name, manufacturer) 用于制造API嘅材料 (e.g. 原料, starting materials, solvents, reagents, 催化劑) 應列出識別在此過程中使用每個材料嘅位置. 應提供有關呢啲材料嘅質素同控制嘅信息. 應提供表明材料符合其預期用途嘅標準嘅信息, as appropriate (details in 3.2.A.2). Where the APIMF procedure is used, 對APIMF嘅受限部分嘅交叉引用被認為足以滿足本節. The following requirements apply to the fourth option for submission of API information, where full details are provided in the dossier. API起始材料應具有完全的特徵,並提出適當的規格並說明理由, including, at a minimum, 標識控件, assay, 雜質含量和材料的任何任何其他關鍵屬性. 對於每個API起始材料, 生產基地嘅名S.2製造he manufacturer(s) 應指示. 應向每家製造商提供API起始材料嘅準備簡要說明, 包括溶劑, 使用嘅催化劑同試劑. 應為適用於來自所有來源嘅材料嘅起始材料提出一套單一嘅規格. API起始材料製造商嘅任何未來更改, 應通知準備模式或規格. 如第3.2.S.2節所述,有時可能需要定義合成的起始材料. In general, PD中描述嘅合成嘅啟動材料應該: a)            最終API中間體之前成為一個或多個合成步驟緊嘅合成前體. 酸, 基地, 鹽, API嘅酯同類似衍生物, 以及一個單一嘅阿尼蒂默API嘅種族鎂侶, 唔被視為最終中間體; b)            係一個良好嘅特點, 孤立和純化的物質,其結構完全闡明,包括其立體化學 (when applicable); c)            具有定義明確嘅規範,其中包括一個或多個特定嘅身份測試和測試,以及檢測和指定嘅限制, 未指定和總雜質; d)            作為一個重要嘅結構片段納入API嘅結構. 合成材料使用嘅規格副本, 提取,標籤下要求適用於提交API信息嘅第四个選項其中完整嘅細節喺檔案中提供廠使用嘅材料. 應提供合成起始材料分析證書. 應喺QOS-PD中提供有關起始材料嘅信息摘要. 應考慮和討論合成成最終API的起始材料的雜質的結轉. 應提供證明信,確認API同用于製造API嘅起始材料同試劑冇傳播動物海綿狀腦病劑的風險. 可用時,CEP可證明符合關於可傳播海綿狀腦病的建議 (謝) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1. Reference documents: ICH試劑2. S.2.4關鍵步驟和中間體的控制 (name, manufacturer) Critical steps: 測試和驗收標準 (理由包括實驗數據) 喺製造工藝3.2.S.2中肯定嘅關鍵步驟執行,以確保流程得到控制. Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, 除了與申請人相關嘅信息. The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier. 應確定關鍵步驟. 呢啲可以包括: 去除或引入顯著雜質的步驟; 引入基本分子結構元素(如手性中心或導致重大化學轉化)的步驟; 對可能與固體劑型使用相關嘅API嘅固態屬性同同質性有影響嘅步驟. 應提供隔離中間體嘅規範,並應包括身份測試和驗收標準, 純度同測定, where applicable. Reference documents: ICH Q6A. 3.2. S.2.5過程驗證和/或評估 (name, manufacturer) 應包括無菌處理和滅菌的工藝驗證和/或評估研究. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD. The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier. 預期所有API嘅製造流程都得到適當控制. 如果API係無菌製備嘅,則下列要求適用於提交API信息嘅第四个選項,其中喺檔案中提供了全部詳細信息明. 替代過程應合理並描述 (請參閱3.2.S.2.2中預期詳細信息級別嘅指南). 3.2. S.2.6製造工藝開發 (name, manufacturer) 應說明和討論用于生產比較生物可用性或生物豁免嘅API嘅製造工藝和/或製造場地嘅重大變化, 放大縮小字體功能放大縮小字體功能, pilot, and, if available, 生產規模批次.  應參考該科提供的API數據 3.2. S.4.4. Where the APIMF procedure is used, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD. 3.2. S.3特徵化 (name, manufacturer) 3.2. S.3.1結構同其他特徵嘅闡明 (name, manufacturer) 基於結構嘅確認, e.g. 應提供合成路線和光譜分析. 信息,如同位素主義嘅潛力, 立體化學嘅鑑定, 或形成多態性的潛力也應包括在內. 結構闡明PD應包括質素保證 (Qa) 光譜嘅認證副本, 峰值分配同對所執行研究數據嘅詳細解釋,以闡明同/或確認API嘅結構對APIMF受限部分嘅交叉引用被認為足以滿足PD嘅部分官方認可嘅藥典中未描述嘅ABI, 為闡明和/或確認化學結構而進行的研究通常包括元素分析, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (核磁共振) 同質素光譜 (MS) studies. 其他測試可能包括X射線粉末衍射 (XRPD) 同微分掃描熱量計度 (DSC). 對於官方認可嘅藥典中描述嘅API,通常足以由每個擬議製造商提供API嘅IPI嘅IR頻譜副本(s) 與官方認可嘅藥典參考標準同時運行. 有關可接受嘅參考標準或材料嘅詳細信息,請參閱第3.2.S.5節.  当API係手性化學時,等位主義/立體化學, 應具體說明在比較生物研究中是否使用了特定的立體異構體或立體異構體混合物, 以及應提供有關喺FPP中使用嘅API嘅立體異構體嘅信息. 立體異構症存在嘅地方, 應討論製造過程可能導致嘅異構體以及引入性嘅步驟. 應確定API與比較產品中API嘅同位素組成相同. 應提供關於同位素混合物或單一同體體嘅物理同化學性質嘅信息, as appropriate. API規範應包括一項測試,以確保同位素標識同純度. 同位素混合物中同構體嘅相互轉換潛力, 或種族化嘅單一嘅謎語應該討論. 当API嘅單個電工因非藥典API而索賠時, 應提供唔啱稱中心絕對配置嘅明確證明, 如由單個晶體的X射線確定. 如果, 基於API嘅結構, 冇立體主義嘅潛力, 它足以包括一個聲明,以呢種效果. 多態性好多ABI可以喺固態中以不同嘅物理形式存在. 多態性被描述為API作為兩個或兩個以上晶體相存在嘅能力,呢啲晶體相位對晶格中嘅分子有不同嘅排列同/或構象. 無定形固體由分子的無序排列組成,不具有可區分的晶格. 溶劑是晶體形式,含有溶劑的口感或非收縮量. 如果合併溶劑是水,溶劑也通常被稱為水合物. 同一化合物嘅多態性形式喺內部固態結構中不同,, therefore, 可能具有不同的化學和物理性質, 包括包裝, 熱力學, 光譜, 動力學, 面間同機械特性. 呢啲屬性可直接影響API可處理性, 藥品嘅可製造性和產品質量及性能, 包括穩定性, 溶解和生物可用性. 多態形式的意外外觀或消失可能導致嚴重的藥物後果. 打算向NAFDAC同API製造商註冊產品嘅申請人應充分了解所用和/或生產嘅API嘅多態性. 關於多態性嘅信息可以來自科學文獻, 專利, 匯編或其使用亞太基金基金程序嘅地方為問題, e.g. 對於唔係BCS高可溶性嘅API. 喺冇已公佈嘅數據嘅情況下,ABI唔係BSC高度可溶性嘅, 多態性篩選將係必要嘅,以確定API是否可以存在於一個以上嘅晶體形式. 多態性篩選通常通過使用不同溶劑和條件的結晶研究完成. 好多方法可用于描述API嘅多態性形式. 单晶X射綫衍射嘅非等效結構演示目前被視為多態性嘅明確證據. XRPD都可用于提供多態性嘅明確證明. 其他方法, 包括顯微鏡, 熱分析 (e.g. DSC, 熱重力分析和熱階段顯微鏡) 同光譜 (e.g. IR, 拉曼, 同固態核磁共振 (斯尼姆尔)) 有助於進一步描述多態性形式. 多態性係一個問題, ABI的申請人或製造商應證明採用合適的方法, 能夠區分不同嘅多態性, 可供他們使用. 決策樹 4 ICH Q6A可用于必要嘅篩查同 4(2) 可用于調查不同嘅多態性形式是否具有可能影響性能嘅不同屬性, FPP嘅生物可用性和穩定性,並決定是否喺API發佈和存儲時對首選多態性進行監測. 邊度有首選嘅多態性, 驗收標準應納入API規範,以確保商業材料與比較生物可用性或生物豁免研究中使用的API批次的多態等效性. 應提供上述方法用于比較生物可用性或生物豁免研究嘅API批次嘅多態性特徵. 用于控制多態性形態嘅方法應證明係針對首選形式嘅特殊性. 多態性也可以包括解脫或水化產品 (都被稱為偽多態性). 如果API以已解決的形式使用, 應提供以下信息: ·3.2.S.2.4中無溶劑API嘅規格, 如果該化合物係合成前體; ·溶解API嘅規格,包括適當限DscPI與溶劑嘅重量比 (與數據,以支持建議嘅限制); ·用于準備安撫嘅方法嘅描述 3.2. S.2.2. 非BCS高可溶性包含喺固體FP中嘅AIP嘅粒子大小分布, 或含有未溶解API的液體FPP, 材料的粒子大小分佈可能對FPP的體外和/或體內行為產生影響. 顆粒大小分佈在劑量形式性能方面也很重要 (e.g. 提供吸入產品), 實現低劑量片劑中內容的均勻性 (e.g. 2 毫克或更少), 眼科製備所需嘅平滑性同懸架嘅穩定性. 如果粒子大小分佈係一個重要參數 (e.g. 如上述情況), 應提供幾批API嘅調查結果, 包括批次嘅表徵 (es) used in the comparative bioavailability or biowaiver studies. API規格應包括粒子大小分佈的控制,以確保與批次中的材料一致 (es) 用于比較生物可用性和生物豁免研究 (e.g. d10嘅限制, d50同d90). 標準應從統計學上確定, 基紫外對測試結果嘅標準偏差. 為說明性目的提供以下示例,作為粒子大小分佈限制的可能接受標準: ▪d10唔超過 (NMT) 10% of total volume less than X µm; ▪ d50 XX μm-x μm; ▪D90唔低於 (西北) 90% of total volume less 總體積小於Xμm其他控制可以被認為係可以接受嘅, 如果科學合理嘅話. Reference documents: ICH Q6A. 3.2. S.3.2雜質 (name, manufacturer) 應提供有關雜質嘅信息. 關於雜質控制原則嘅詳細信息 (e.g. reporting, identification and qualification) ICH Q3A中概述, Q3B同Q3C雜質指南 (10–12。). 下文概述咗關於國際信息發展準則中討論的一些內容嘅其他信息. 無論是否聲稱藥典標準, 應討論合成產生的潛在和實際雜質, API嘅製造或降解. 應該包括啟動材料, by-products, intermediates, 手性雜質和降解產品,應包括化學名稱, 雜質的結構和來源. 藥典API嘅討論不應局限於API專著中指定嘅雜質. QOS-PD糢闆中嘅表應用於匯總有關AP更新和流程相關雜質嘅信息. 在QOSPD中, 術語"原產地"係指如何以及在何處引入雜質 (e.g. "合成中間從步驟 4 合成"或"由于步驟重新排列而產生嘅潛在次要產品" 6 合成ŋ). 如果雜質係API嘅新陳代謝物,都應說明. 報告嘅ICH閾值, identification (用于設置個人未知雜質嘅限制) 同資格係根據潛在嘅接觸雜質決定嘅, e.g. 按每日最大劑量 (Mdd) 的API. 對於具有不同MDD值嘅多種劑量形式同優勢嘅ABI, 必須考慮每個演示文稿嘅閾值同相應嘅控制,以確保解決雜質帶嚟嘅風險. 通常係透過使用最高潛力嘅每日MDD實現嘅, 而唔係維護劑量. 對於父產品,API嘅最大鐘頭劑量都應包括在內. 承認半合成來源嘅ABI唔屬於ICH雜質指南嘅範圍. However, 取決於API嘅性質同化學改性步驟嘅程度, 有關控制雜質的原則 (e.g. reporting, identification and qualification) 可擴展到適用於半合成來源嘅ABI. As an illustrative example, 其前體分子來自發酵過程或植物或動物起源的天然產物的API, 隨後經歷咗幾次化學反應, 一般屬於ICH雜質指南嘅範圍, 而一個API,其唯一嘅化學步驟係形成由發酵產品嘅鹽一般唔會. 據瞭解,呢啲類型嘅API有一定的自由度. 藥典承認,ABI可以由各種來源獲得,因此可以含有專著開發過程中未考慮嘅雜質. Furthermore, 生產或來源嘅改變可能導致額外嘅雜質,而呢啲雜質不受官方編目專著嘅充分控制. As a result, 每個PD報告身份同資格認證生嘅潛在雜質(s) 合成. 由於呢啲原因,ICH限制未指明嘅雜質 (e.g. NMT 0.10% or 1.0 毫克每日攝入量 (以較低者為準) 對於具有MDD≤的API 2 g/天) 一般建議, 而唔係官方簡編專著中可能出現嘅未指明雜質嘅一般限制, 可能高於適用嘅ICH限制. 雜質資格ICH雜質指南應諮詢雜質資格選項. 喺官方認可嘅藥典中肯定雜質嘅限值通常被認為係合格嘅. 以下係現有ABI中雜質資格嘅附加選項: 透過將現有API中發現嘅雜質測試結果與使用相同驗證嘅創新產品中觀察到嘅雜質測試D果進行比較,可以接受現有API中存在嘅雜質限制, 穩定性指示分析程序 (e.g. comparative (高性能液體色譜 (HPLC) studies). 如果冇創新產品樣品, 雜質配置文件都可以與具有相同管理路線同類似特徵嘅不同資格預審FPP進行比較 (e.g. 平板電腦與膠囊). 建議對可比樣品進行研究。 (e.g. 類似年齡嘅樣本) 獲得雜質配置文件嘅有意義嘅比較. 創新者或合格定嘅FPP加速或強調存儲條件下嘅研究產生嘅雜質水平被認為係不可接受嘅/合格嘅. 如果現有API中嘅雜質素反映咗喺創新者尼姆特觀察到嘅水平或資格預審FPP中觀察到嘅雜質,則現有API中存在嘅指定雜質將被視為合格.  制定驗收標準的依據應提供確定雜質驗收標準的依據. 係透過考慮與API相關嘅雜質嘅識別和鑑定閾值而建立嘅 (e.g. starting materials, by-products, intermediates, 人性雜質或降解產物) 同工藝相關雜質嘅濃度限制 (e.g. 殘留溶劑) 根據適用嘅ICH準則 (e.g. Q3A, Q3C). 合格級別應被視為允許嘅最大限制. However, 一般唔鼓勵過實際製造工藝能力寬得多嘅限制. For this reason, 驗收標準仲考慮到每個製造商喺幾批API中發現嘅實際雜質水平, 包括用于比較生物可用性或生物豁免研究嘅批次中發現嘅水平. 報告定量測試結果時, 應提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合". 已測試大量批次緊嘅情況下,可以用一系列分析結果匯總所有測試批次嘅結果。. 如果官方簡編專著中指定咗不受擬議常規內部分析程序控制嘅雜質, 應提供將其排除喺常規分析之外嘅理由 (e.g. 蕨雜質D, 《國際藥典》中列出嘅E同F (Ph.Int.) 專著唔係製造商X使用嘅擬議合成路線嘅潛在雜質"). S.2.2不能提供可接受的理由,則應證明常規內部方法能夠在可接受的水平上分離和檢測官方編目專著中規定的雜質 (e.g. 0.10%). 如果無法執行此類演示, 應在最近幾批中應用藥典方法進行一次性研究,以證明藥典中所列雜質的缺失. ICH II類溶劑(s) 如果提供適當理由,則喺製造過程嘅最後一步之前使用嘅API規範可免於常規控制. 提交嘅結果顯示少於 10% ICH Q3C農副產品I) of the solvent(s) 連續三個生產規模批次或連續六個試點規模批次嘅API或合適嘅中間體將被視為可接受嘅理由. 在此過程中使用嘅最後一步溶劑應始終喺最終嘅API中進行常規控制. 有關可接受嘅剩餘溶劑限制嘅指導,請參閱ICH Q3C. 三甲胺殘留限值 (茶) 一係係 320 基於ICH Q3C選項I或 3.2 毫克/日嘅基礎上,允許每日暴露 (Pde). 缺乏已知, 已建立劇毒雜質 (遺傳毒性) 應討論在此過程中使用或作為子產品形成,並建議適當的限制. 應適當參考現有指南嚟證明呢啲限制嘅合理性 (e.g. 歐洲、歐洲、中國/歐洲、中國/ 251344/2006 (13) 或美國自由貿易協定行業指南. 藥物物質和產品中嘅基因毒性和致癌雜質, 推薦的方法) 或通過提供實驗安全數據或喺同行評審嘅期刊中發佈數據. 製造過程中使用嘅金屬催化劑殘留物,並被確定為成批嘅API,應控制喺規格中. 此要求不適用於作為藥物物質嘅特登成分嘅金屬 (如鹽的計數器離子) 或在FPP中用作藥物輔料的金屬 (e.g. 氧化鐵顏料). 金屬催化劑或金屬試劑殘留物規格限制指南 (歐洲、中國/瑞士國際中心/4446/2000) 或任何等研究法可用于解決此問題. 該要求通常不適用於GMP更恰當地處理嘅無關金屬污染物, 良好的分銷做法 (Gdp) 或任何其他相關的質量規定,如在公認的藥典專著中對來自製造設備和環境的金屬污染進行重金屬測試. Reference documents: ICH Q6A, Q3A, Q3C. 3.2. S.4 API控制 (name, manufacturer) 3.2. S.4.1規格 (name, manufacturer) 應提供API嘅規範. As defined in ICH’s Q6A guideline (6), a specification is: ''測試列表, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. "符合規範"係指API同/或FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. 規格係關鍵嘅質量標準,由製造商提出並證明其合理性,並經監管機構批准。 API規範嘅副本, dated and signed by authorized personnel (e.g. the person in charge of the quality control or quality assurance department) should be provided in the PD, 包括每個API製造商以及FPP製造商嘅規格. FPP製造商嘅API規範應根據標題的QOS-PD糢闆中嘅表進行匯總: 測試, acceptance criteria and analytical procedures (包括類型, sources and versions for the methods). ▪申請人申報嘅標準可以係官方認可嘅簡編標準 (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard. ▪規範參考號同版本 (e.g. revision number and/or date) should be provided for version control purposes. 分析程序▪, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC或激光衍射), the source refers to the origin of the analytical procedure (e.g. BP, JP, and Ph.Eur. Ph.Int., USP或內部) and the version (e.g. 代碼號/版本/日期) should be provided for version control purposes. 喺有多個API製造商嘅情況下, FPP製造商嘅API規範應係單個編譯嘅規範集,每個製造商嘅規格相同. 在規範中為單個參數規定多個驗收標準和/或分析方法,並聲明"用于製造商A嘅API"係可以接受嘅 (e.g. 喺殘留溶劑嘅情況下). 任何非常規測試都應明確識別為此類測試,並結合關於非常規測試頻率嘅建議進行合理性. ICH Q6A指南 (6) 概述一些通用同特定嘅ABI測試和標準嘅建議. Reference documents: ICH Q6A, Q3A, Q3C同官方認可嘅藥典. 3.2. S.4.2分析程序 (name, manufacturer) 應提供用于測試API嘅分析程序. 用于生成PD中提供嘅測試結果嘅內部分析程序嘅副本, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. 除非修改,否則冇必要提供官方認可嘅簡編分析起始材料bles for summarizing a number of the different analytical procedures and validation information (e.g. HPLC檢測/雜質方法, 氣色譜 (Gc) 方法) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). 呢啲表應用於總結FPP製造商嘅內部分析程序,以確定殘留溶劑, assay and purity of the API, 在QOS-PD第2.3.S.4.2節. 用于喺PD中生成檢測和純度數據嘅其他方法可以總結為2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. 除非進行了修改,否則無需總結官方認可嘅簡編方法. 雖然HPLC通常被認為係肯定與API相關嘅雜質嘅首選方法, 其他色譜方法,如GC和薄層色譜 (薄) 如果經過適當驗證,都可以使用. 用于確定相關物質, 參考標準通常應可用于每個已識別嘅雜質, 特別是那些已知有毒嘅同雜質嘅濃度應該根據自己嘅參考標準進行量化. 唔純度標準可由藥典中獲取 (單個雜質或分辨率混合物), 來自商業來源或內部準備. 使用API作為外部標準嚟估計雜質水平被認為係可以接受嘅, 只要呢啲雜質嘅響應系數足夠接近API嘅響應系數, i.e. 之間 80 and 120%. 如果響應因子超出此範圍,使用API仍是可以接受嘅, 如果應用更正因子. 應為內部方法提供支持修正因子計算嘅數據. 未指明嘅雜質可以使用API溶液作為參考標準進行量化,其濃度與針對個別未指定雜質嘅限值相對應 (e.g. 0.10%). Ph.Int 中相關物質嘅測試. 拉米武丁專著作為一個典型例子. 系統適宜性測試 (SS) 代表該方法嘅一個組成部分,用于確保所選色譜系統嘅滿意性能. 作為最低限度, HPLC同GC純度方法應包括用于分辨率和可重複性嘅SST. 用于HPLC控制API相關雜質嘅方法, 通常係使用API嘅解決方案完成嘅,其濃度與未指定雜質嘅限制相對應. 一般建議解決兩個最接近嘅山峰. However, 如果合理,可以使用替代峰嘅選擇 (e.g. 有毒雜質嘅選擇). In accordance with the Ph.Int. 關於分析方法嘅部分可重複性測試應包括可接受嘅複製注射次數. HPLC檢測方法應包括可重複性嘅SST,此外仲包括峰值唔啱稱, 理論板或分辨率. 對於TLC方法, SST應驗證系統分離和檢測分析器嘅能力(s) (e.g. 透過喺與未指定雜質限制相對應嘅濃度的應用與API對應嘅啲). Reference documents: ICH Q2, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.4.3分析程序嘅驗證 (name, manufacturer) Analytical validation information, 包括用于測試API嘅分析程序嘅實驗數據, should be provided. 應提供用于生成PD中提供嘅測試結果嘅分析程序嘅驗證報告嘅副本, as well as those proposed for routine testing of the API by the FPP manufacturer. Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods, GC方法) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). 呢啲表應用於匯總FPP製造商用于肯定殘留溶劑嘅分析程序嘅驗證信息, assay and purity of the API, 在QOSPD第2.3.S.4.3節. 用于喺PD中生成檢測和純度數據嘅其他方法嘅驗證數據可以用2.3.S.4.4嚟概括 (c) or 2.3.S.7.3 (b) of the QOS-PD. As recognized by regulatory authorities and pharmacopoeias themselves, verification of compendia methods can be necessary. The compendia methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. 同一API或FPP嘅不同來源可能包含專著開發過程中未考慮嘅雜質和/或以及FPP製造商提議對AP進行常規測試嘅測試API嘅雜質配置文件(s). 一般來說,匯編API測定方法不需要驗證. However, 如果本匯編專著中未指定任何潛在雜質,應證明特定匯編測定方法的特異性. 如果使用官方認可嘅簡體方法嚟控制專著中未指定嘅與API相關嘅雜質, 預計對API嘅檢測和純度充分驗證. If an officially recognized compendia standard is claimed and an in-house method is used in lieu of the compendia method (或2.3.S.7.3測QOS-PD), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. 對於雜質方法, 所分析的樣品應在相當于其規格限制的濃度下含有雜質的原料藥. Reference documents: ICH Q2. 3.2. S.4.4 批次分析 (name, manufacturer) 應提供批次解同批次分析結果. 所提供的信息應包括批號, batch size, 用于度生物利用度或生物量研究的相關原料藥批次嘅日期同生產地點, 臨床前和臨床數據 (if relevant), stability, pilot, 擴大規模同, if available, production-scale batches. 呢啲數據用于建立API質素嘅規格同評估一致性. 分析結果應至少由API每個擬議製造地點嘅兩批至少試點規模提供,並應包括該批(es) used in the comparative bioavailability or biowaiver studies. 試驗規模批次應採用完全代表同模擬應用於完整生產規模批次嘅程序製造. 分析證書副本, 都來自API製造商(s) 同FPP製造商, 應提供剖析批次,並應確定負責生成測試結果的任何公司. FPP製造商嘅測試結果應喺QOS-PD中總結. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. A discussion and justification should be provided for any incomplete analyses (e.g. 未根據擬議規範測試嘅結果). Reference documents: ICH Q6A, Q3A, Q3C). 3.2. S.4.5規範嘅理由 (name, manufacturer) 應提供API規範嘅理由. 應討論是否包括某些測試, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendia standard(s). 如果官方認可嘅簡編方法已被修改或替換,則討論修改或替換方法(s) should be included. The justification for certain tests, 分析程序和驗收標準可能已喺PD嘅其他部分討論過 (e.g. 用于雜質或顆粒大小分布) 唔需要喺呢度重複, although a cross-reference should be provided. Reference documents: ICH Q6A, Q3A, Q3C, 同官方認可嘅藥典. 3.2. S.5 Reference standards or materials (name, manufacturer) 應提供有關用于API測試嘅參考標準或參考材料嘅信息. 應提供有關參考標準嘅信息(s) 用于喺PD中生成數據, 以及FPP製造商喺常規API同FPP測試中使用嘅測試. 源(s) 應提供用于API測試嘅參考標準或材料 (e.g. 用于識別嘅, 純度同測定測試). 這些可以歸類為主要或次要參考標準. 應從官方認可的藥典來源獲得適當的初級參考標準 (e.g. BP, JP, and Ph.Eur. Ph.Int., USP) 一個人存在嘅地方, 同批號應該提供. 如果為API同/或FPP申請藥典標準, 主要參考標準應從該藥典中獲取,當可用. 來自官方認可嘅藥典來源嘅主要參考標準不需要進一步嘅結構闡明. 否則,主要標準可能係已完全具有特徵嘅API嘅一批 (e.g. 由Ir, UV, NMR同質譜 (MS) 分析). 可能需要進一步嘅淨化技術,要材料可作為化學參考標準使用. 化學參考物質的純度要求取決於其預期用途. 建議進行鑑定測試嘅化學參考物質不需要仔細純化,因為該物質中含有小部分雜質,因此通常對測試冇明顯影響。. On the other hand, 用于檢測嘅化學參考物質應具有高度嘅純度 (如 99.5% 在乾燥或水/溶劑免費的基礎上). 必須申報主要參考標準嘅絕對內容,並遵循該方案: 100% 減去有機雜質 (透過檢測程序量化, e.g. HPLC或DSC) 減去無機雜質減去乾燥損失的揮發性雜質 (或含水量減去殘留溶劑). 輔助 (or in-house) 參考標準可以透過建立它對一個合適的初級參考標準使用, e.g. 同時提供主要同次要參考標準嘅IR清晰副本,並提供其分析證書, 包括根據主要參考標準肯定嘅檢測. 二級參考標準通常針對其預期目的進行特徵和評估,除常規測試中使用嘅程序外,仲具有其他程序 (e.g. 如果喺唔用于常規目的嘅額外淨化過程中使用咗額外嘅溶劑). 通此外指定雜質制定參考標準. 有關其他指導,請參閱3.2.S.4.2. Reference documents: ICH Q6A, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.6集裝箱關閉系統 (name, manufacturer) 集裝箱關閉系統嘅描述(s) should be provided, 包括每個主要包裝部件嘅構建材料嘅身份, 及其規格. The specifications should include description and identification (同關鍵尺寸與圖紙, where appropriate). Non-compendia methods (with validation) should be included, where appropriate.  For non-functional secondary packaging components (e.g. 嗰啲唔提供額外保護嘅人), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.  是否合適,應討論, for example, choice of materials, protection from moisture and light, 建築材料與API嘅兼容性, including sorption to container and leaching, 和/或建築材料的安全性. 應徵詢世衛組織關於藥品包裝嘅準則同官方認可嘅藥典,以徵求關於API包裝信息嘅建議. Primary packaging components are those that are in direct contact with the API or FPP. 應提供主要包裝部件嘅規格,並應包括特定嘅標識測試 (e.g. IR). 應提供API二次包裝上應用嘅標籤副本,並應包括存儲條件. In addition, API製造商嘅名稱同地址應喺容器上註出, 無論API派過程中是否在任何階段重新標記. 2. S.7 Stability (name, manufacturer) 3.2. S.7.1穩定性摘要和結論 (name, manufacturer) ThQ3Aypes of studies conducted, protocols used, and the results of the studies should be summarized. 摘要應包括結果, for example, 從強迫退化研究和壓力條件, 以及關於儲存條件和重新測試日期或保質期的結論, as appropriate. The WHO guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs. As outlined in the WHO stability guidelines, the purpose of stability testing is to: “provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light.” The tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (e.g. conditions, testing parameters, conclusions and commitments). Stress Testing As outlined in the ICH Q1A guidance document, API嘅壓力測試可以幫助識別可能退化嘅產品, 反過來, 有助於建立分子嘅降解途徑和內在穩定性,驗證所用分析程序嘅穩定性指示能力. 壓力測試嘅性質將取決於單個API同所涉及嘅FPP類型. 壓力測試可在單批API上進行. 有關典型應力條件嘅例子,請參閱部分 2.1.2 of WHO Technical Report Series, No. 953, Annex 2, 以及以及, "活性藥物成分降解路徑嘅典型研究", in: WHO Technical Report Series, No. 929, Annex 5, 表A1. 壓力測試嘅目的唔係完全降低API,而是導致退化喺好細嘅程度, 與未降級嘅API相比,透過檢測通常損失API 10-30%. 選擇此目標,以便發生一些降級, 但不足以生成二級產品. 因此,当API特別易受到特定壓力因素的影響時,條件和持續時間可能需要變化. 在完全沒有降解產品後 10 在特定壓力條件下,API被認為係穩定嘅天數. QOS-PD糢闆中嘅表格應用於匯總應力測試結果,並應包括治療條件 (e.g. temperatures, 相對濕度, 解決方案和持續時間的集中度) 同各種測試參數嘅觀測結果 (e.g. assay, degradation products). The discussion of results should highlight whether mass balance was observed. Photo stability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies when the container-closure system is shown to be light protective. When available it is acceptable to provide the relevant data published in the scientific literature (including, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways. Accelerated and long-term testing Available information on the stability of the API under accelerated and long-term storage conditions should be provided, including information in the public domain or obtained from scientific literature. The source of the information should be identified. The required long-term storage conditions for APIs is 30 ºC ± 2 ºC/75% ± 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the Nigerian environmental conditions (i.e. Zone IVB). 替代條件應有適當證據作為證據, 可能包括文獻參考或內部研究, 演示存儲在 30 oC唔適合API. 用于用于儲存喺冰箱中嘅API同用于存放喺冰櫃中嘅API, refer to the WHO stability guidelines in the WHO Technical Report Series, No. 953, Annex 2. 旨在存儲低於+20°C嘅API應按案例處理. 建立重新測試期間, 數據應至少提供三批至少試點規模. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD. The information on the stability studies should include details such as storage conditions, batch number, batch size, container-closure system and completed (and proposed) test intervals. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. Ranges of analytical results where relevant and any trends that were observed should be included. For quantitative tests (e.g. individual and total degradation product tests and assay tests), it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. Where methods are different fr女士 those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided. The minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1. Table 1 Minimum data required at the time of submitting the dossier Storage (ºC) temperature Relative humidity (%) Minimum time period (months) Accelerated 40 ± 2 75 ± 5 6 Intermediate          –a       –a Long-term 30 ± 2    65 ± 5 or 75 ± 5       6 aWhere long-term conditions are 30 ºC ± 2 ºC/65% ± 5% RH or 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, No. 953, Annex 2 for further information regarding the storage conditions, container-closure system, test specifications and testing frequency. Proposed storage statement and retest period A storage statement should be established for display on the label, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies. A retest period should be derived from the stability information and should be displayed on the container label. After this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. 在 30 days). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period. Limited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (e.g. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, 提議嘅複試期可能長達長期數據涵蓋嘅兩倍, but should not exceed the long-term data by more than 12 months). Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, Annex 2. 3.2. S.7.2批准後穩定性協議和穩定性承諾 (name, Manufacturer) The post-approval stability protocol and stability commitment should be provided. Primary stability study commitment When the available long-term stability data on primary batches do not cover the proposed retest period granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant. Commitment stability studies The long-term stability studies for the commitment batches should be conducted through the proposed retest period on at least three production batches. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier. The stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters: Number of batch(es) and different batch sizes, if applicable; Relevant physical, 化學, microbiological and biological test methods; Acceptance criteria; Reference to test methods; Description of the container-closure system(s); Testing frequency; Description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);   Other applicable parameters specific to the API. Ongoing stability studies The stability of the API should be monitored according to a continuous and appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches. At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier. Refer to seUvion 2.1.11 of WHO Technical Report Series, No. 953, Annex 2, for further information on ongoing stability studies. Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified. Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, No. 953, Annex 2. 3.2. S.7.3 Stability data (name, manufacturer) Results of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included. The actual stability results used to support the proposed retest period should be included in the dossier. For quantitative tests (e.g. individual and total degradation product tests and assay tests) it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms”. Reference documents: ICH Q1A, Q1B, Q1D, Q1E, Q2 WHO Technical Report Series, No. 953, Annex 2. 3.2. P Drug product (or finished pharmaceutical product (FPP))  3.2. P.1 Description and composition of the FPP (name, dosage form) A description of the FPP and its composition should be provided. The information provided should include, for example: Description of the dosage form The description of the FPP should include the physical description, available strengths, release mechanism (e.g. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, e.g.  “The proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with ‘50’ on one side and a break-line on the other side. The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, debossed with ‘100’ on one side and plain on the other side.” Composition, i.e. list of all components of the dosage form, and their amount on a per unit basis (including overages, if any), the function of the components, and a reference to their quality standards (e.g. compendia monographs or manufacturer’s specifications).  The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (e.g. coatings) should be included in the tables where applicable. All components used in the manufacturing process should be listed, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. “1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride”). All overages should be clearly indicated (e.g. “contains 2% overage of the API to compensate for manufacturing losses”). The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) and, if applicable, their grades (e.g. “microcrystalline cellulose S.5 參考標準或材料l characteristics (e.g. lyophilized, micronized, solubilized or emulsified). The function of each component (e.g. diluent or filler, binder, disintegrate, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated. The qualitative composition, including solvents, should be provided for all proprietary components or blends (e.g. capsule shells, colouring, blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (e.g. summary of product characteristics, labelling and package leaflet). Description of accompanying reconstitution diluent(s) For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another product dossier with NAFDAC, a brief description of the reconstitution diluents(s) should be provided. For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another product dossier with NAFDAC, information on the diluent(s) should be provided in a separate FPP portion (“3.2.P”), as appropriate.  Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable The container-closure used for the FPP (and accompanying reconstitution diluent, if applicable) should be briefly described, with further details provided under 3.2.P.7  Container-closure system, e.g. “The product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminum foil unit dose blisters (in packages of 100s) (cards of 5 × 2, 10 cards per package).”  Reference documents: ICH Q6A (6). 3.2. P.2 Pharmaceutical development (name, dosage form) The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier. Pharmaceutical development information should include, at a minimum: the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, for example, the route of administration, dosage form, bioavailability, strength and stability; identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality; discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality; discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner. These features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8). For a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 of WHO Technical Report Series, No. 929, Annex 5 (21). Reference documents: ICH Q6A, Q8, Q9, Q10. 3.2. P.2.1 Components of the FPP (name, dosage form) 3.2. P.2.1.1 Active pharmaceutical ingredient (name, dosage form) The compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For FDCs, the compatibility of APIs with each other should be discussed. Physicochemical characteristics of the API mayS.7穩定性th the manufacturing capability and the performance of the FPP. Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for registration of fixed-dose combination medicinal products (WHO Technical Report Series, No. 929, Annex 5, 2005). In addition to visual examination, chromatographic results (assay, purity) are required to demonstrate API–API and API–excipient compatibility. In general, API–excipient compatibility is not required to be established for specific excipients when evidence is provided (e.g. in the SmPC or product leaflet) that the excipients are present in the comparator product. 3.2. P.2.1.2 Excipients (name, dosage form) The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions. When choosing excipients those with a compendia monograph are generally preferred and may be required in certain jurisdictions. Other re條件e available for information on acceptable excipients and their concentrations, such as the US Food and Drug Administration (FDA) inactive ingredient guide (IIG) list and the Handbook of pharmaceutical excipients. Use of excipients in concentrations outside established ranges is discouraged and generally requires justification. In addition, available guidelines should be referenced which discuss particular excipients to be avoided, for example azocolourants as listed in the EMA Guideline CPMP/463/00. Other guidance such as the WHO Guidelines on development of paediatric medicines: points to consider in formulation (32) may provide useful general guidance in this regard. Ranges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (e.g. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (e.g. on use of potato or corn starch). Where antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies. Antimicrobial preservatives are discussed in 3.2. P.2.5. 3.2. P.2.2 Finished pharmaceutical product (name, dosage form) 3.2. P.2.2.1 Formulation development (name, dosage form) A brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (i.e. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate. An established multisource product is one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). In addition, a product quality review should be provided as outlined in Appendix 2. The requirements for bioequivalence studies should be taken into consideration, for example, when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (e.g. WHO Technical Report Series, No. 937, Annex 7) should be consulted. Product scoring may be recommended or required, for example, when scoring is specified in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology. If the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (i.e. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for other situations) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. As an illustrative example, the number of units (i.e. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 10 quarters for quadrisect tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (e.g. manually split by hand). The uniformity test on split portions can be demonstrated on a one-time basis and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (e.g. SmPC, labelling and package leaflet) should reflect the presence of a score. If splitting of a tablet is intended for preparation of a paediatric dose a demonstration of content uniformity of tablet fragments may be required. Where relevant, labelling should state that the score line is only to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses. In vitro dissolution or drug release A discussion should be included as to how the development of the formulation relates to development of如果有嘅話issolution method(s) and the generation of the dissolution profile. The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. apparatus, rotation speed and medium) should be provided. Data should also be submitted to demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters. Use of a single point test or a dissolution range should be justified based on the solubility and/ or biopharmaceutical classification of the API. For slower dissolving immediate-release products (e.g. Q = 80% in 90 minutes), a second time point may be warranted (e.g. Q = 60% in 45 minutes). Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro–in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form. For extended-release FPPs, the testing conditions should be set to cover the entire time period of expected 係lease (e.g. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally, the acceptance range at each intermediate test point should not exceed 25% or ± 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1. 3.2. P.2.2.2 Overages (name, dosage form) Any overages in the formulation(s) described in 3.2.P.1 should be justified. Justification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results). Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable. 3.2. P.2.2.3 Physicochemical and biological properties (name, dosage form) Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed. 3.2. P.2.3 Manufacturing process development (name, dosage form) The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified. Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided. 製造工藝之間嘅差異 (es) 應討論用于生產可比較生物可用性或生物豁免批次以及3.2.P.3.3中描述嘅可影響產品性能嘅過程. For products that meet the criteria of an established multisource product, 為咗滿足第2.3節嘅要求, 第2.3節 (b) 應完成檔案和QOS-PD,並提交附錄中概述的產品質量審查 2. 以下指南適用於應完整完成P.2.3節嘅所有其他產品. 選擇特定藥物產品嘅理由 (e.g. Dosage form, 交付系統) should be provided. 選擇製造業嘅科學依據, 應解釋可能影響FPP質素同性能嘅灌裝同包裝流程 (e.g. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (e.g. protection from light or moisture). The scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (e.g. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (Cpp), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8). 3.2. P.2.4 Container-closure system (name, dosage form) The suitability of the container-closure system (described in 3.2.P.7) used for the storage, transportation (shipping) and use of the FPP should be discussed. This discussion should consider, e.g. choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP). Testing requirements to verify the suitability of the container-closure system作為一個說明性嘅例子d on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, including, for example, the following: - glass containers: -       plastic containers: -       rubber/elastomeric closures: Table 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials. Table 2: One-time studies to establish the suitability of the container-closure system contact materials           Solid Products Oral Liquid and Topical Products Sterile Products製造商ophthalmics) Description of any additional × treatmentsa × ×        (sterilization dehydrogenation components) and of the Extraction studies – × × Interaction   studies – (migration/sorption) × × Moisture permeability   材料選擇us防潮和防光t transmission ×b × × × Information sh包括吸附到容器和浸出need to be submitted.  aE.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials.   bNot required if product has been shown to be photostable. For solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (for example (EU) No. 10/2011 (40)) can be considered acceptable. The suitability of the container-closure system used for the storage, 運輸 (航運) and use of any intermediate or in-process products (e.g. premixes or bulk FPP) should also be discussed. A device is required to be included with the container-closure system for administration of oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules), wheneve製造工藝s for multiple doses. In accordance with the Ph.Int. General chapter Liquid preparations for oral use: ‘‘Each dose from a multi-dose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.’’ For a device accompanying a multi-dose container, the results of a study should be provided demonstrating the reproducibility of the device (e.g. consistent delivery of the intended volume), generally at the lowest intended dose. A sample of the device should be provided with Module 1. 3.2. P.2.5 Microbiological attributes (name, dosage form) Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed. Where an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria. As outlined in the WHO stability guidelines (WHO Technical Report Series, No. 953, Annex 2, 2009), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelflife acceptance criteria for preservative content. 3.2. P.2.6 Compatibility (name, dosage form) The compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. precipitation of API in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labelling. Where a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required. Where sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, sub visible particulate matter and extractables fro按照 Ph.Inthould be demonstrated in glass, PVC and polyolefin containers. However, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers. Studies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (i.e. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported). 3.2. P.3 Manufacture (name, dosage form) 3.2. P.3.1 Manufacturer(s) (name, dosage form) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. The facilities involved in the manufacturing, packaging, labelling and testing should be listed. If certain companies are responsible only for specific steps (e.g. manufacturing of an intermediate), this should be clearly indicated (WHO good distribution practices for pharmaceutical products). The list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) involved (including block(s) and unit(s)), rather than the administrative offices. For a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, therefore, the mixture does not fall under the definition of an API. 唯一嘅例外係喺API本身無法存在嘅情況下. Similarly, 用于API嘅混合物, ABI嘅混合被認為係製造最終產品嘅第一酌情步驟的站點應列在本節中. 藥品生產嘅有效製造授權, 以及營銷授權, 應提交以證明產品係按照國家要求註冊或許可嘅 (Mo麻麻.2.2). 對於主要生產步驟嘅每個站點(s) 執行, when applicable, 附上世衛組織主管當局頒發嘅關於國際商務中藥品質量嘅世衛組織型GMP認證 (Module 1, 1.2.2). 喺簽發WHOtype證書嘅國家/地區對產品產生任何差異嘅理由(s) 当提交此申請嘅產品與提供世衛組織類型證書緊嘅國家/地區銷售嘅產品之間存在差異時(s), 有必要提供數據,以支持證書嘅適用性(s) 儘管存在分歧. Depending on the case, 可能需要提供驗證數據,例如製造地點嘅差異, 規格同配方. 請注意,只有細微嘅差異至有可能被受落. 容器標籤嘅差異通常唔需要合理.  其他國家/地區嘅監管情況應提供本產品獲得營銷授權嘅國家/地區上市, 本產品已退出市場和/或此營銷申請已被拒絕, 推遲或撤回 (Module 1, 1.2.2). Reference documents: WHO Technical Report Series, No. 961, Annex 3 和否. 957, Annex 5 3.2. P.3.2批次公式 (name, dosage form) 應提供批量公式,包括用于製造過程嘅劑型嘅所有組件列表, 每批金額, including overages, and a reference to their quality standards. QOS-PD糢闆中嘅表應用於匯總每個建議嘅商業批次大小嘅FPP批次公式,並按每個批次表示每個組件嘅數量, 包括批次總重量或量嘅陳述. 應包括製造過程中使用嘅所有組件, including those that may not be added to every batch (e.g. acid and alkali), those that may be removed during processing (e.g. solvents) and any others (e.g. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (e.g. "1公斤活性成分基數= 1.075 千克活性成分鹽酸化物"). All overages should be clearly indicated (e.g. 朕包含 5 公斤 (對應 2%) overage of the API to compensate for manufacturing losses”). The components should be declared by their proper or common names, quality standards (e.g. BP, JP, and Ph.Eur. Ph.Int., USP, in-house) and, if applicable, their grades (e.g. 迨微晶纖維素NF (PH 102)”) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified). 3.2. P.3.3 製造工藝和工藝控制描述 (name, dosage form) 應顯示流程圖,說明流程嘅步驟,並顯示材料進入流程嘅位置. 過程控制嘅關鍵步驟同啲, 應確定中間測試或最終產品控制. 製造過程嘅敘述性描述, 仲應提供代表所採取步驟順序和生產規模嘅包裝. 應更詳細地描述直接影響產品質素的新工藝或技術和包裝操作. 設備應, 假假地, 按類型識別 (e.g. 翻滾攪拌機, 內聯同質化器) 同工作能力, where relevant.  過程中的步驟應確定適當的過程參數, 如時間, temperature, 或電話. 相關嘅數值可以作為預期範圍呈現. 關鍵步驟嘅數字範圍應喺第3.2.P.3.4節中合理. 在某些情況下, 環境條件 (e.g. 發泡產品嘅低濕度) should be stated. 應說明最終包裝前批量FPP嘅最大持有時間. 如果超過 30 days. 對於無能處理嘅FPP, 散裝物嘅無菌過濾同填充到最終容器最好係連續嘅; 任何持有時間都應該係合理嘅. 關於材料後處理的建議應有理有據. 支持此理由嘅任何數據都應喺本節中引用或歸檔 (3.2.P.3.3). 上述信息應喺QOS-PD糢闆中總結,並應反映擬議商業批次嘅生產情況. 請參閱詞彙表 (section 2) 試點規模和生產規模批次嘅定義. 用于制造無菌產品, 類 (e.g. A, B或C) 每個活動應說明嘅區域 (e.g. 復合, 填充和密封), 以及滅菌參數, 包括設備, 集裝箱關閉系統同碼頭消毒. Reference documents: ICH Q8, Q9, Q10. 3.2. P.3.4關鍵步驟和中間體的控制 (name, dosage form) Critical steps: 應提供測試和驗收標準 (有理有據, including experimental data) 喺製造工藝3.2.P.3.3中肯定嘅關鍵步驟執行, 確保過程得到控制.  Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. 適用嘅流程控制示例包括: 顆粒: moisture (以範圍表示嘅限制), blend uniformity (e.g. 低劑量片劑), 散裝和挖掘密度和顆粒大小分佈; 固體口服產品: 平均重量, weight variation, hardness, 厚度, 易碎性, 和解體檢查定期喺成個壓縮, weight gain during coating; 半固體: viscosity, 均勻, pH; Transdermal dosage forms: API-粘合多態性測, 塗層貼片嘅每個區域嘅重量,無後盾; 計量劑量吸入器: 填充重量或體積, 洩漏測試, 閥門交付; 乾粉吸入器: API-興奮混合的檢測, moisture, 單獨包含的劑量(如膠囊或水泡)的重天化;水分: pH, 比重, 解決方案嘅清晰性; 家長: appearance, 清晰, 填充體積或重量, pH, 過濾器完整性測試, 顆粒物, 安培洩漏測試, 過濾前和/或滅菌前生物負擔測試. Reference documents: ICH Q2, Q6A, Q8, Q9, Q10, WHO Technical Report Series, No. 929, Annex 5. 3.2. P.3.5過程驗證和/或評估 (name, dosage form) 描述, 文檔, 應提供驗證和/或評估研究嘅結果,用于製造過程中嘅關鍵步驟或關鍵檢測 (e.g. 絕育過程或無菌處理或填充的驗證). 病毒安全評估應喺3.2A.2中提供。, if necessary. For products that meet the criteria of an established multisource product, 附錄中概述嘅產品質量審查 2 可以代替以下信息提交. 應為所有其他產品提供以下信息: 1.     過程驗證協議嘅副本, 具體到此FPP, 如下所述; 2.     承諾,連續三個, 本FPP嘅生產規模批次將按照上述協議進行預期驗證. 申請人應提交書面承諾,NAFDAC檢査組資格預審之後緊,這些研究提供的信息將供核實。; 3.     如果過程驗證研究已經進行 (e.g. 無菌產品), 流程驗證報告嘅副本應喺PD中提供,以代替 1. and 2. 以上. 過程驗證最實用嘅形式之一, 主要用于非無菌產品, 係產品嘅最終測試,在一定程度上大於常規質量控制所需嘅水平. 它可能涉及廣泛嘅採樣, 遠遠超出常規質量控制和測試中要求嘅正常質量控制規範,並且通常僅針對某些參數. Thus, for instance, 每批幾百片可以稱量以確定單位劑量均勻性. 然後對結果進行統計分析,以驗證分布嘅"正常性",並肯定標準偏離平均權重. 仲估計個人結果同批次同質性嘅信心限制. 提供強有力嘅保證,如果信心限制完全喺簡編規範範圍內,隨機採集嘅樣品將符合監管要求. Similarly, 可針對任何質素要求進行廣泛嘅抽樣同測試. In addition, 中間階段可以以同樣嘅方式驗證, e.g. 数十个樣品可以單獨檢測,透過內容均勻性測試嚟驗證低劑量片劑生產嘅混合或造粒階段. 某些產品特性偶爾可能會跳過測試. Thus, 親子製劑中嘅亞視覺顆粒物可以透過電子設備肯定, 或片劑或膠囊測試其解散配置文件,如果此類測試唔執行每批. 建議批次大小嘅範圍, 應該表明,批量大小嘅變化唔會對成品嘅特性產生不利影響. 據設想,一旦喺資格預審後提議進一步擴大,以下驗證計劃中列出嘅參數將需要驗證番。. 過程驗證協議應包括, b同博士limited to, the following: 當前主生產文檔嘅引用; 關鍵設備嘅討論; 可能影響FPP質素嘅過程參數 (關鍵過程參數 (Cpps)) 包括挑戰實驗和故障模式操作; 抽樣詳情: 採樣點, 抽樣階段, 抽樣方法同抽樣計劃 (包括攪拌機或儲物箱嘅示意圖,用于最終混合物嘅均勻性測試); 測試參數和驗收標準,包括驗證批次嘅流程和發佈規格及相對溶解配置文件(es) 用于生物可用性或生物豁免研究; 分析程序或引用適當嘅部分(s) 檔案; 記錄和評估結果嘅方法; – 完成協議的擬議時間框架. 無菌FP嘅製造需要喺控制良好嘅製造領域進行 (e.g. 使用高度可靠嘅程序同適當嘅處理控制嘅嚴格控制環境). 呢啲條件嘅詳細描述, 應提供程序和控制, 以及以下標準操作程序嘅實際副本: 洗, 治療, 容器嘅滅菌同脫氫, 關閉和設備; 過濾解決方案; 嗜酸過程; 填充同密封安培嘅洩漏測試; – 產品的最後檢查; – 滅菌周期. 用于破壞或去除微生物嘅滅菌過程可能係製造父性FP嘅單一最緊要過程. 呢個過程可以利用潮濕嘅熱量 (e.g. 蒸汽), 乾熱, 過濾, 氣態滅菌 (e.g. 乙烯氧化物) 或輻射. 應當指出,終端蒸汽滅菌, 實用時, 被認為係確保最終FPP不育嘅首選方法. Therefore, 應提供選擇任何其他絕育方法的科學理由. 滅菌過程應詳細描述,並提供證據,以確認其將生產具有高度可靠性的無菌產品,並且不會影響FPP的物理和化學性質以及安全性。. 詳細信息,如F同樣應提供FPP同容器關閉系統嘅溫度範圍同峰值停留時間. 雖然標準自動拍手周期 121 °C用于 15 分鐘或更多將不需要一個詳細的理由, 應為降低溫度周期或降低暴露時間嘅溫度周期提供此類理由. 如果使用氧化乙烯, 研究和驗收標準應控制殘留嘅乙烯氧化物和相關化合物嘅水平. 使用嘅任何過濾器都應根據毛孔尺寸進行驗證, 與產品嘅兼容性, 缺乏可提取物和缺乏API或任何組件的吸附. 用于驗證無法絕育嘅無菌處理父產品, 應進行模擬過程試驗. 涉及到喺正常條件下用文化介質填充容器, 其次係孵化. 有關詳細信息,請參閱當前嘅NAFDAC或世衛組織GMP指南. Reference documents: ICH Q8, Q9, Q10, WHO Technical Report Series, No. 961, Annex 3. 3.2. P.4對輔料的控制 (name, dosage form) 3.2. P.4.1規格 (name, dosage form)  應提供輔料的規格. 應向所有備件提供申請人或FPP製造商嘅規格, including those that may not be added to every batch (e.g. acid and alkali), 嗰啲冇出現喺最後嘅FPP (e.g. solvents) 以及製造過程中使用嘅任何其他設備 (e.g. nitrogen or silicon for stoppers). 如果要求為輔料提供嘅標準係官方認可嘅簡編標準, 足以說明,根據該標準嘅要求對輔料進行測試, 而唔係複製官方認可嘅簡編專著中發現嘅規格. 如果為輔料索賠嘅標準是非合成標準 (e.g. 內部標準) 或包括與官方認可嘅編目專著中出現嘅測試相補充嘅測試, 應提供供不應求的規格副本. 提交NAFDAC註冊嘅產品, 只有具有官方認可嘅藥典專著嘅輔料才應該使用. 例外可能係合理嘅. 對於自然來源嘅輔料, 微生物限量測試應包含喺規範中. 跳過測試係可以接受嘅,如果合理嘅話 (提交五個生產批次嘅可接受結果). 植物原產油 (e.g. 大豆油或花生油) 應證明沒有黃曲黴毒素或生物去除蟲劑. 允許使用嘅顏色僅限於"日本藥品輔料"中列出嘅色水, 歐盟 (EU) "允許食物顏色列表", 同FDA"非活性成分指南". 對於專有混合物, 應提交具有定性配方嘅供應商產品表, 除了FPP製造商嘅產品規格, 包括身份識別測試. 對於口味, 應提交定性組合, 以及一個聲明,即輔料符合食品法規 (e.g. 美國或歐盟法規). 被視為機密嘅信息可由供應商直接提交畀NAFDAC,供應商應求職信中提及特定緊嘅相關產品. 可能需要根據個案對風險組件進行其他認證. 如果對商業上可用的輔料進行額外的淨化, 應提交淨化和修改規格過程嘅詳細信息. Reference documents: ICH Q6A. 3.2. P.4.2分析程序 (name, dosage form) 應提供用于測試輔料嘅分析程序, where appropriate. 無需提交官方認可嘅簡編專著嘅分析程序副本. Reference document: ICH Q2. 3.2. P.4.3分析程序嘅驗證 (name, dosage form) Analytical validation information, including experimental data, 對於用于測試嘅分析程序,應提供輔料, where appropriate. 分析驗證信息副本一般唔提交用于檢測輔料, 除在適當情況下驗證內部方法外. Reference document: ICH Q2. 3.2. P.4.4規格嘅理由 (name, dosage form) 應提供擬議嘅次要規格嘅理由, where appropriate. 應提供對官方認可嘅簡編專著中所述測試嘅補充嘅討論. 3.2. P.4.5 人類或動物起源的起源 (name, dosage form) 人類或的名稱地址同每個製造商嘅責任息 (e.g. 來源, 規格以及每個提議嘅生產場地或涉及製造和測試嘅工廠製造所涉及的設施包裝果輔料是植物來如果某些公司只負責特定步驟供證明信,確認用于制造F應該清楚地表明狀腦病劑的風險. 應儘可能避免動物來源嘅材料. 在可用時,應提供展示TSE合規性嘅CEP. A complete copy of 涉及(i包括蚊nexes) should be p而唔係行政辦公室ts: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908, Annex 1. 3.2. P.4.6新奇嘅輔料 (name, dosage form) 對於輔料(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3). Novel excipients are not accepted by NAFDAC. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO. 3.2. P.5 Control of FPP (name, dosage form)  3.2. P.5.1 Specification(s) (name, dosage form) The specification(s) for the FPP should be provided. As defined in ICH’s Q6A guideline, a specification is: ‘‘a list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which an API or FPP should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the API and/or FPP, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.’’ A copy of the FPP specification(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), dated and signed by authorized personnel (i.e. the person in charge of the quality control or quality assurance department) should be provided in the PD. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life. The specifications should be summarized according to the tables in the QOS-PD template including the tests, acceptance criteria and analytical procedures (listing types, sources and versions for the methods). The standard declar包括 applicant could be an officially recognized compendia standard (e.g. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard. The specification reference number and version (e.g. revision number and/or date) should be provided for version control purposes. For the analytical procedures, the type should indicate the kind of analytical procedure used (e.g. visual, IR, UV or HPLC); the source refers to the origin of the analytical procedure (e.g. BP, JP, Ph.Eur. Ph.Int., USP, in-house) and the version (e.g. code number/version/ date) should be provided for version control purposes. ICH’s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, at a minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability and particle size), uniformity of dosage units, and, as applicable, id應提供在此過程中隔離嘅中間體嘅質素同控制信息mit tests. The following information provides guidance on specific tests that are not addressed by ICH’s Q6A guideline: ▪ fixed-dose combination FPPs (FDC-FPPs): Analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated, Acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards, A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit, For the API(s) present at ≥溫度 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing; Modified-release products: a meaningful API release method; Inhalation and nasal products: consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss; Suppositories: uniformity of dosage units,P.3製造 Transdermal dosage forms: peel or shear force, mean weight per unit area and dissolution. Unless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is ± 5% of the label claim (i.e. 95.0–105.0%). For products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. Otherwise, the test for mass uniformity may be applied. Skip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, at a minimum, the following skip-testing requirements: at least every tenth batch包括承包商ch annually is tested. In addition, for stability indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during 中間體dies. Any differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted. Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.2 Analytical procedures (name, dosage form) The analytical procedures used for testing the FPP should be provided. Copies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia. Tables for summarizing a number of the different analytical procedures and the validation information (e.g. HPLC assay and impurity methods) can be found in the 2.3.R Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP. Refer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures. Reference document: ICH Q2 (16). 3.2. P.5.3 Validation of analytical procedures (name, dosage form) Analytical validation information, including experimental data, for the analytical procedures used for testing the FPP, should be provided. Copies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided. Tables for 視情況而定 number of the different analytical procedures and validation information (e.g. HPLC assay and impurity methods, and GC methods) can be found in the 2.3.R Regional information section of the QOSPD (i.e. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, rela透皮劑量表lution of the FPP. As recognized by regulatory authorities and pharmacopoeias themselves, verification of compendia methods can be necessary. The compendia methods as publi液體e typically validated based on an API or an FPP originating from a specific manufacturer. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. Therefore, the monograph and compendia method(s) should be demonstrated suitable for the control of the proposed FPP. For officially recognized compendia FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendia method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances. If an officially recognized compendia standard is claimed and an in-house method is used in lieu of the compendia method (e.g. for assay or for related compounds), equivalence of the inhouse and compendia methods should be demonstrated. This could be accomplished by performing duplicate analyses of one sample by both methods and providing the results from the study. For methods for the determination of related compounds, the sample analyzed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits. Reference document: ICH Q2. 3.2. P.5.4 Batch analyses (name, dosage form) A description of batches and results of batch analyses should be provided. Information on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, batch size, date and site of production and use (e.g. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (if relevant), stability, pilot, scale-up and, if available, production-scale batches). Analytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated[1] FPP (e.g. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a正如ICH嘅Q6A指南所定義嘅(e規範係 dosage forms, 25 參考分析程序和適當的接受標準. 這是數值限制d 範圍ro或所述測P.3.3他標準ti它規定咗API或FPP例如一套標準,呢啲標準被認為係可接受嘅,用于預期用途in the comparative bioavailability or biowaiver根據列出嘅分析程序進行測試時e 符合所列驗收標準 the company responsible for generating the testing results should be identified. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The dis日期同由授權人員簽署cal res質檢總局、質檢部門負責人ur應在PD中提供it should be ensured that actual numerical results are provided rather than vague statements such as “within limits” or “conforms” (驗收標準和分析程序d from 0.2 to 方法嘅來源同版本d be expressed, at a minimum, as both the average and the range of individual results. Recommendati或內部ti製造商嘅 c標準ve dissolution profiles c修訂編號和/或日期A discussion and justification should be provided for any incomp類型應表示所使用的分析過程的類型 the pr視覺 specificatio來源係指分析程序嘅起源acterization of impurities (name, dosage fo同版本 on the characterization of impurities should be provided, if Bpt Jpev欧尔博士 provided iUsp3.2.S.3.2 Impuri應提供用于版本控制目的 impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipientA 個鍵步驟iner-closure system) and FPP process-related impurities (e.g. residual solvents i部分anufacturing process for the FPP). Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.6 Justification of specification(s) (name, dosage form) Justification for the proposed FPP specification(s) should be provided. A discussion should be provided on the omission or inclusion of certain tests, evolution of tests, analytical procedures and acceptance criteria, and differences from the officially recognized compendia standard(s). If the officially recognized compendia methods have been modified or replaced, a discussion should be included. The justification for certain tests, analytical procedures and acceptance criteria (e.g. degradation products or dissolution method development) may have been discussed in other sections of the PD and woulPh.Inteed to be repeated here, although a cross-reference should be provided. ICH Q6A should be consulted for the development of specifications for FPPs. 3.2. P.6 Reference standards or materials (name, dosage form) Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in “3.2.S.5 Reference standards or materials”. See section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5. Reference documents: ICH Q6A (6), WHO Technical Report Series, No. 943, Annex 3. 3.2. P.7 Container-closure system (name, dosage form) A description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specification溶劑 include description and identification (and critical dimensions, with drawings where appropriate). Non-compendia methods (with validation) should be included, where appropriate. For non-functional secondary packaging components (e.g. those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.  Suitability information should be located in 3.2.P.2. The WHO Guidelines on packaging 總結若干不同分析過程和驗證信息嘅表格 recommendations on the packaging information for FPPs. Descriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are: In direct contact with the dosage form (e.g. container, closure, liner, desiccant and filler); Used for drug delivery (including the device(s) for multidose solutions, emulsions, suspen識別ers or granules for reconstitution into solution, emulsion or suspension; Used as a protective barrier to help ensure stability or sterility; 分析驗證信息PP quality during storage and shipping. Primary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should include a specific test for identification (e.g. IR). Specifications for film and foil materials should include limits for thicknHPLC檢測和雜質方法 to establish the suitability (e.g. qualificatio可在QOS-PD嘅2.3.R區域信息部分搵到2.P.2. Comparative studies may be warranted for certain changes in 監管部門和藥典本詳情在3.2.A.2) 可能需要對簡編方法進行驗證. 已發佈嘅簡編方法通常基於來自特定製造商嘅API或FPP進行驗證cted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions with respect to storage conditions and shelf-life, and, if applicable, in-use storage conditions and shelf-life. The WHO stability guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (19) should be consulted for recommendations on the core如果聲稱有官方認可嘅簡編標準,並且使用內部方法代替簡編方法es, the purpose of stability testi應用于總結若干不同分析程序和驗證信息嘅表格分析並提供研究結果嚟實現。lso includes the study of product related factors that inR.2ence the quality of the API or FPP, for example, interaction of API with excipients, container-closure systems and packaging materials.  Stress testing As outlined in the WHO stability guidelines, photo stability testing should be conducted on at least one primary batch of the FPP if appropriate. If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies, whe穩定性tainer-closure system is shown to be lig生產規模的批次l stress testing of specific types of dosage forms may be appropriate (e.g. cyclic studies for semi-solid products or freeze–thaw studies for liquid products). Accelerated, intermediate (if necessary) and long-term testing Stability data must demonstrate stability of the medicinal product throughout its intended shelf-life under the climatic conditions prevalent in the target countries. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to WHO Technical Report Series, No. 953, Annex 2, Appendix 1 (7) for information on climatic zones. Effective as of September 2011, the required longterm storage conditions for the WHO Prequalification of Medicines Programmed are 30 ºC ± 2 ºC/75% ± 5% RH, and after this date the long-term data submitted in the PD (see Table 3) shoul個人和總雜質測試和檢測測試ng-應確保提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合"WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below −20 °C should be treated on a case-by-case basis. Table 3: Minimum data required at the time of subm對於任何唔完整嘅分析,應提供討論和理由umidity (%) Minimum Time Period (months) Accelerated 40 ± 2 75 ± 5 6 Intermediate N/A N/A Long-term 30 ± 2 75 ± 5 6 aWhere long-term conditions are 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, No. 953, Annex 2 (19) for further information regarding the storage conditions. To establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be ap測試嘅演變oduction-scale batch. The stability testing progr與官方認可嘅簡編標準嘅差異ould be reported in the dossier and summarized in the tables in the QOS某些測試嘅理由oportional strengths can be applied if scientifically justified. For sterile products, s分析程序和驗收標準and end o規雖然應該提供交叉引用orted frequently, but not nec非合成方法t 與驗證rial endotoxins need only be reported at 對於非功能性二次包裝組件containers should be reported over the shelf-life. Any in-use period and asso只應提供簡短嘅描述ed用于功能二次包裝組件pe應提供其他信息ny sterile and/or multidose products or after first opening of FPPs packed in bulk multidose containers (e.g. bottles of 1000s). If applicable, the inuse period and storage conditions should be stated in the product information. The information on the stability studies should include details such as storage conditions; strength; batch number, including the API batch number(s) and manufacturer(s); batch size; a container-closure system including orientation (e.g. erect, inverted, on-side) where applicable; completed (and proposed) test intervals. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all test主要包裝組件係嗰啲與API或FPP直接接觸嘅組件and any trends that were observed. For quantitative tests (e.g. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, at a minimum, as both the average and range of individual results. Applicants should consult ICH’s Q1E guideline (23) for details on the evaluat所進行的研究類型ts使用嘅協議y 研究結果應總結ithin 6 months at accelCEP嘅完整副本at包括任何附件ar應在模塊中提供-life could be up to twice the period covered by the long-term data, but should not exceed the long-term data by more than 12 months).  Proposed storage statement and shelf-life The proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable) for the FPP should be provided. The recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines. Reference documents: WHO Technical Report Series, No. 953, Annex 2, ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q3B, Q6A. 3.2. P.8.2 Post-approval stability protocol and stability commitment (name, dosage form) The post-approval stability protocol and stability commitment should be provided. Primary stability study commitment When the available data on long-term stability of primary batches do not cover the proposed shelf-life granted at the time of assessment of the PD, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.  Commitment stability studies The long-term stability studies for the commitment batches should be conducted throughout the proposed shelf-life on at least three production batches of each strength in each container-closure system. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.  Ongoing stability studies As described in the WHO stability guidelines, an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per ye第3季度of product manufactured in every strength and every container-closure system, if relevant, should be included in用于比較生物可用性或生物豁免研究t year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier. Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified. Reference document: ICH Q1A. 3.2. P.8.3 Stability data (name, dosage form) Results of the stability studies should be presented in an appropriate format (e.g. tabular, graphical, and narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.  Information on characterization of impurities is located in 3.2. P.5.5. The actual stability results and reports used to support the proposed shel熔點 be provided in the PD. For quantitative tests (e.g. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, at a minimum, as both the average and range of individual results. Reference documents: ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q2. 3.2. A  Appendices 3.2. A.1 Facilities and equipment Not applicable (i.e. not a biotech product). 3.2. A.2        Advent飛行員s agent’s safety evaluation  3.2. A.3        Novel excipients Novel excipients are not accepted. 3.2. R Regional information  3.2. R.1 Production documentation 3.2. R.1.1 Executed production documents A minimum of two batches of at least pilot scale, or in the case of an uncomplicated FPP (e.g. immediate-release solid FPPsQ6Aith noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For solid oral dosage forms, pilot sc批號ally, at a minimum, one-tenth that of full production scale or 100 000 tablets or capsules, whichever is the larger. Copies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible. If not included in the executed batch records through sufficient in process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the bio batch should involve testing to an extent greater than that required in routine quality control. English translations of executed records should be provided where relevant. 3.2.R.1.2 Master production documents Copies of the FPP master production documents should be provided for each proposed strength, commercial batch size and manufacturing site. The details in the master production documents should include, but not be limited to, the following: ■ master formula但不應超過長期數據超過ith relevant material and operational details; ■ relevant calculations (e.g. if the amount of API is adjusted based on the assay results or on the anhydrous basis); ■ identification of all equipment by, at a minimum, type and working capacity (including make, model and equipment number, where possible); ■ process parameters (e.g. mixing time, mixing speed, milling screen size, 另外.temperature range, granulation end-point and tablet machine speed ( expressed as target and range)); ■ 應提供批准後穩定性協議和穩定性承諾y, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity and filter integrity checks) and specifications; ■ sampling plan with regard to the: –   steps at which sampling should be done (e.g. 乾燥, lubrication and compression), –    number of samples that should be tested (e.g. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender), –    frequency of testing (e.g. weight variation every x minutes during compression or capsule filling); ■ precautions necessary to ensure product quality (e.g. temperature and humidity control and maximum holding times); ■ for sterile products, reference to standard operating procedures ( SOPs) in appropriate sections and a list of all relevant SOPs at the end of the document; ■ theoretical and actual yield; ■ compliance with the GMP requirements. Re對結果嘅討論應側重於為各種測試所記錄嘅觀察結果ur而唔係報告評論,如"所有測試符合批處理大小t;he QOS-PD template should be used to summarize the analytical procedures and validation information from sections 3.2.S.4.2, 3.2.S.4.3, 2.3.S.4.4 (c), 2.3. S.7.3 (b), 3.2.P.5.2 and 3.2.P.5.3 where relevant. 4.3     Literature references  References to the scientific literature relating to both the API and FPP should be included in this section of the PD when appropriate. Module 4: Non-clinical Summaries This module is not normally needed for multisource (generic) pharmaceutical products. It deals with the toxicity testing intended to justify the stability and safety of the product. The module is included for completeness to indicate the appropriate format and placement of the nonclinical data. Refer to ICH M4S (R2) for additional detail on the organization of Module 4 and for ICH references on study de叶斯gn and data content. 4.1 Table of Contents (Module 4) 4.2 Study Reports The study reports should be presented in the following order: 4.2.1 Pharmacology 4.2.1.1   Primary Pharmacodynamics 4.2.1.2   Secondary Pharmacodynamics 4.2.1.3   Safety Pharmacology 4.2.1.4   Pharmacodynamic Drug Interactions 4.2.2 Pharmacokinetics 4.2.2.1   Analytical Methods and Validation Reports (if separate reports are available) 4.2.2.2   Absorption 4.2.2.3   Distribution 4.2.2.4 Metabolism 4 2.2.5 Excretion 4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical) 4.2.2.7 Other Pharmacokinetic Studies 4.2.3 Toxicology 4.2.3.1 Single-DoseQ1Bxicity Q1D oQ1Er by species, by route) 4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations) 4.2.3.3 Genotoxicity 4.2.3.3.1 In vitro 4.2.3.3.2 In vivo (supportive toxicokinetics evaluations) 4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations) 4.2.3.4.1 Long-term studies (in or紅外r by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics) 4.2.3.4.2 Short- or medium-term studies (including range-finding studies that外觀propriately be included under repeat-dose toxicity or pharmacokinetics) 4.2.3.4.3 Other st粘度.3.5 Reproductive and Deve混合均勻性ty 4.2.3.5.1 Fertility and early embryo重量變化4.硬度程中體重增加pment 4.2.3.5.3 Prenatal and postnatal development, including maternal function 4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated. 4.2.3.6 Local Tolerance 4.2.3.7 Other Toxicity Studies (if available) 4.2.3.7.1 Antigenicity 4.2.3.7.2 Immunotoxicity 4.2.3.7.3 Mechanistic studies (if not included elsewhere) 4.2.3.7.4 Dependence 4.2.3.7.5 Metabolites 4.2.3.7.6 Impurities 4.2.3.7.7 其他 4.3 Literature References Module 5: Clinical Summaries For multisource (generic) pharmaceutical products, only Module 5.3.1 Reports of Biopharmaceutical Studies would normally be needed. However, all parts of the module are included for completeness to indicate the approp如果相關t and placement of the nonclinical data. ICH E3 provides guidance on the organisation of clinical study reports, other clinical data, and references within a Common Technical Document (CTD). Module 5 provides the recommended organization for the placement of clinical study reports and related information to simplify preparation and review of dossiers and to ensure completeness. The placement of a report should be determined by the primary objective of the study. Each study report should appear in only one section. Where there are multiple objectives, the study should be cross-referenced in the various sections. An expla用于定量測試applicable” or “no study conducted” should be provided when no report or information is available for a section or subsection. Refer to ICH M4E (R2) for additional detail on the organization of Module 5 and for additional ICH references on study design and data content.  5.1 Table of Contents (Module 5) A Table of Contents for study reports should be provided. 5.2 Tabular Listing of Clinical Studies 5.3 臨床研究報告 5.3.1 Reports of Bio-pharmaceutic Studies Bioavailability (BA) studies evaluate the rate and extent of release of the active substance from the medicinal product. Comparative BA or bioequivalence (BE) studies may use Pharmacokinetic (PK), Pharmacodynamic (PD), clinical or in vitro dissolution endpoints, and may be either single dose or multiple doses. When the primary purpose of a study is to assess the PK of a drug, but also includes BA information, the study report should be submitted in Section 5.3.1, and referenced in Sections 5.3.1.1 and/or 5.3.1.2. 5.3.1.1 Bioavailability (BA) Study Reports BA studies in this section should include •      studies comparing the release and systemic availability of a drug substance from a solid oral dosage form to the systemic availability of the drug substance given intravenously or as an oral liquid dosage form •      dosage form proportionality studies, and •      food-effect studies. 5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports Studies in this section compare the rate and extent of release of the drug substance from similar drug products (e.g., tablet to tablet, tablet to capsule). Comparative BA or BE studies may include comparisons between •      the drug product used in clinical studies supporting effectiveness and the to-be-marketed drug product, •      the drug product used in clinical studies supporting effectiveness and the drug product used in stability batches, and •      similar drug products from different manufacturers. 5.3.1.3 In vitro-In vivo Correlation Study Reports In vitro dissolution studies that provide BA information, including studies used in seeking to correlate in vitro data with in vivo correlations, should be placed in this section. Reports of in vitro dissolution tests used for batch quality control and/or batch release should be placed in the Quality section (module 3) of the CTD. 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Bioanalytical and/or analytical methods for biopharmaceutics studies or in vitro dissolution studies should ordinarily be provided in individual study reports. Where a method is used in multiple studies, the method and its validation should be included once in Section 5.3.1.4 and referenced in the appropriate individual study reports. 5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials 5.3.2.1 Plasma Protein Binding Study Reports 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies 5.3.2.3 Reports of Studies Using Other Human Biomaterials 5.3.3 Reports of Human Pharmacokinetic Studies 5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports 5.3.3.2 Patient PK and Initial Tolerability Study Reports 5.3.3.3 Intrinsic Factor PK Study Reports 5.3.3.4 Extrinsic Factor PK Study Reports 5.3.3.5 Population PK Study Reports 5.3.4 Reports of Human Pharmacodynamic Studies 5.3.4.1 Healthy Subj相關情況PD Study Reports 5.3.4.2 Patient PD and PK/PD Study Reports 5.3.5 Reports of Efficacy and Safety Studies 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.3.5.2 Study Reports of Uncontrolled Clinical Studies References 5.3.5.3 Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses 5.3.5.4 Other Clinical Study Reports 5.3.6 Reports of Post-marketing Experience For products that are currently marketed, reports that summarize marketing experience (including all significant safety observations) should be included. 5.3.7 Case Report Forms and Individual Patient Listings (when submitted) Case report forms and individual patient data listings that are described as appendices in the ICH or WHO clinical study report guideline should be placed in this section when submitted in the same order as the clinical study reports and indexed by study. 5.4 Literature References Copies of referenced documents, including important published articles, official meeting minutes, or other regulatory guidance or advice should be provided here. This includes copies of all references cited in the Clinical Overview, and copies of important references cited in the Clinical Summary or in the individual technical reports that were provided in Module 5, Only one copy of each reference should he provided. Copies of references that are not included here should be immediately available on request. Appendix 1 Recommendations for conducting and assessing comparative dissolution profiles The dissolution measurements of the two FPPs (e.g. test and reference (comparator) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) should be included, the time-points for both reference (comparator) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) minutes). The 15-minute time-point is critical to determine whether a product is very rapidly dissolving and to determine whether f2 must be calculated. For extended release FPPs, the time-points should be set to cov或 the entire duration of expected release, e.g. 1, 2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration of release. Studies shoul因此ormed in at least three media covering the physiological range, inc應提供ochloric acid, pH 4.5 buffer and pH 6.8 buffer. International Pharmacopoeia buffers are recommended; other pharmacopoeia buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media自o the extent that the data are unusable. If both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). Oth否則 Similarity of the resulting comparative dissolution profil± should be calculated using the following equation that defines a similarity factor (f2): f2 = 50 LOG {[1+1/n ∑nt=1 (Rt−Tt) 2] −0.5 × 100} wh在適當時 the mean per cent API dissolved in reference (comparator) and test product, 分別, at each time-point. An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. ▪ A maximum of one time-point should be considered after 85% dissolution of the reference (comparator) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached. ▪ At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%. ▪ When delayed-release products (e.g. enteric coated) are being compared, the recommended conditions are acid medium (pH 1.2) 適用於 2 hours and buffer pH 6.8 medium. ▪ When comparing extended-release beaded cP.8穩定性e different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice. ▪ Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised. REFERENCES: ICH Common Technical Document References (http://www.ich.org) 1.    ICH M4 - Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (2016) 2.    ICH M4E(R2) - Common Technical Document for the Registration of Pharmaceuticals for Human Use:  Efficacy  (2016) 3.    ICH M4Q(R1) - Common Technical Document for the Registration of Pharmaceuticals for Human Use: 質量 (2002) 4.    ICH M4S(R2) - Common Technical Document for the Registration of Pharmaceuticals for Human Use: Safety (2002) ICH Quality Guidelines 1.    ICH Q1A(R2) - Stability Testing of New Drug Substances and Products (2003) 2.    ICH Q1B Stability Testing: Photo stability Testing of New Drug Substances and Products (1996) 3.    ICH Q1D - Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (2002) 4.    ICH Q1E - Evaluation for Stability Data (2003) 5.    ICH Q2(R1) - Validation of Analytical Procedures: Text and Methodology (2005) [combines the previous Q2A and Q2B Guidelines] 6.    ICH Q3A(R2) - Impurities in New Drug Substances (2006) 7.    ICH Q3B(R2) - Impurities in New Drug Products (2206) 8.    ICH Q3C(R6) - Impurities: Guideline For Residual Solvents Q3C(2016) 9.    ICH Q5A, QICH Q5A, Q5D  Quality of Biological Products [not needed for multisource (generic) pharmaceutical products] 10.  ICH Q6A - Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999) 11.  ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (1999) [not needed for multisource (generic) pharmaceutical products] World Health Organization Guidelines 1.    Guidelines on packaging for pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2002 ( WHO Technical Report Series, No. 902), Annex  9 2.    Stability testing of active pharmaceutical ingredients and finished pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009 (WHO Technical Report Series, No. 953), Annex 2. [Together with 2015 update table Stability Conditions for WHO Member States by Region] 3.    Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part, In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2012 (WHO Technical Report Series, No. 970), Annex 4 4.    Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. . World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 7. 5.    Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. 世界衛生組織, (WHO Technical Report Series, No. 992), Annex 8 2015 6.    Guidance for organizations performing in vivo bioequival分鐘udies (revision), In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fiftieth report. 7.    WHO Technical Report Series, No. 996, Annex 9, 2016 World Health Organization Templates [https://extranet.who.int/prequal/content/who-medicines-prequalification-guidance] Quality Templates 1.    Quality overall summary - product dossier (QOS-PD) 2.    Quality information summary (QIS) Bioequivalence Template 1.    Bioequivalence trail information form (BTIF) 2.    Biowaiver Application Form (BAF) 3.    Make reference to WHO guideline for bioavailability and bioequivalence studies and the WHO Template 假假地.r] Labelling Templates 1.    Patient information leaflet – Template 2.    Summary Product Characteristics (SmPC) Template 3.    Labelling Template S.4.4 A: PRODUCT LABELLING GUIDANCE The Guidance and templates for product labelling shall be based on the NAFDAC Labelling Template guidance for the Package Leaflet, Summar測定Product Characteristics and labelling which is available from the NAFDAC website at https://extranet.who.int/prequal/content/contents-and-structure-whopar. Module 1.3.1 Summary of Product Characteristics (SmPC) The format of the 參考文檔o be consistent with the NAFDAC SmPC Template. The information should be provided in English language. Refer to NAFDAC SmPC Guidance Use NAFDAC SmPC Template Module 1.3.2 Patient Information Leaflet The format of the PIL is to be consistent with the NAFDAC PIL template. The information should be provided in the English Language Refer to NAFDAC PIL Guidance Use NAFDAC PIL Template Module 1.3.3 Container Labelling (Inner and Outer Labels) The primary and secondary packaging must include the following information in a legible, understandable and indelible manner. The information should be provided in English. The Container Labelling is to be consistent with the WHO template. Refer to NAFDAC Label Guidance ANNEX B: TEMPLATES Refer to NAFDAC Templates found at Quality Overall Summary –Bproduct dossier (QOS-PD) Quality information Summary (QIS) ANNEX C:  MANAGEMENT OF APPLICATIONS AND STANDARD OPERATING PROCEDURES For pharmaceutical products that have been prequalified by the World He對於固體口服劑型tion will be via the Collaborative Procedure for the Accelerated Registration of WHO Prequalified medicines and vaccines. As for other products, including those for specific or neglected tropical diseases, a complete application will be required. 1.4 GENERAL POLICIES ON APPLICATIONS A separate application isICH Q1Aed for each product. For purposes of clarification, one application could be submitted for products containing the same active ingredients and the same strength made by the same manufacturer at the same manufacturing site, to the same specifications and dosage form, but differing only in packing 強度sizes. On the other hand, 對於含有相同活性成分嘅產品,應單獨提交申請(s) 但不同嘅鹽, 不同嘅強度, 劑型和專有或品牌名稱. 1.4.1 申請類別應分為三類 (3) ·新應用程序»申請續訂 (i.e., 註冊) ·應用變化 ( i.e., 註冊產品嘅 ) 1.4.2 藥品註冊嘅新申請,或提交畀國家食品藥品監督管理局總幹事,並複製主任註冊和監管事務局,以授予市場授權. 除了提交的檔案, 申請人應提供: 我.             生產該產品嘅工廠嘅站點主文件. (submitted in Module 3) 第二.            對於NCEs同創新產品,應提交藥監計劃. (Submitted in Module 1.2.在糢塊中提交3 申請續簽登記申請的註冊申請,至少應提出 3 現有註冊期滿前幾在適用的情況下《藥品銷售授權許可證續期指引》 1.4.4 註冊產品變更申請變更為註冊產品應按照《NAFDAC變更指南》嘅要求提出 1.5 申請市場授權產品註冊嘅申請,應當按照核准格式向國家食品藥品監督管理局局長提出,並抄送國家食品藥品監督管理局嘅註冊管理處處長。. 用于特定國家/地區嘅營銷授權產品, 申請應發送畀該国嘅NMRA負責人. 1.6 申請費申請費應支付每提交申請. -應按照核准嘅北美自由貿易協定關稅. 其他國家MRA可能會根據其立法要求向其他國家MR收取費用. 1.8 時間線完成快速註冊申請 (僅本地製造和優先藥物), 註冊後審批變更和續簽將在 90 收到申請的Fpp日.  完整嘅新申請將在內部處理 12 收到申請嘅月份. 申請人將被要求提供任何要求嘅其他數據內 6 months. 如果需要額外嘅時間, 必須提交正式請求. 1.9 申請人未對內部查詢提交書面答覆嘅,撤回申請 6 自其發行之日起嘅幾個月, 將被視為申請人已撤回申請,抑或如果查詢已第二次發出番,並且申請人提供唔滿意嘅答覆, 產品將被取消資格,申請將被拒絕. 申請人必須重新申請. 1.10 註冊有效性藥品註冊有效期為五 (5) 年,除非否則暫停或撤銷NAFDAC, 或由申請人撤回. 1.11 因任何藥品營銷授權申請而受害嘅人員,可在兩項範圍內 (2) 決定通知之日起數月, 以書面形式向NAFDAC提出陳述,並提交其他數據以支持上訴. 支持製造商對監管決定提出上訴請求嘅文件已放入糢塊中 1.1.5 of the CTD.  1.1.5 of the CTD. NAFDAC糢闆質素糢闆 1.            Quality overall summary - product dossier (QOS-PD) 2.            Quality information summary如果適用,ivalence Template 1.              Bioequivalence Trial Information Form (BTIF) 2.              Biowaiver Application Form ( BAF ) a.            纳夫达克BCS生物豁免糢闆B.            纳夫达克額外強度生物豁免糢闆. Labelling Templates 1.              患者信息傳單  (PIL)– 模板 2.              Summary Product Characteristics (SmPC) Template 3.              NAFDAC標籤糢闆打理糢闆 1.              CEP嘅訪問權限 2.              Letter of Access for APIMF [1] 術語"複雜嘅FPP"包括無菌產品, 計量劑量吸入器產品, 乾粉吸入器產品和皮下輸送系統. 徜徉複雜FPPx下嘅其他特定產品包括利托纳维尔/洛皮纳维尔FDC片劑和含有利福匹辛或青黴素嘅FDC. 關於莱克斯·阿蒂菲克斯Llp莱克斯·阿蒂菲克斯Llp係製造商嘅窗口, 出口商, 同受管制食品和藥品產品的經銷商在尼日利亞尋求許可證, 並尋求進入尼日利亞市場. 我哋係尼日利亞法律合規和盡職調查服務嘅一站式商店. 我哋透ICH第2季度流程嘅每一步及以後為客戶提供法律指導.  To learn m然而ut the Lex Artifex LLP's F&D幫助台以及我哋點樣透過尼日利亞NAFDAC幫助你進行食品和藥品倉庫檢查, 請發送電子郵件: lexartifexllp@lexartifexll如果可用234.803.979.5959.月另一方面世衛組織技術報告系列和ICH Q6APh附件唔係.R 2ICH M4S應包括例如.即。R1藥物奇斯Btif生物等價試驗信息表必斯姆普克產品特性摘要APIMF嘅訪問權限目錄劑型附錄糢塊名字例如:比較即通用CasCtd

尼日利亞藥品註冊指南

尼日利亞藥品註冊質量準則

Lex Artifex LLP, 尼日利亞律師樓, 引入了食品 & 德鲁德 (F&D) 協助參與製造嘅人同公司, 分布, 出口和進口受管制食品和藥品,以滿足尼日利亞國家食品藥品監督管理局規定嘅要求 ("NAFDAC"). 本出版物提供咗尼日利亞藥品註冊嘅質量準則.

確認

該機構承認世界衛生組織嘅技術支持 (边个), 西非世界衛生組織 (瓦霍) 同協調國際會議 (Ich) 在制定本準則時.

目的

本文根據國際協調理事會進程達到嘅被廣泛接受嘅格式同共同要求,為編寫尼日利亞人類用藥品註冊法規呈件提供指導。 (Ich) 人類用藥登記嘅監管要求.
特別是, 該文件旨在令原子能機構關於為人類使用的藥物登記提交監管要求與西非國家共同體由西非國家世界衛生組織錨定嘅統一努力保持一致 (瓦霍).
因此, 本文件嘅介紹將最終有助於以下;
  • 透過就產品檔案嘅組織同格式提供指導,為藥品準備監管提交.
  • 共同技術文件嘅透過 (Ctd) 透過國際衞生中心進程制定,世界衛生組織喺世衛組織資格預審方案同西非衛生組織中採用,促進統一人類使用註冊醫藥產品的監管要求·
  • 在西非經共體成員國促進監管協調;
  • 藥品監管機構之間嘅拍檔同信息共享就其他技術同一般要求提供指導
  • 詳細說明活性藥物成分嘅要求 (Api) 同成品藥品;
  • 便於提交和評估;
  • 增加獲得優質基本藥物的機會;
  • 促進更透明的監管制度

縮寫列表

爱滋病
獲得性免疫缺陷綜合症
Api
活性藥物成分
阿普伊姆
活性藥物成分主文件
.Atc
解剖學治療和化學分類
Cep
歐洲質量局頒發嘅適用性證書
醫藥和醫療保健 (埃德QM)
Cpp
醫藥產品證書
Ctd
通用技術文檔
Dmf
藥物主文件
西非經共體
西非國家經濟共同體
Fpp
成品藥品
Gmp
良好嘅製造規範
Hiv
人類免疫缺陷病毒
Ich
國際協調技術要求理事會
人類用藥註冊
酒店.
國際非專有名稱
市場授權
NCE
新化學實體
恩姆格拉
國家藥品管理局
Otc
在處方藥
患者信息傳單
聚甲醛
處方藥
斯姆普克
產品特性摘要
瓦霍
西非世界衛生組織
边个
世界衛生組織

 

提交尼日利亞藥品註冊申請嘅一般原則

語言

  • 申請營銷授權嘅產品應以英文提交.
  • 如果需要把文檔由原始語言翻譯為英文, 翻譯嘅準確性由申請人負責,翻譯應由原產国認證專家認證。.

數據演示

  • 檔案應以電子形式提交,並遵循CTD格式. 應為每個糢塊中嘅CTD嘅不同部分為不同嘅糢塊創建單獨嘅文件夾和子文件夾. 文檔應以可搜索嘅PDF格式提交,但QIS除外,該QIS應採用MS Word格式.

參考文獻和文本

· 必須遵循檔案任何部分引用引用嘅國際標準. 任何參考源嘅最新版本, 指定必須使用出版年.
· 應根據本版《提交生物醫學期刊的手稿統一要求》引用文獻參考, 國際醫學期刊編輯委員會 (伊姆杰).
· 首字母縮略詞和縮寫應在每個模塊中首次使用. 必要時, 特別是用于分析方法, 規範和程序, 參考源相關部分嘅副本(s) 必須包括.
· 文檔中引用嘅所有內部流程必須經過驗證並引用適當嘅引用.
促進PD嘅編制, 呢啲準則係按照ICH通用技術文檔嘅結構組織嘅 (M4Q) 指引.
M4Q嘅文本 (CTD-Q) 準則喺呢啲準則中逐字重複。 粗體文本, 稍作修改,以適應NAFDAC術語,並包括適用於藥品嘅某些文本, 尤其係:
a) 狻藥物物質狻被替換為狻活性藥物成分狻或狻APIó
B) "藥品"被替換為"成品"或"FPP".
C) "應用"替換為"產品檔案"或"PD".
D) "組合產品"替換為"固定劑量組合"或"FDC".
nafdac 根據世衛組織關於提交多源文件嘅準則提供嘅補充指導 (通用) 成品, 在以下 大膽 由 m4q 轉載的文本 (CTD-Q) 指引 (2), 以普通文本打印,使其易於與ICH文本區分,並包含以進一步澄清NAFDAC對PD內容嘅期望. 呢種方法嘅目的係便利呢啲準則中案文嘅肯定同來源 (即. 從Ich或世衛組織).
呢啲準則嘅內容應與世衛組織或國際信息委員會其他現有參考文件和指南中描述嘅相關信息一起閱讀. 現有API同相應多源產品嘅質素不應低於新嘅API同創新者 (比較) FFP. 因此, 本文件同其他世衛組織指南中提及嘅ICH指南原則可能同樣適用於現有API同多源產品.
科學文獻可能適合滿足呢啲準則中概述嘅一些信息或參數嘅要求 (例如:. 指定識別嘅雜質嘅資格). 此外, 某些部分中列出嘅要求可能不適用於建議嘅API或FPP. 喺呢啲情況下, 應提供摘要或對科學文獻嘅完整參考, 或所要求嘅信息唔適用,應明確註明隨附嘅解釋性說明.

格式指南

世衛組織關於多源文件提交一般落案準則中概述嘅建議 (通用) 成品: 一般格式: 在PD的格式和演示中,應遵循以共同技術文檔格式編製產品檔案.
喺好多情況下,重複節可以被認為係適當嘅. 每當重複一節時, 應該透過喺M4Q之後喺括號中創建一個區分標題嚟明確該節所指嘅 (CTD-Q) 指南標題, 例如:. 3.2.S藥物物質 (或Api) (名字, 製造商A).
以下係喺質素糢塊中介紹可能遇到嘅不同方案嘅信息嘅建議:
  • 開放部分 (非專有信息) 每個APIMF應始終將其全部納入PD中, 作為3.2. s嘅附件.
  • 對於包含多個API嘅FPP, 一個完整嘅"3.2.S"部分應為一個API提供, 然後係其他API嘅另一個完整"3.2.S"部分.
  • 來自多個製造商嘅API, 一個製造商應為API提供一個完整嘅"3.2.S"部分, 然後係來自其他API製造商嘅API嘅另一個完整"3.2.S"部分.
  • 對於具有多種優勢嘅FPP (例如:. 10, 50, 100 鎂) 應提供一個完整嘅"3.2.P"部分,其中應提供分節內提供嘅不同優勢嘅信息. 應為每種FPP強度提供一份完整嘅PD副本.
  • 對於具有多個容器關閉系統嘅FPP (例如:. 瓶子和單位劑量水泡) 應提供一個完整嘅"3.2.P"部分,其中應提供分節內提供嘅不同演示文稿嘅信息.
  • 用于多個FFP (例如:. 片劑和母產品) 每個Fpp都需要單獨嘅檔案.
  • 對於提供重組二噁英嘅Fpp(s) 應為FPP提供一個完整嘅"3.2. p"部分, 然後係天拿水上嘅信息(s) 喺單獨嘅部分"3.2. p", 酌情.
  • 對於共起泡嘅FPP,應為每種產品提供完整嘅"3.2.P"部分.

CTD格式嘅結構

CTD內嘅信息被組織成一系列結構化文檔,然後組織成糢塊. 通用技術文檔同ICH一般問答嘅M4指導組織提供咗文檔嘅定義同內容表指南 (Toc) 格式, CTD內嘅交叉引用同文檔分頁, 隔離同分區編號.

表 1: 共同技術文件中嘅主要章節標題 (Ctd) 格式

數量

標題同主要部分標題

1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.A 個
糢塊 1: 行政和產品信息
求職信
目錄 (糢塊 1 自 5)
應用程序信息
產品信息
區域摘要
電子審查文件
產品示例(s) (如果在提交時可用)
附錄
2.1
2.2
2.3
2.4
2.5
2.6
2.7
糢塊 2: 通用技術文檔 (Ctd) 摘要
CTD目錄 (糢塊 2 自 5)
CTD簡介
質量總體摘要
非臨床概述
臨床概述
非臨床書面和表格摘要
臨床總結
3.1
3.2
3.3
糢塊 3: 質量
糢塊目錄 3
數據主體
文獻參考
4.1
4.2
4.3
糢塊 4: 非臨床研究報告
不需要
糢塊目錄 4 通用產品
學習報告
文獻參考
5.1
5.2
5.3
5.4
糢塊 5: 臨床研究報告
生物等效性或
糢塊目錄 5 生物威威弗需要
適用泛型
所有臨床研究嘅表格列表
臨床研究報告
文獻參考

糢塊 1 (行政和產品信息)

1.0 求職信:

· 向監管機構提交嘅任何數據應附上求職信. 求職信應清楚地說明提交緊嘅内容, 包括提及請求書 (如果適用,) 同包裝嘅簡要說明.
· 求職信不應包含任何科學信息.
· 任何相互引用嘅監管文件都應喺求職信中明確說明, 以及以下信息應包含在內:
·應用類型, 指定是否新, 續約或變更;
·NMRA申請號 (由NMRA發佈);
·如果適用,則監管授權日期.
·品牌名稱, Dci, 劑量, 表示, 劑型;
·製造商名稱
·申請人姓名
·提交嘅樣本數量
附件B提供了求職信樣本: 形式

1.1 包括糢塊在內嘅應用程序內容表 1 (糢塊 1-5)

目錄 (Toc) 成個監管檔案應該放喺一節. 它應該列出糢塊中包含嘅所有文檔 1-5. 每個糢塊都包含糢塊特定嘅ToC.
1.2 應用程序信息
1.2.1 申請信
1.2.2 報名表
1.2.3 公司成立證書
1.2.4 授權書
1.2.5 申請人公證申報. (申請人應聲明提交嘅信息真實且正確. 有關名稱嘅信息, 申請人嘅地位同簽名, 產品細節應在公證的申報中提供,並且應註明日期, 由公證人簽名和蓋章)
1.2.6 委託書/合同製造協議
1.2.7 醫藥產品證書
1.2.8 良好製造實踐證書
1.2.9 製造授權
1.2.10 商標註冊證據
1.2.11 藥劑師年度執業執照
1.2.12 房地登記和保留證書
1.2.13 以前營銷授權嘅证据 (如果適用,)
1.2.14 GMP檢查邀請函
1.2.15 歐洲藥典適宜性證書副本 (在適用的情況下)
1.2.16 APIMF嘅訪問權限(s) (在適用的情況下)
1.2.17 與開展基於BCS嘅生物可用性研究有關嘅生物豁免請求
1.2.18 與開展額外強度生物可用性研究相關嘅生物豁免請求

1.3. 產品信息

1.3.1. 產品特性摘要 (斯姆普克)
產品特徵摘要副本 (斯姆普克) 將放在本節中. 在評估過程中請求修訂時, 需要修訂後的SMPC的注釋版本. 註釋應識別所有更改, 或與上一次批准嘅 smpc 有關嘅, 或應監管當局的要求提出的要求.

1.3.2. 標籤 (外 & 內部標籤)

· 所有容器標籤, 包括內部和外部標籤, 應在本節中提供.
· 應該包括所有優勢嘅標籤, 劑型和重組天拿水.
· 在審查過程中請求進一步修訂時, 修改後的標籤的附加說明嘅版本可能會要求, 並應放置在節中.

1.3.3. 包裝插入 (都稱為患者信息PIL)

· 患者信息傳單副本 (必) 將放在本節中.
1.4. 區域摘要
1.4.1. 生物等價試驗信息表 (Btif)
1.4.2. 質量信息摘要 (奇斯)
1.5. 電子審查文件
  • 鼓勵使用可搜索嘅便攜式文檔格式使用應用程序嘅電子版本 (Pdf). 此電子文檔應保存到光盤中. 所有提交支持藥品監管文件嘅電子媒體都應放在本節中
1.6. 樣品
· 應隨申請一起提交用于商業目的嘅相同包裝中產品嘅樣品. 請注意,当最終產品包裝不可用時,可以使用模型包裝.

糢塊 2: 通用技術文檔 (Ctd) 摘要

糢塊 2 包括以下內容 7 部分. 對於多源 (通用) 藥物, 糢塊 2.4-2.7 通常不需要.
2.1 CTD目錄 (糢塊 2-5)
2.2 CTD簡介
2.3 質量總體摘要
2.4 非臨床概述
2.5 臨床概述
2.6 非臨床書面和表格摘要
2.7 臨床總結

 

2.1 CTD目錄 (糢塊 2-5)

糢塊內容表 2 自 5 應提供.

2.2 CTD簡介

簡介應包括專有名稱, 非專有名稱或藥物物質的通用名稱, 公司名稱, 劑型(s), 強度(s), 管理路線, 同建議嘅指示(s). 它應該簡要描述糢塊嘅内容 2 自 5 與適當嘅交叉引用佢哋.

2.3 質量總體摘要

質量總體摘要 (Qos) 係遵循範圍同大綱嘅摘要。
糢塊中嘅數據正文 3. QOS包含API部分 (2.3.S), Fpp部分 (2.3.P), 附錄 (2.3.A 個) 同區域信息 (2.3.R). QOS不應包含信息, 糢塊中尚未包含嘅數據或理由 3 或喺CTD嘅其他部分.
QOS-PD糢闆應按照本節中嘅指南完成.
請參閱ICH M4Q (R1).

2.3. S藥物 物質

對於含有多個藥物物質的藥物產品, 糢塊2.3.S.1至2.3.S.7中嘅信息應提交每種藥物物質, 明確識別每個糢塊標題中嘅物質名稱同製造商.
2.3. S.1一般信息 (名字, 製造商)
包括糢塊3.2.S.1中嘅信息
2.3. S.2製造 (名字, 物理地址, 即。, 網站)
包括糢塊3.2.S.2中嘅信息
有關製造商嘅信息,
·提供名稱, 每個製造商嘅地址同責任, 包括承包商, 以及每個提議嘅生產場地或設施,涉及製造和測試.
·製造過程簡要描述 (包括, 例如., 參考起始材料, 關鍵步驟, 和後處理) 以及旨在導致材料嘅常規同一致生產嘅控制(s) 適當質素; 可以呈現為流程圖.
·流程圖, 如3.2.S.2.2中提供;
·用于制造API嘅生物來源同起始材料和原材料嘅說明, 如3.2.S.2.3中所述;
·突出顯示關鍵工藝中間體, 如3.2.S.2.4中所述;
·過程驗證和/或評估嘅描述, 如3.2.S.2.5中所述.
2.3. S.3特徵 (名字, 製造商)
結構和異構體證據解釋嘅摘要, 如中所述
3.2.S.3.1, 應包括.
3.2.S.3.2中提供嘅數據嘅表格摘要, 具有圖形表示, 在適當時應包括.
2.3. S.4藥物物質控制 (名字, 製造商)
規範理由嘅簡要摘要(s), 分析程序, 和驗證應包括.
應提供3.2.S.4.1嘅規格.
3.2.S.4.4嘅批處理分析嘅表格摘要, 在適當時用圖形表示, 應提供.
2.3. S.5 參考標準或材料 (名字, 製造商)
來自3.2.S.5嘅信息 (表格演示文稿, 在適當時) 應包括.
2.3. S.6集裝箱封閉系統 (名字, 製造商)
簡要說明和討論信息, 從3.2.S.6應包括在內.
2.3. S.7穩定性 (名字, 製造商)
本節應包括所進行研究嘅摘要 (條件, 批次, 分析程序) 簡要討論結果和結論, 建議嘅存儲條件, 複試日期或保質期, 相關情況, 如中所述 3.2. S.7.1.
批准後穩定性協議, 如3.2.S.7.2中所述, 應包括.
穩定性嘅表格摘要來自3.2.S.7.3, 在適當時用圖形表示, 應提供.

2.3. P成品藥品

2.3. P.1藥品嘅描述同成分 (名字, 劑型) 應提供3.2.P.1嘅信息.
應提供3.2.P.1嘅組成.
2.3. P.2藥物開發 (名字, 劑型)
應討論3.2.P.2嘅信息同數據.
應提供臨床試驗中使用嘅配方成分嘅表格摘要同溶解圖嘅介紹, 相關情況.
2.3. P.3製造 (名字, 劑型) 3.2.P.3嘅信息應包括:
·製造商信息.
·簡要描述製造工藝和控制,旨在導致適當質量產品嘅常規同一致生產.
·流程圖, 根據以下規定 3.2. P.3.3.
·過程驗證和/或評估嘅簡要描述, 如中所述 3.2. P.3.5.
2.3. P.4輔料控制 (名字, 劑型)
關於輔料質素嘅簡要總結, 如3.2.P.4中所述, 應包括.
2.3. P.5藥品控制 (名字, 劑型)
規範理由嘅簡要摘要(s), 分析程序和驗證摘要, 和雜質的特徵應提供.
規範(s) 應提供3.2.P.5.1起.
3.2.P.5.4下提供嘅批次分析嘅表格摘要, 在適當時應包含圖形表示.
2.3. P.6 參考標準或材料 (名字, 劑型)
來自3.2.P.6嘅信息 (表格演示文稿, 在適當時) 應包括.
2.3. P.7集裝箱封閉系統 (名字, 劑型)
應包括3.2.P.7中嘅信息簡要說明和討論.
2.3. P.8穩定性 (名字, 劑型)
所進行的研究摘要 (條件, 批次, 分析程序) 簡要討論穩定性研究嘅結果同結論,並包括數據分析. 關於儲存條件同保質期嘅結論,, 如果適用,, 應給予使用中嘅存儲條件同保質期.
穩定性嘅表格摘要來自3.2.P.8.3, 在適當時用圖形表示, 應包括.
批准後穩定性協議, 如3.2.P.8.2中所述, 應提供.
2.3. 附錄
2.3. 區域信息

2.4. 非臨床概述

非臨床概述應提供糢塊中信息嘅綜合整體分析 4. 麻麻., 非臨床概述不應超過約 30 頁面.
非臨床概述應按以下順序顯示:
·非線性測試策略概述
·藥理學
·藥理動力學
·毒理學
·綜合概述和結論
·文獻參考列表
綜合概述和結論應明確界定非臨床研究所證明的人類藥物特徵,並得出邏輯, 支持產品用于預期臨床用途嘅充分結論. 服用藥理學, 藥代動力學, 同毒理學結果考慮在內, 應討論非臨床性發現對人類安全使用藥物的影響 (即。, 適用於標籤).
ICH M4S (R 2) 糢塊 2.4 為非臨床概述嘅內容提供指導. 糢塊中嘅非臨床信息 2.4 同糢塊 4 通常唔需要多源 (通用) 藥品. 但是,在某些情況下,例如安全雜質配置文件嘅變化, 應進行安全評估研究.

2.5 臨床概述

臨床概述旨在對常見技術文檔中嘅臨床數據進行批判性分析. 臨床概述必須參考綜合臨床摘要中提供的應用數據, 個別臨床研究報告 (ICH E3), 同其他相關報告; 但它應該主要提出呢啲數據嘅結論同影響, 唔應該重述佢哋.
特別, 臨床摘要應提供CTD臨床信息嘅詳細事實匯總, 臨床概述應提供呢啲發現以及任何其他相關信息嘅簡明討論同解釋 (例如., 可能具有臨床影響嘅相關動物數據或產品質量問題).
臨床概述應按以下順序顯示:
目錄
2.5.1 產品開發理念
2.5.2 生物製藥概述
2.5.3 臨床藥理學概述
2.5.4 效率概述
2.5.5 安全概述
2.5.6 收益和風險結論
2.5.7 文獻參考
ICH M4E (R1) 糢塊 2.5 為臨床概述嘅內容提供指導.

M奥杜莱 3: 質量

質素糢塊遵循ICH M4Q中概述嘅結構同說明性說明 (R1). 文本僅在需要強調的情況下由文檔中複製.

3.1 目錄 (糢塊 3)

目錄應畀出糢塊中每個研究報告嘅位置 3

3.2. S數據主體 – 藥物物質

以下信息可以作為API嘅信息提交(如適用):
  • 選項 1 – 確認API資格預審文件
  • 選項 2- 歐洲藥典適用性證書 (Cep)
  • 選項 3 – 活性藥物成分主文件 (阿普伊姆) 程序
  • 選項 4 ·產品檔案中嘅完整詳細信息
對於含有多個藥物物質的藥物產品, 應提交每種藥物物質嘅信息.
其中提到CEP, 申請人必須提供CEP持有人嘅出(訪問信). 訪問信應喺糢塊中提供 1.2.16. 世衛組織資格預審的證據也應在本節下提供(如適用).
申請人應喺API部分嘅開頭明確說明 (喺Pd同Qos - pd中) 如何提交每個API製造商嘅API信息. 申請人或FPP製造商提交嘅API信息應包括以下選項,根據使用嘅選項.

選項 1: 確認API資格預審文件.

糢塊中應提供API資格預審文件確認嘅完整副本 1, 以及以FPP製造商或申請人嘅名義正式填寫嘅授權箱.
申請人應在檔案中提供以下信息, 數據匯總喺QOS-PD中.
– 3.2. S.1.3一般屬性–討論不受API製造商規範控制嘅其他適用物理化學品同其他相關API屬性, 例如:. 根據本節中嘅指南,溶解性同多態性.
– 3.2. S.2 =如果FPP嘅無菌性基於API嘅無菌製造,則應提供滅菌過程嘅數據以及完整嘅驗證數據.
– 3.2. S.3.1結構同其他特徵嘅闡明–用于識別多態和顆粒大小分布嘅研究, 在適用的情況下, 根據本節中嘅指南.
– 3.2.S.4.1規格- FPP製造商嘅規格,包括API製造商規格嘅所有測試和限制,以及API製造商嘅規格(如多態性同/或顆粒大小分布)無法控制嘅任何附加測試和驗收標準.
– 3.2. S.4.2/3.2.S.4.3分析程序和驗證–FPP製造商使用嘅任何方法,以及API製造商規範中嘅方法.
– 3.2. S.4.4批量分析–至少兩批試點比例嘅結果, 證明符合FPP製造商嘅API規範.
– 3.2. S.5參考標準或材料–有關FPP製造商參考標準嘅信息.
– 3.2.S.7穩定性–支持重新測試期嘅數據,如果提議嘅重試期較長,抑或建議嘅存儲條件溫度或濕度高於資格預審API.

·選項 2: 歐洲藥典嘅適用性證書 (Cep)

CEP嘅完整副本 (包括任何附件) 應在模塊中提供 1. CEP嘅准入聲明應由CEP持有人代表FPP製造商或申請人向WHO藥品資格預審方案(參考CEP )正式填寫,.
另外., 應包括書面承諾,如果CEP被撤銷,申請人將通知NAFDAC. 申請人仲應承認,退出CEP將需要額外考慮API數據要求以支持PD. 書面承諾應隨糢塊中嘅CEP副本一起附 1.
與CEP一起, 申請人應在檔案中提供以下信息, 數據匯總喺QOS-PD中.
  • 3.2. S.1.3一般屬性–討論不受CEP同Ph.Eur控制嘅API任何其他適用物理化學品同其他相關屬性. 專著, 例如:. 根據本節中嘅指南,溶解性同多態性.
  • 3.2. S.3.1結構同其他特徵嘅闡明–識別多態性嘅研究 (除非CEP指定多態形式) 同顆粒大小分佈, 在適用的情況下, 根據本節中嘅指南.
  • 3.2. S.4.1規範–FPP製造商嘅規格,包括CEP同Ph.Eur嘅所有測試和限制. 專著同CEP同Ph.Eur中未控制嘅任何附加測試和驗收標準. 專著, 例如多態和/或顆粒大小分佈.
  • 3.2. S.4.2/3.2. S.4.3分析程序和驗證–除CEP同Ph.Eur中嘅方法外,FPP製造商使用嘅任何方法. 專著.
  • 3.2. S.4.4批量分析–至少兩批試點比例嘅結果, 證明符合FPP製造商嘅API規範.
  • 3.2. S.5參考標準或材料–有關FPP製造商參考標準嘅信息.
  • 3.2.S.6集裝箱封口系統-規格包括主要包裝部件嘅說明同識別,除非CEP指定咗集裝箱關閉系統,申請人聲明有意使用相同嘅容器閉合系統.
  • 3.2.S.7穩定性–除非CEP指定與申請人提議嘅相同或更長嘅測試周期番, 和存儲條件相同或溫度和濕度高於申請人建議的溫度和濕度.
喺無菌API嘅情況下, 有關API滅菌過程嘅數據,包括驗證數據,應包含喺PD中.

選項 3: 活性藥物成分主文件 (阿普伊姆) 程序

化學嘅全部細節, 製造工藝, API製造和流程驗證期間嘅質素控制可能由API製造商作為APIMF提交
喺呢種情況下, 打開部分 (非專有信息) 需要作為3.2. s嘅附件完整地納入Pd. 另外., 申請人或FPP製造商應完全按照所提供的指導完成PD同QOS-PD中嘅以下部分,除非相關部分另有說明:
一般信息S.1.1+S.1.3
製造S.2
製造商(s) S.2.1
製造工藝和工藝控制S.2.2嘅描述
關鍵步驟同中間體嘅控制S.2.4結構同其他特徵嘅闡明S.3.1
雜質S.3.2
API S.4.1+S.4.5嘅控制
參考標準或材料S.5
集裝箱封閉系統S.6
穩定性S.7.1=S.7.3
申請人有責任確保完整嘅APIMF (即. 申請人嘅開放部件同API製造商嘅受限部件) 由API製造商直接提供畀NAFDAC,並且申請人有權訪問APIMF中有關API當前製造嘅相關信息.
PDF糢塊中應提供訪問信嘅副本 1. APIMF持有人可以使用為選項"PD中嘅全部詳細信息"提供嘅指南嚟準備其APIMF嘅開放同受限部分嘅相關部分.
仲應參考世衛組織技術報告系列中嘅亞太基金基金準則, 唔係.. 948, 附件 4 (4).

選項 4: PD中嘅完整詳細信息

有關3.2.S活性藥物成分部分嘅信息, 包括化學嘅全部細節, 製造工藝, API製造和流程驗證期間嘅質素控制, 應如本準則後續部分所述,PD中提交緊. QOS-PD應按節完成 3.1 呢啲準則.
3.2. S.1一般信息 (名字, 製造商)
3.2. S.1.1命名 (名字, 製造商)
應提供有關藥物物質名稱的信息. 例如:
·舉薦國際非專有名稱 (酒店.);
·簡稱(如果相關);
·化學名稱(s);
·公司或實驗室代碼;
·其他非專有名稱(s), 例如., 國家名稱, 美國採用名稱 (蘇桑), 日語接受名稱 (1月); 英國批准名稱 (禁止), 同化學文摘服務 (Cas) 註冊表編號.
所列化學名稱應與科學文獻中出現嘅化學品名稱同產品標籤信息中出現嘅名稱一致 (例如:. 在產品特性摘要中 (斯姆普克) 同包裝傳單, 都稱為患者信息單張 (必)).
如果存在多個名稱,應指示首選名稱.
3.2. S.1.2結構 (名字, 製造商)
結構公式, 包括相對同絕對嘅立體化學, 分子公式, 同相對分子質素應提供.
此信息應與第一節中提供嘅信息一致 3.2. S.1.1. 對於作為鹽存在嘅API,仲應提供自由堿或酸嘅分子質素.
3.2. S.1.3一般屬性 (名字, 製造商)
結構, 分子公式, 分子量和結構公式指定. 人性中心,如果發現任何.
此信息可用于開發規範, 在制定FP和測試以釋放和穩定性目的.
應討論API嘅物理同化學性質, 包括物理描述, 普通溶劑中嘅溶解性 (例如:. 水, 醇, 二氯甲烷和丙酮), 定量水性pH溶解性剖面 (例如:. pH 1.2~6.8, 劑量/溶解度體積), 多態性, pH同pKa值, 紫外 (Uv) 吸收最大值和摩爾吸收率, 熔點, 折射 (液體), 吸濕性和分區系數 (請參閱QOS - pd中嘅表格). 此列表並非詳盡無遺,但會說明可包含的信息類型.
下面將更詳細地討論API需要考慮的一些最相關嘅屬性.

物理描述

物理描述應包括外觀, 顏色同物理狀態. 固體形式應確定為晶體或無定形 (有關API實體窗體嘅更多信息,請參閱3.2.S.3.1).
溶解度同定量水性pH溶解性剖面
對於提交API數據嘅所有選項,應提供以下內容.
應提供一些常見溶劑中的溶解性 (例如:. 在水中, 醇, 二氯甲烷和丙酮).
生理pH範圍內嘅溶解性 (pH 1.2~6.8) 在幾個緩衝介質中應提供毫克/毫升. 如果此信息不易獲得 (例如:. 從文獻參考), 它應該喺內部生成.
對於固體口服劑型, 劑量/溶解度應根據公式確定:
最大劑量強度 (鎂)
劑量/溶解量=
藥物的最小濃度 (毫克/毫升) *
* 對應於喺生理pH範圍內確定嘅最低溶解度 (pH 1.2~6.8) 同溫度 (37 ± 0.5 °C).
根據生物製藥分類系統 (Bcs), 高溶性 (或高水溶性) API係嗰啲劑量/溶解度≤ 250 毫升.
例如, 化合物A具有其最低的溶解度 37 ±0.5°C, 1.0 毫克/毫升在pH 6.8 並喺 100 鎂, 200 毫克和 400 毫克強度. 此API唔會被視為BCS高可溶性API,因為它的劑量/溶解度大於 250 毫升 (400 毫克/1.0毫克/毫升| 400 毫升).
多態性
如ICH嘅CTD-Q問題同答案/位置問題文檔中建議 (5) 以下列表說明特定數據應位於PD中嘅位置:
·多態形式(s) 建議嘅API中應列喺第一節中 3.2. S.1.3.
·製造工藝和工藝控制嘅描述 (3.2.S.2.2) 應指示製造哪種多態形式, 相關情況.
·為識別API嘅潛在多態形式而執行嘅文獻參考或研究, 包括研究結果, 應在第一節中提供 3.2. S.3.1.
·如果要定義或限制多態形式 (例如:. 對於非BCS高可溶性和/或多態性已被確定為問題嘅API), 詳細信息應包含在
3.2.S.4.1+ 3.2. S.4.5.
呢啲準則嘅參考部分包含其他信息.
顆粒大小分佈
如ICH嘅CTD-Q問題同答案/位置問題文檔中建議 (5), 為確定API嘅粒徑分布而進行的研究應喺第3.2.S.3.1節中提供 (有關更多信息,請參閱本指南嘅一部分).
來自文獻嘅信息
具體研究或出版文獻嘅支持性數據同結果可以包含喺本部分內或附加到本節中.
請參閱ICH指南: Q6A同Q6B
3.2. S.2製造 (名字, 製造商)
3.2. S.2.1製造商(s) (名字, 製造商)
的名稱, 地址, 同每個製造商嘅責任, 包括承包商, 以及每個提議嘅生產場地或涉及製造和測試嘅工廠.
製造所涉及的設施, 包裝, 標籤, 應列出API嘅測試同存儲. 如果某些公司只負責特定步驟 (例如:. API嘅銑削) 應該清楚地表明.
製造商或公司名單應指定生產或製造站點的實際地址(s) 涉及 (包括蚊(s) 同單位(s)), 而唔係行政辦公室. 電話號碼(s), 傳真號碼(s) 同電子郵件地址 (叶斯) 應提供.
應為API嘅生產提供有效的製造授權. 如果可用, 糢塊中嘅PD中應提供符合GMP嘅紙 1.
3.2. S.2.2製造工藝和工藝控制說明 (名字, 製造商)
API製造流程嘅描述代表申請人對API製造嘅承諾. 應提供信息,以充分描述製造流程和工藝控制. 例如:
合成過程嘅流程圖(叶斯) 應提供包括分子公式, 權重, 屈服範圍, 起始材料嘅化學結構, 中間體, 反映立體化學的試劑和API, 並確定工作條件和溶劑.
應提交製造過程嘅順序程序敘述. 敘述應包括, 例如., 原材料數量, 溶劑, 反映商業製造嘅代表性批次規模嘅催化劑和試劑, 確定關鍵步驟, 過程控制, 設備和操作條件 (例如:. 溫度, 壓力, Ph, 和時間).
應以與主要流程相同嘅細節嚟解釋同描述替代過程. 應確定後處理步驟並證明其合理性. 任何支持理由嘅數據都應引用或以3.2.S.2.5提交.
使用亞太基金基金程序嘅地方, 可指示對APIMF受限部分嘅交叉引用以提供機密信息. 喺呢種情況下, 如果詳細信息在"受限"部件中顯示, 為PD嘅一部分提供嘅信息包括流程圖 (包括分子結構和所有試劑和溶劑) 以及製造過程嘅簡要概述, 特別強調最後嘅步驟, 包括淨化程序. 然而, 用于無菌API, 應於"打開"部分提供滅菌過程嘅完整驗證數據 (如果冇對最終產品進行進一步滅菌).
以下要求適用於提交API信息嘅第四个選項, 其中完整嘅細節喺檔案中提供.
如ICH Q7同世衛組織技術報告系列所討論, 唔係.. 957, 附件 2, 把API起始材料引入製造流程嘅啲係應用GMP要求嘅起點. API起始材料本身需要提出,其選擇需要製造商證明其合理性,並由評估員接受。. 考慮到分子嘅複雜性,應提出API起始材料, API起始材料與最終API嘅接近性, API起始材料作為商用化學品嘅可用性以及對API起始材料嘅質素控制. 理由應記錄在檔案中,並可供NAFDAC GMP檢查員審查.
喺API起始材料係一個複雜嘅分子,並且只有最少數量嘅合成步驟由最終API, 應提出另一個稱為合成起始材料的分子,申請人有理由選擇. 合成起始材料定義製造過程中要喺應用程序中描述API嘅起點. 申請人應提出並證明哪些物質應被視為合成的起始材料 (有關進一步指導,請參閱第3.2.S.2.3節). 喺透過發酵獲得API嘅前體嘅情況下, 或植物或動物起源, 呢種分子可以被認為係API起始材料,無論複雜性如何.
在特殊情況下,可接受一步合成, 例如., 其中API起始材料由CEP覆蓋, 或API起始材料係透過喺世衛組織規劃嘅藥物資格預審程序中透過APIMF或API資格預審程序接受嘅API, 抑或当API嘅結構如此簡單,一步合成可以合理, 例如:. 埃瑟姆丁醇或乙酰胺.
除了根據ICH M4Q對製造流程嘅詳細說明, 材料回收, 如果有嘅話, 應詳細描述它們被引入到流程中嘅步驟. 應充分控制恢復操作,使雜質水平不會隨著時間的推移而增加. 用于溶劑嘅恢復, 任何加工,以提高回收溶劑嘅質素應描述. 關於過濾嘅回收 (母親酒) 獲得第二作物, 應提供母酒最大持有時間嘅信息,以及可回收材料嘅最大次數. 應提供雜質水平數據,以證明過濾油的回收合理性.
如果一個API製造商正在使用多個製造站點, 應提供表格形式嘅綜合列表,比較每個站點嘅流程並突出顯示任何差異.
製造中使用嘅所有溶劑 (包括淨化和/或結晶步驟(s)) 應明確識別. 最後步驟中使用的溶劑應是高純度. 不建議在淨化和/或結晶的最後步驟中使用回收溶劑; 然而, 提供足夠緊嘅數據以證明回收嘅溶劑符合ICH Q7中概述嘅適當標準時,其使用係合理嘅。.
已識別多態性或無定形形式嘅地方, 應說明合成產生嘅表單.
粒子大小被視為關鍵屬性嘅地方 (詳情請參閱3.2.S.3.1) 粒子大小縮小方法(s) (例如:. 銑削或微化) 應描述.
應為使用替代製造工藝提供理由. 替代流程嘅解釋應與主要流程嘅詳細程度相同. 應證明,替代流程獲得嘅批次與主要流程獲得嘅雜質配置文件相同. 如果獲得嘅雜質配置文件不同,則應根據S.3.2中描述嘅要求證明該配置文件係可以接受嘅.
提供試點規模製造嘅信息係可以接受嘅, 只要它代表生產規模,並根據NAFDAC變異指南嘅要求立即向NAFDAC報告規模.

3.2. S.2.3材料控制 (名字, 製造商)

用于制造API嘅材料 (例如:. 原料, 起始材料, 溶劑, 試劑, 催化劑) 應列出識別在此過程中使用每個材料嘅位置. 應提供有關呢啲材料嘅質素同控制嘅信息. 應提供表明材料符合其預期用途嘅標準嘅信息, 酌情 (詳細信息在
3.2.A.2). 使用亞太基金基金程序嘅地方, 對APIMF嘅受限部分嘅交叉引用被認為足以滿足本節.
以下要求適用於提交API信息嘅第四个選項, 其中完整嘅細節喺檔案中提供.
API起始材料應具有完全的特徵,並提出適當的規格並說明理由, 包括, 假假地., 標識控件, 測定, 雜質含量和材料的任何任何其他關鍵屬性. 對於每個API起始材料, 生產基地嘅名稱同地址(s) 製造商(s) 應指示. 應向每家製造商提供API起始材料嘅準備簡要說明, 包括溶劑, 使用嘅催化劑同試劑. 應為適用於來自所有來源嘅材料嘅起始材料提出一套單一嘅規格. API起始材料製造商嘅任何未來更改, 應通知準備模式或規格.
如第3.2.S.2節所述,有時可能需要定義合成的起始材料. 麻麻., PD中描述嘅合成嘅啟動材料應該:
a) 最終API中間體之前成為一個或多個合成步驟緊嘅合成前體. 酸, 基地, 鹽, API嘅酯同類似衍生物, 以及一個單一嘅阿尼蒂默API嘅種族伴侶, 唔被視為最終中間體;
B) 係一個良好嘅特點, 孤立和純化的物質,其結構完全闡明,包括其立體化學 (在適用的情況下);
C) 具有定義明確嘅規範,其中包括一個或多個特定嘅身份測試和測試,以及檢測和指定嘅限制, 未指定和總雜質;
D) 作為一個重要嘅結構片段納入API嘅結構.
合成材料使用嘅規格副本, 提取, PD中應提供隔離和淨化步驟, 包括起始材料, 試劑, 溶劑, 催化劑和回收材料. 應確認該規格適用於每個製造廠使用嘅材料. 應提供合成起始材料分析證書. 應喺QOS-PD中提供有關起始材料嘅信息摘要.
應考慮和討論合成成最終API的起始材料的雜質的結轉.
應提供證明信,確認API同用于製造API嘅起始材料同試劑冇傳播動物海綿狀腦病劑的風險.
可用時,CEP可證明符合關於可傳播海綿狀腦病的建議 (謝) 應提供. CEP嘅完整副本 (包括任何附件) 應在模塊中提供 1.
參考文檔: ICH Q6A.

3.2. S.2.4關鍵步驟和中間體的控制 (名字, 製造商)

關鍵步驟: 測試和驗收標準 (理由包括實驗數據) 喺製造工藝3.2.S.2中肯定嘅關鍵步驟執行,以確保流程得到控制.
中間體: 應提供在此過程中隔離嘅中間體嘅質素同控制信息.
使用亞太基金基金程序嘅地方, 對APIMF受限部分嘅交叉引用被認為足以滿足PD嘅部分, 除了與申請人相關嘅信息.
下列要求適用於提交API信息嘅第四个選項,其中喺檔案中提供了全部詳細信息.
應確定關鍵步驟. 呢啲可以包括: 去除或引入顯著雜質的步驟; 引入基本分子結構元素(如手性中心或導致重大化學轉化)的步驟; 對可能與固體劑型使用相關嘅API嘅固態屬性同同質性有影響嘅步驟.
應提供隔離中間體嘅規範,並應包括身份測試和驗收標準, 純度同測定, 在適用的情況下.
參考文檔: ICH Q6A.

3.2. S.2.5過程驗證和/或評估 (名字, 製造商)

應包括無菌處理和滅菌的工藝驗證和/或評估研究.
使用亞太基金基金程序嘅地方, 對APIMF受限部分嘅交叉引用被認為足以滿足PD嘅部分.
下列要求適用於提交API信息嘅第四个選項,其中喺檔案中提供了全部詳細信息.
預期所有API嘅製造流程都得到適當控制. 如果API係無菌製備嘅,則應提供無菌處理和/或滅菌方法嘅完整描述. 仲應提供用于維護API喺存儲同運輸過程中嘅無菌性嘅控件嘅說明. 替代過程應合理並描述 (請參閱3.2.S.2.2中預期詳細信息級別嘅指南).

3.2. S.2.6製造工藝開發 (名字, 製造商)

應說明和討論用于生產比較生物可用性或生物豁免嘅API嘅製造工藝和/或製造場地嘅重大變化, 放大縮小字體功能放大縮小字體功能, 飛行員, 和, 如果可用, 生產規模批次.
應參考該科提供的API數據 3.2. S.4.4.
使用亞太基金基金程序嘅地方, 對APIMF受限部分嘅交叉引用被認為足以滿足PD嘅部分.

3.2. S.3特徵化 (名字, 製造商)

3.2. S.3.1結構同其他特徵嘅闡明 (名字, 製造商) 基於結構嘅確認, 例如:. 應提供合成路線和光譜分析. 信息,如同位素主義嘅潛力, 立體化學嘅鑑定, 或形成多態性的潛力也應包括在內.

結構嘅闡明

PD應包括質素保證 (Qa) 光譜嘅認證副本, 峰值分配同對所執行研究數據嘅詳細解釋,以闡明同/或確認API嘅結構. QOS-PD應包括所執行研究的列表和研究結論 (例如:. 結果是否支持提議嘅結構).
對於官方認可嘅藥典中未描述嘅ABI, 為闡明和/或確認化學結構而進行的研究通常包括元素分析, 紅外 (紅外), 紫外 (Uv), 核磁共振 (核磁共振) 同質素光譜 (女士) 研究. 其他測試可能包括X射線粉末衍射 (XRPD) 同微分掃描熱量計度 (Dsc).
對於官方認可嘅藥典中描述嘅API,通常足以由每個擬議製造商提供API嘅IPI嘅IR頻譜副本(s) 與官方認可嘅藥典參考標準同時運行. 有關可接受嘅參考標準或材料嘅詳細信息,請參閱第3.2.S.5節.

伊索默主義/立體化學

当API係手性, 應具體說明在比較生物研究中是否使用了特定的立體異構體或立體異構體混合物, 以及應提供有關喺FPP中使用嘅API嘅立體異構體嘅信息.
立體異構症存在嘅地方, 應討論製造過程可能導致嘅異構體以及引入性嘅步驟. 應確定API與比較產品中API嘅同位素組成相同. 應提供關於同位素混合物或單一同體體嘅物理同化學性質嘅信息, 酌情. API規範應包括一項測試,以確保同位素標識同純度.
同位素混合物中同構體嘅相互轉換潛力, 或種族化嘅單一嘅謎語應該討論.
当API嘅單個電工因非藥典API而索賠時, 應提供唔啱稱中心絕對配置嘅明確證明, 如由單個晶體的X射線確定.
如果, 基於API嘅結構, 冇立體主義嘅潛力, 它足以包括一個聲明,以呢種效果.

多態性

好多ABI可以喺固態中以不同嘅物理形式存在. 多態性被描述為API作為兩個或兩個以上晶體相存在嘅能力,呢啲晶體相位對晶格中嘅分子有不同嘅排列同/或構象. 無定形固體由分子的無序排列組成,不具有可區分的晶格. 溶劑是晶體形式,含有溶劑的口感或非收縮量. 如果合併溶劑是水,溶劑也通常被稱為水合物.
同一化合物嘅多態性形式喺內部固態結構中不同,, 因此, 可能具有不同的化學和物理性質, 包括包裝, 熱力學, 光譜, 動力學, 面間同機械特性. 呢啲屬性可直接影響API可處理性, 藥品嘅可製造性和產品質量及性能, 包括穩定性, 溶解和生物可用性. 多態形式的意外外觀或消失可能導致嚴重的藥物後果.
打算向NAFDAC同API製造商註冊產品嘅申請人應充分了解所用和/或生產嘅API嘅多態性. 關於多態性嘅信息可以來自科學文獻, 專利, 匯編或其他參考,以確定多態性是否為問題, 例如:. 對於唔係BCS高可溶性嘅API. 喺冇已公佈嘅數據嘅情況下,ABI唔係BSC高度可溶性嘅, 多態性篩選將係必要嘅,以確定API是否可以存在於一個以上嘅晶體形式. 多態性篩選通常通過使用不同溶劑和條件的結晶研究完成.
好多方法可用于描述API嘅多態性形式. 单晶X射綫衍射嘅非等效結構演示目前被視為多態性嘅明確證據. XRPD都可用于提供多態性嘅明確證明. 其他方法, 包括顯微鏡, 熱分析 (例如:. Dsc, 熱重力分析和熱階段顯微鏡) 同光譜 (例如:. 紅外, 拉曼, 同固態核磁共振 (斯尼姆尔)) 有助於進一步描述多態性形式. 多態性係一個問題, ABI的申請人或製造商應證明採用合適的方法, 能夠區分不同嘅多態性, 可供他們使用.
決策樹 4 ICH Q6A可用于必要嘅篩查同 4(2) 可用于調查不同嘅多態性形式是否具有可能影響性能嘅不同屬性, FPP嘅生物可用性和穩定性,並決定是否喺API發佈和存儲時對首選多態性進行監測. 邊度有首選嘅多態性, 驗收標準應納入API規範,以確保商業材料與比較生物可用性或生物豁免研究中使用的API批次的多態等效性. 應提供上述方法用于比較生物可用性或生物豁免研究嘅API批次嘅多態性特徵. 用于控制多態性形態嘅方法應證明係針對首選形式嘅特殊性.
多態性也可以包括解脫或水化產品 (都被稱為偽多態性). 如果API以已解決的形式使用, 應提供以下信息:
·3.2.S.2.4中無溶劑API嘅規格, 如果該化合物係合成前體; ·溶解API嘅規格,包括適當限制API與溶劑嘅重量比 (與數據,以支持建議嘅限制); ·用于準備安撫嘅方法嘅描述 3.2. S.2.2.
顆粒大小分佈
對於唔係BCS高可溶性包含喺固體FP中嘅AIP, 或含有未溶解API的液體FPP, 材料的粒子大小分佈可能對FPP的體外和/或體內行為產生影響. 顆粒大小分佈在劑量形式性能方面也很重要 (例如:. 提供吸入產品), 實現低劑量片劑中內容的均勻性 (例如:. 2 毫克或更少), 眼科製備所需嘅平滑性同懸架嘅穩定性.
如果粒子大小分佈係一個重要參數 (例如:. 如上述情況), 應提供幾批API嘅調查結果, 包括批次嘅表徵 (叶斯) 用于比較生物可用性或生物豁免研究. API規格應包括粒子大小分佈的控制,以確保與批次中的材料一致 (叶斯) 用于比較生物可用性和生物豁免研究 (例如:. d10嘅限制, d50同d90). 標準應從統計學上確定, 基於上述研究對測試結果嘅標準偏差. 為說明性目的提供以下示例,作為粒子大小分佈限制的可能接受標準:
▪d10唔超過 (尼姆特) 10% 總體積小於Xμm;
▪ d50 XX μm-x μm;
▪D90唔低於 (西北) 90% 總體積小於Xμm.
粒子大小分布嘅其他控制可以被認為係可以接受嘅, 如果科學合理嘅話.
參考文檔: ICH Q6A.

3.2. S.3.2雜質 (名字, 製造商)

應提供有關雜質嘅信息.
關於雜質控制原則嘅詳細信息 (例如:. 報告, 身份同資格認證) ICH Q3A中概述, Q3B同Q3C雜質指南 (10–12。). 下文概述咗關於國際信息發展準則中討論的一些內容嘅其他信息.
無論是否聲稱藥典標準, 應討論合成產生的潛在和實際雜質, API嘅製造或降解. 應該包括啟動材料, 農副產品, 中間體, 手性雜質和降解產品,應包括化學名稱, 雜質的結構和來源. 藥典API嘅討論不應局限於API專著中指定嘅雜質.
QOS-PD糢闆中嘅表應用於匯總有關AP更新和流程相關雜質嘅信息. 在QOSPD中, 術語"原產地"係指如何以及在何處引入雜質 (例如:. "合成中間從步驟 4 合成"或"由于步驟重新排列而產生嘅潛在次要產品" 6 合成ŋ). 如果雜質係API嘅新陳代謝物,都應說明.
報告嘅ICH閾值, 識別 (用于設置個人未知雜質嘅限制) 同資格係根據潛在嘅接觸雜質決定嘅, 例如:. 按每日最大劑量 (Mdd) 的API. 對於具有不同MDD值嘅多種劑量形式同優勢嘅ABI, 必須考慮每個演示文稿嘅閾值同相應嘅控制,以確保解決雜質帶嚟嘅風險. 通常係透過使用最高潛力嘅每日MDD實現嘅, 而唔係維護劑量. 對於父產品,API嘅最大鐘頭劑量都應包括在內.
承認半合成來源嘅ABI唔屬於ICH雜質指南嘅範圍. 然而, 取決於API嘅性質同化學改性步驟嘅程度, 有關控制雜質的原則 (例如:. 報告, 身份同資格認證) 可擴展到適用於半合成來源嘅ABI. 作為一個說明性嘅例子, 其前體分子來自發酵過程或植物或動物起源的天然產物的API, 隨後經歷咗幾次化學反應, 一般屬於ICH雜質指南嘅範圍, 而一個API,其唯一嘅化學步驟係形成由發酵產品嘅鹽一般唔會. 據瞭解,呢啲類型嘅API有一定的自由度.

雜質嘅識別

藥典承認,ABI可以由各種來源獲得,因此可以含有專著開發過程中未考慮嘅雜質. 此外, 生產或來源嘅改變可能導致額外嘅雜質,而呢啲雜質不受官方編目專著嘅充分控制. 因此, 每個PD獨立評估,以考慮擬議路線可能產生嘅潛在雜質(s) 合成. 由於呢啲原因,ICH限制未指明嘅雜質 (例如:. 尼姆特 0.10% 或 1.0 毫克每日攝入量 (以較低者為準) 對於具有MDD≤的API 2 g/天) 一般建議, 而唔係官方簡編專著中可能出現嘅未指明雜質嘅一般限制, 可能高於適用嘅ICH限制.

雜質資格

應諮詢ICH雜質指南,以選擇雜質嘅資格. 喺官方認可嘅藥典中肯定雜質嘅限值通常被認為係合格嘅. 以下係現有ABI中雜質資格嘅附加選項:
透過將現有API中發現嘅雜質測試結果與使用相同驗證嘅創新產品中觀察到嘅雜質測試結果進行比較,可以接受現有API中存在嘅雜質限制, 穩定性指示分析程序 (例如:. 比較 (高性能液體色譜 (HPLC) 研究). 如果冇創新產品樣品, 雜質配置文件都可以與具有相同管理路線同類似特徵嘅不同資格預審FPP進行比較 (例如:. 平板電腦與膠囊). 建議對可比樣品進行研究。 (例如:. 類似年齡嘅樣本) 獲得雜質配置文件嘅有意義嘅比較.
創新者或合格定嘅FPP加速或強調存儲條件下嘅研究產生嘅雜質水平被認為係不可接受嘅/合格嘅.
如果現有API中嘅雜質素反映咗喺創新者中觀察到嘅水平或資格預審FPP中觀察到嘅雜質,則現有API中存在嘅指定雜質將被視為合格.

設定驗收標準嘅基礎

應提供確定雜質驗收標準的依據. 係透過考慮與API相關嘅雜質嘅識別和鑑定閾值而建立嘅 (例如:. 起始材料, 農副產品, 中間體, 人性雜質或降解產物) 同工藝相關雜質嘅濃度限制 (例如:. 殘留溶劑) 根據適用嘅ICH準則 (例如:. Q3A, 第3季度).
合格級別應被視為允許嘅最大限制. 然而, 一般唔鼓勵過實際製造工藝能力寬得多嘅限制. 因此, 驗收標準仲考慮到每個製造商喺幾批API中發現嘅實際雜質水平, 包括用于比較生物可用性或生物豁免研究嘅批次中發現嘅水平. 報告定量測試結果時, 應提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合". 已測試大量批次緊嘅情況下,可以用一系列分析結果匯總所有測試批次嘅結果。.
如果官方簡編專著中指定咗不受擬議常規內部分析程序控制嘅雜質, 應提供將其排除喺常規分析之外嘅理由 (例如:. 蕨雜質D, 《國際藥典》中列出嘅E同F (Ph.Int) 專著唔係製造商X使用嘅擬議合成路線嘅潛在雜質"). 如果不能提供可接受的理由,則應證明常規內部方法能夠在可接受的水平上分離和檢測官方編目專著中規定的雜質 (例如:. 0.10%). 如果無法執行此類演示, 應在最近幾批中應用藥典方法進行一次性研究,以證明藥典中所列雜質的缺失.
ICH II類溶劑(s) 如果提供適當理由,則喺製造過程嘅最後一步之前使用嘅API規範可免於常規控制. 提交嘅結果顯示少於 10% ICH Q3C限制 (選項I) 溶劑(s) 連續三個生產規模批次或連續六個試點規模批次嘅API或合適嘅中間體將被視為可接受嘅理由. 在此過程中使用嘅最後一步溶劑應始終喺最終嘅API中進行常規控制.
有關可接受嘅剩餘溶劑限制嘅指導,請參閱ICH Q3C. 三甲胺殘留限值 (茶) 一係係 320 基於ICH Q3C選項I或 3.2 毫克/日嘅基礎上,允許每日暴露 (Pde).
缺乏已知, 已建立劇毒雜質 (遺傳毒性) 應討論在此過程中使用或作為子產品形成,並建議適當的限制. 應適當參考現有指南嚟證明呢啲限制嘅合理性 (例如:. 歐洲、歐洲、中國/歐洲、中國/ 251344/2006 (13) 或美國自由貿易協定行業指南. 藥物物質和產品中嘅基因毒性和致癌雜質, 推薦的方法) 或通過提供實驗安全數據或喺同行評審嘅期刊中發佈數據.
製造過程中使用嘅金屬催化劑殘留物,並被確定為成批嘅API,應控制喺規格中. 此要求不適用於作為藥物物質嘅特登成分嘅金屬 (如鹽的計數器離子) 或在FPP中用作藥物輔料的金屬 (例如:. 氧化鐵顏料). 金屬催化劑或金屬試劑殘留物規格限制指南 (歐洲、中國/瑞士國際中心/4446/2000) 或任何等效嘅方法可用于解決此問題. 該要求通常不適用於GMP更恰當地處理嘅無關金屬污染物, 良好的分銷做法 (Gdp) 或任何其他相關的質量規定,如在公認的藥典專著中對來自製造設備和環境的金屬污染進行重金屬測試.
參考文檔: ICH Q6A, Q3A, 第3季度.

3.2. S.4 API控制 (名字, 製造商)

3.2. S.4.1規格 (名字, 製造商)
應提供API嘅規範.
正如ICH嘅Q6A指南所定義嘅 (6), 規範係:
''測試列表, 參考分析程序和適當的接受標準, 這是數值限制, 範圍, 或所述測試的其他標準. 它規定咗API或FPP應符合嘅一套標準,呢啲標準被認為係可接受嘅,用于預期用途. "符合規範"係指API同/或FPP, 根據列出嘅分析程序進行測試時, 符合所列驗收標準. 規格係關鍵嘅質量標準,由製造商提出並證明其合理性,並經監管機構批准。
API規範嘅副本, 日期同由授權人員簽署 (例如:. 質檢總局、質檢部門負責人) 應在PD中提供, 包括每個API製造商以及FPP製造商嘅規格.
FPP製造商嘅API規範應根據標題的QOS-PD糢闆中嘅表進行匯總: 測試, 驗收標準和分析程序 (包括類型, 方法嘅來源同版本).
▪申請人申報嘅標準可以係官方認可嘅簡編標準 (例如:. Bp, Jp, 欧尔博士. Ph.Int, Usp) 或內部 (製造商嘅) 標準.
▪規範參考號同版本 (例如:. 修訂編號和/或日期) 應提供用于版本控制目的.
分析程序▪, 類型應表示所使用的分析過程的類型 (例如:. 視覺, 紅外, Uv, HPLC或激光衍射), 來源係指分析程序嘅起源 (例如:. Bp, Jp, 同博士. Ph.Int, USP或內部) 同版本 (例如:. 代碼號/版本/日期) 應提供用于版本控制目的.
喺有多個API製造商嘅情況下, FPP製造商嘅API規範應係單個編譯嘅規範集,每個製造商嘅規格相同. 在規範中為單個參數規定多個驗收標準和/或分析方法,並聲明"用于製造商A嘅API"係可以接受嘅 (例如:. 喺殘留溶劑嘅情況下).
任何非常規測試都應明確識別為此類測試,並結合關於非常規測試頻率嘅建議進行合理性.
ICH Q6A指南 (6) 概述一些通用同特定嘅ABI測試和標準嘅建議.
參考文檔: ICH Q6A, Q3A, Q3C同官方認可嘅藥典.

3.2. S.4.2分析程序 (名字, 製造商)

應提供用于測試API嘅分析程序.
用于生成PD中提供嘅測試結果嘅內部分析程序嘅副本, 以及FPP製造商提議對AP進行常規測試嘅測試, 應提供. 除非修改,否則冇必要提供官方認可嘅簡編分析程序嘅副本.
用于總結若干不同分析程序和驗證信息嘅表格 (例如:. HPLC檢測/雜質方法, 氣色譜 (Gc) 方法) 可在QOS-PD嘅2.3.R區域信息部分搵到 (即. 2.3.R.2). 呢啲表應用於總結FPP製造商嘅內部分析程序,以確定殘留溶劑, API嘅檢測和純度, 在QOS-PD第2.3.S.4.2節. 用于喺PD中生成檢測和純度數據嘅其他方法可以總結為2.3.S.4.4 (C) 或2.3.S.7.3 (B) QOS-PD. 除非進行了修改,否則無需總結官方認可嘅簡編方法.
雖然HPLC通常被認為係肯定與API相關嘅雜質嘅首選方法, 其他色譜方法,如GC和薄層色譜 (薄) 如果經過適當驗證,都可以使用. 用于確定相關物質, 參考標準通常應可用于每個已識別嘅雜質, 特別是那些已知有毒嘅同雜質嘅濃度應該根據自己嘅參考標準進行量化. 唔純度標準可由藥典中獲取 (單個雜質或分辨率混合物), 來自商業來源或內部準備. 使用API作為外部標準嚟估計雜質水平被認為係可以接受嘅, 只要呢啲雜質嘅響應系數足夠接近API嘅響應系數, 即. 之間 80 和 120%. 如果響應因子超出此範圍,使用API仍是可以接受嘅, 如果應用更正因子. 應為內部方法提供支持修正因子計算嘅數據. 未指明嘅雜質可以使用API溶液作為參考標準進行量化,其濃度與針對個別未指定雜質嘅限值相對應 (例如:.
0.10%). Ph.Int 中相關物質嘅測試. 拉米武丁專著作為一個典型例子.
系統適宜性測試 (SS) 代表該方法嘅一個組成部分,用于確保所選色譜系統嘅滿意性能. 作為最低限度, HPLC同GC純度方法應包括用于分辨率和可重複性嘅SST. 用于HPLC控制API相關雜質嘅方法, 通常係使用API嘅解決方案完成嘅,其濃度與未指定雜質嘅限制相對應. 一般建議解決兩個最接近嘅山峰. 然而, 如果合理,可以使用替代峰嘅選擇 (例如:. 有毒雜質嘅選擇). 按照 Ph.Int. 關於分析方法嘅部分可重複性測試應包括可接受嘅複製注射次數. HPLC檢測方法應包括可重複性嘅SST,此外仲包括峰值唔啱稱, 理論板或分辨率. 對於TLC方法, SST應驗證系統分離和檢測分析器嘅能力(s) (例如:. 透過喺與未指定雜質限制相對應嘅濃度的應用與API對應嘅啲).
參考文檔: ICH第2季度, 世衛組織技術報告系列, 唔係.. 943, 附件 3.

3.2. S.4.3分析程序嘅驗證 (名字, 製造商)

分析驗證信息, 包括用于測試API嘅分析程序嘅實驗數據, 應提供.
應提供用于生成PD中提供嘅測試結果嘅分析程序嘅驗證報告嘅副本, 以及FPP製造商提議對AP進行常規測試嘅測試.
總結若干不同分析過程和驗證信息嘅表格 (例如:. HPLC檢測和雜質方法, GC方法) 可在QOS-PD嘅2.3.R區域信息部分搵到 (即. 2.3.R.2). 呢啲表應用於匯總FPP製造商用于肯定殘留溶劑嘅分析程序嘅驗證信息, API嘅檢測和純度, 在QOSPD第2.3.S.4.3節. 用于喺PD中生成檢測和純度數據嘅其他方法嘅驗證數據可以用2.3.S.4.4嚟概括 (C) 或2.3.S.7.3 (B) QOS-PD.
監管部門和藥典本身都承認咗啲, 可能需要對簡編方法進行驗證. 已發佈嘅簡編方法通常基於來自特定製造商嘅API或FPP進行驗證. 同一API或FPP嘅不同來源可能包含專著開發過程中未考慮嘅雜質和/或退化產品. 因此, 應證明專著和簡編方法適合由預期來源控制API嘅雜質配置文件(s).
一般來說,匯編API測定方法不需要驗證. 然而, 如果本匯編專著中未指定任何潛在雜質,應證明特定匯編測定方法的特異性. 如果使用官方認可嘅簡體方法嚟控制專著中未指定嘅與API相關嘅雜質, 預計對呢啲雜質嘅方法進行充分驗證.
如果聲稱有官方認可嘅簡編標準,並且使用內部方法代替簡編方法 (例如:. 用于檢測或指定雜質), 應證明內在和簡編方法的等價性. 可以透過透過兩種方法對一個樣本進行重複分析並提供研究結果嚟實現。. 對於雜質方法, 所分析的樣品應在相當于其規格限制的濃度下含有雜質的原料藥.
參考文檔: ICH第2季度.

3.2. S.4.4 批次分析 (名字, 製造商)

應提供批次解同批次分析結果.
所提供的信息應包括批號, 批處理大小, 用于度生物利用度或生物量研究的相關原料藥批次嘅日期同生產地點, 臨床前和臨床數據 (如果相關), 穩定性, 飛行員, 擴大規模同, 如果可用, 生產規模的批次.
呢啲數據用于建立API質素嘅規格同評估一致性.
分析結果應至少由API每個擬議製造地點嘅兩批至少試點規模提供,並應包括該批(叶斯) 用于比較生物可用性或生物豁免研究. 試驗規模批次應採用完全代表同模擬應用於完整生產規模批次嘅程序製造.
分析證書副本, 都來自API製造商(s) 同FPP製造商, 應提供剖析批次,並應確定負責生成測試結果的任何公司. FPP製造商嘅測試結果應喺QOS-PD中總結.
對結果嘅討論應側重於為各種測試所記錄嘅觀察結果, 而唔係報告評論,如"所有測試符合規範". 用于定量測試 (例如:. 個人和總雜質測試和檢測測試), 應確保提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合". 對於任何唔完整嘅分析,應提供討論和理由 (例如:. 未根據擬議規範測試嘅結果).
參考文檔: ICH Q6A, Q3A, 第3季度).

3.2. S.4.5規範嘅理由 (名字, 製造商)

應提供API規範嘅理由.
應討論是否包括某些測試, 測試嘅演變, 分析程序和驗收標準, 與官方認可嘅簡編標準嘅差異(s). 如果官方認可嘅簡編方法已被修改或替換,則討論修改或替換方法(s) 應包括.
某些測試嘅理由, 分析程序和驗收標準可能已喺PD嘅其他部分討論過 (例如:. 用于雜質或顆粒大小分布) 唔需要喺呢度重複, 雖然應該提供交叉引用.
參考文檔: ICH Q6A, Q3A, 第3季度, 同官方認可嘅藥典.

3.2. S.5 參考標準或材料 (名字, 製造商)

應提供有關用于API測試嘅參考標準或參考材料嘅信息.
應提供有關參考標準嘅信息(s) 用于喺PD中生成數據, 以及FPP製造商喺常規API同FPP測試中使用嘅測試.
源(s) 應提供用于API測試嘅參考標準或材料 (例如:. 用于識別嘅, 純度同測定測試). 這些可以歸類為主要或次要參考標準.
應從官方認可的藥典來源獲得適當的初級參考標準 (例如:. Bp, Jp, 同博士. Ph.Int, Usp) 一個人存在嘅地方, 同批號應該提供. 如果為API同/或FPP申請藥典標準, 主要參考標準應從該藥典中獲取,當可用. 來自官方認可嘅藥典來源嘅主要參考標準不需要進一步嘅結構闡明.
否則,主要標準可能係已完全具有特徵嘅API嘅一批 (例如:. 由Ir, Uv, NMR同質譜 (女士) 分析). 可能需要進一步嘅淨化技術,要材料可作為化學參考標準使用. 化學參考物質的純度要求取決於其預期用途. 建議進行鑑定測試嘅化學參考物質不需要仔細純化,因為該物質中含有小部分雜質,因此通常對測試冇明顯影響。. 另一方面, 用于檢測嘅化學參考物質應具有高度嘅純度 (如 99.5% 在乾燥或水/溶劑免費的基礎上). 必須申報主要參考標準嘅絕對內容,並遵循該方案: 100% 減去有機雜質 (透過檢測程序量化, 例如:. HPLC或DSC) 減去無機雜質減去乾燥損失的揮發性雜質 (或含水量減去殘留溶劑).
輔助 (或內部) 參考標準可以透過建立它對一個合適的初級參考標準使用, 例如:. 同時提供主要同次要參考標準嘅IR清晰副本,並提供其分析證書, 包括根據主要參考標準肯定嘅檢測. 二級參考標準通常針對其預期目的進行特徵和評估,除常規測試中使用嘅程序外,仲具有其他程序 (例如:. 如果喺唔用于常規目的嘅額外淨化過程中使用咗額外嘅溶劑).
通常應針對指定雜質制定參考標準. 有關其他指導,請參閱3.2.S.4.2.
參考文檔: ICH Q6A, 世衛組織技術報告系列, 唔係.. 943, 附件 3.

3.2. S.6集裝箱關閉系統 (名字, 製造商)

集裝箱關閉系統嘅描述(s) 應提供, 包括每個主要包裝部件嘅構建材料嘅身份, 及其規格. 規範應包括描述和標識 (同關鍵尺寸與圖紙, 在適當時). 非合成方法 (與驗證) 應包括, 在適當時.
對於非功能性二次包裝組件 (例如:. 嗰啲唔提供額外保護嘅人), 只應提供簡短嘅描述. 用于功能二次包裝組件, 應提供其他信息.
是否合適,應討論, 例如., 材料選擇, 防潮和防光, 建築材料與API嘅兼容性, 包括吸附到容器和浸出, 和/或建築材料的安全性.
中。 世衛組織藥品包裝指南同官方承認嘅 藥典 應諮詢有關API包裝信息嘅建議.
主要包裝組件係嗰啲與API或FPP直接接觸嘅組件. 應提供主要包裝部件嘅規格,並應包括特定嘅標識測試 (例如:. 紅外).
應提供API二次包裝上應用嘅標籤副本,並應包括存儲條件. 另外., API製造商嘅名稱同地址應喺容器上註出, 無論API派過程中是否在任何階段重新標記.

2. S.7穩定性 (名字, 製造商)

3.2. S.7.1穩定性摘要和結論 (名字, 製造商)
所進行的研究類型, 使用嘅協議, 研究結果應總結. 摘要應包括結果, 例如., 從強迫退化研究和壓力條件, 以及關於儲存條件和重新測試日期或保質期的結論, 酌情.
世衛組織準則 活性藥物成分的穩定性測試並完成 藥物 should be consulted for recommendations on the core stability data package required for the prequalification of APIs and FPPs.
As outlined in the WHO stability guidelines, the purpose of stability testing is to: “provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, 濕度和光。
應使用QOS-PD糢闆中嘅表嚟總結穩定性研究嘅結果同相關信息 (例如:. 條件, testing parameters, conclusions and commitments).

壓力測試

如ICH Q1A指導文件所述, API嘅壓力測試可以幫助識別可能退化嘅產品, 反過來, 有助於建立分子嘅降解途徑和內在穩定性,驗證所用分析程序嘅穩定性指示能力.
壓力測試嘅性質將取決於單個API同所涉及嘅FPP類型.
壓力測試可在單批API上進行. 有關典型應力條件嘅例子,請參閱部分 2.1.2 的 世衛組織技術報告系列, 唔係.. 953, 附件 2, 以及以及, "活性藥物成分降解路徑嘅典型研究", 係: 世衛組織技術報告 系列, 唔係.. 929, 附件 5, 表A1.
壓力測試嘅目的唔係完全降低API,而是導致退化喺好細嘅程度, 與未降級嘅API相比,透過檢測通常損失API 10-30%. 選擇此目標,以便發生一些降級, 但不足以生成二級產品. 因此,当API特別易受到特定壓力因素的影響時,條件和持續時間可能需要變化. 在完全沒有降解產品後 10 在特定壓力條件下,API被認為係穩定嘅天數.
QOS-PD糢闆中嘅表格應用於匯總應力測試結果,並應包括治療條件 (例如:. 溫度, 相對濕度, 解決方案和持續時間的集中度) 同各種測試參數嘅觀測結果 (例如:. 測定, degradation products). The discussion of results should highlight whether mass balance was observed.
Photo stability testing should be an integral part of stress testing. The standard conditions are described in ICH Q1B (22). If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API, it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies when the container-closure system is shown to be light protective.
When available it is acceptable to provide the relevant data published in the scientific literature (包括, but not limited to, WHO Public Assessment Reports (WHOPARs), European Public Assessment Reports (EPARs)) to support the identified degradation products and pathways.

加速和長期測試

應提供關於加速和長期儲存條件下API穩定性嘅信息, including information in the public domain or obtained from scientific literature.
The source of the information should be identified.
The required long-term storage conditions for APIs is 30 ºC ± 2 ºC/75% ± 5% RH. Studies covering the proposed retest period under the above-mentioned long-term storage conditions will provide better assurance of the stability of APIs at the conditions of the supply chain corresponding to the Nigerian environmental conditions (即. Zone IVB). 替代條件應有適當證據作為證據, 可能包括文獻參考或內部研究, 演示存儲在 30 oC唔適合API. 用于用于儲存喺冰箱中嘅API同用于存放喺冰櫃中嘅API, 參考世衛組織在 世衛組織技術報告系列, 唔係..
953, 附件 2. 旨在存儲低於+20°C嘅API應按案例處理.
建立重新測試期間, 數據應至少提供三批至少試點規模. The batches should be manufactured by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The stability testing programme should be summarized and the results of stability testing should be summarized in the dossier and in the tables in the QOS-PD.
The information on the stability studies should include details such as storage conditions, 批號, 批處理大小, container-closure system and completed (and proposed) test intervals. 對結果嘅討論應側重於為各種測試所記錄嘅觀察結果, 而唔係報告評論,如"所有測試符合規範". Ranges of analytical results where relevant and any trends that were observed should be included. 用于定量測試 (例如:. individual and total degradation product tests and assay tests), 應確保提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合". Where methods are different from those described in S.4.2, descriptions and validation of the methodology used in stability studies should be provided.

The minimum data required at the time of submitting the dossier (in the general case) are shown in Table 1.

Table 1 Minimum data required at the time of submitting the dossier
存儲
(ºC)
temperature Relative humidity (%) 最短時間
時期
(月)
Accelerated 40 ± 2 75 ± 5 6
中間-a-a
長期 30 ± 2 65 ± 5 或 75 ± 5 6
a長期條件喺邊度 30 ºC ± 2 ºC/65% ± 5% RH or 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition.
請參閱 世衛組織技術報告系列, 唔係.. 953, 附件 2 for further information regarding the storage conditions, container-closure system, test specifications and testing frequency.
建議嘅存儲報表同重新測試期
應建立存儲語句以顯示在標籤上, based on the stability evaluation of the API. The WHO stability guidelines include a number of recommended storage statements that should be used when supported by the stability studies.
A retest period should be derived from the stability information and should be displayed on the container label.
After this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (例如:. 在 30 天). If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. 然而, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For APIs known to be labile (例如:. certain antibiotics) it is more appropriate to establish a shelf-life than a retest period.
Limited extrapolation of the real-time data from the long-term storage condition beyond the observed range to extend the retest period can be done at the time of assessment of the PD, if justified. Applicants should consult the ICH Q1E guideline (23) for further details on the evaluation and extrapolation of results from stability data (例如:. if significant change was not observed within 6 months at accelerated conditions and the data show little or no variability, 提議嘅複試期可能長達長期數據涵蓋嘅兩倍, 但不應超過長期數據超過 12 月).
參考文檔: ICH Q1A, Q1B, Q1D, Q1E, 世衛組織技術報告系列, 唔係.. 953, 附件 2.

3.2. S.7.2批准後穩定性協議和穩定性承諾 (名字, 製造商)

應提供批准後穩定性協議和穩定性承諾.

初級穩定性研究承諾

当主要批次嘅可用長期穩定性數據唔包括喺PD評估時授予嘅建議重新測試期時, a commitment should be made to continue the stability studies in order to firmly establish the retest period. A written commitment (signed and dated) to continue long-term testing over the retest period should be included in the dossier when relevant.

承諾穩定性研究

承諾批次嘅長期穩定性研究應通過對至少三個生產批次嘅擬議複檢期進行. Where stability data were not provided for three production batches, a written commitment (signed and dated) should be included in the dossier.
The stability protocol for the commitment batches should be provided and should include, but not be limited to, the following parameters:
  • Number of batch(叶斯) and different batch sizes, 如果適用,;
  • Relevant physical, 化學, microbiological and biological test methods;
  • Acceptance criteria;
  • Reference to test methods;
  • Description of the container-closure system(s);
  • Testing frequency;
  • Description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines and consistent with the API labelling, should be used);  Other applicable parameters specific to the API.

正在進行的穩定性研究

應根據一個持續和適當的方案監測API的穩定性,以便發現任何穩定性問題 (例如:. changes in levels of degradation products). The purpose of the ongoing stability programme is to monitor the API and to determine that the API remains stable and can be expected to remain stable within the retest period in all future batches.
At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring programme and tested at least annually to confirm the stability. In certain situations, additional batches should be included. A written commitment (signed and dated) to ongoing stability studies should be included in the dossier.
Refer to section 2.1.11 的 世衛組織技術報告系列, 唔係.. 953, 附件 2, for further information on ongoing stability studies.
Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.
參考文檔: ICH Q1A, Q1B, Q1D, Q1E, 世衛組織技術報告系列, 唔係.. 953, 附件 2.

3.2. S.7.3 Stability data (名字, 製造商)

Results of the stability studies (例如:. forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included.
The actual stability results used to support the proposed retest period should be included in the dossier. 用于定量測試 (例如:. individual and total degradation product tests and assay tests) 應確保提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合".
參考文檔: ICH Q1A, Q1B, Q1D, Q1E, Q2 WHO Technical Report Series, 唔係.. 953, 附件 2.

3.2. P Drug product (or finished pharmaceutical product (Fpp))

3.2. P.1 Description and composition of the FPP (名字, 劑型)
A description of the FPP and its composition should be provided. The information provided should include, 例如.:
劑量表嘅描述
  • FPP嘅描述應包括物理描述, available strengths, release mechanism (例如:. immediate or modified (delayed or extended)), as well as any other distinguishable characteristics, 例如:.
  • “The proposed XYZ 50-mg tablets are available as white, oval, film-coated tablets, debossed with ‘50’ on one side and a break-line on the other side.
  • The proposed XYZ 100-mg tablets are available as yellow, round, film-coated tablets, 一路係徜徉100歳,另一邊係平原。
  • 組成, 即. list of all components of the dosage form, and their amount on a per unit basis (including overages, 如果有嘅話), the function of the components, and a reference to their quality standards (例如:. compendia monographs or manufacturer’s specifications).
  • The tables in the QOS-PD template should be used to summarize the composition of the FPP and express the quantity of each component on a per unit basis (例如:. mg per tablet, mg per ml, mg per vial) and a percentage basis, including a statement of the total weight or measure of the dosage unit. The individual components for mixtures prepared in-house (例如:. coatings) should be included in the tables where applicable.
  • All components used in the manufacturing process should be listed, including those that may not be added to every batch (例如:. acid and alkali), those that may be removed during processing (例如:. 溶劑) and any others (例如:. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (例如:. “1 mg of active ingredient base = 1.075 mg active ingredient hydrochloride”). All overages should be clearly indicated (例如:. “contains 2% overage of the API to compensate for manufacturing losses”).
  • The components should be declared by their proper or common names, quality standards (例如:. Bp, Jp, 同博士. Ph.Int, Usp, in-house) 和, 如果適用,, their grades (例如:. “microcrystalline cellulose NF (PH 102)") and special technical characteristics (例如:. lyophilized, micronized, solubilized or emulsified).
  • The function of each component (例如:. diluent or filler, binder, disintegrate, lubricant, glidant, granulating solvent, coating agent or antimicrobial preservative) should be stated. If an excipient performs multiple functions the predominant function should be indicated.
  • The qualitative composition, including solvents, should be provided for all proprietary components or blends (例如:. capsule shells, colouring, blends or imprinting inks). This information (excluding the solvents) is to be listed in the product information (例如:. summary of product characteristics, labelling and package leaflet).

Description of accompanying reconstitution diluent(s)

  • For FPPs supplied with reconstitution diluent(s) that are commercially available or that have been assessed and considered acceptable in connection with another product dossier with NAFDAC, a brief description of the reconstitution diluents(s) 應提供.
  • For FPPs supplied with reconstitution diluent(s) that are not commercially available or have not been assessed and considered acceptable in connection with another product dossier with NAFDAC, information on the diluent(s) should be provided in a separate FPP portion (“3.2.P”), 酌情.
  • Type of container and closure used for the dosage form and accompanying reconstitution diluent, 如果適用,
  • 用于FPP嘅容器關閉 (and accompanying reconstitution diluent, 如果適用,) should be briefly described, 提供3.2.P.7以下的進一步細節
  • 集裝箱關閉系統, 例如:. “The product is available in HDPE bottles with polypropylene caps (in sizes of 100s, 500s and 1000s) and in PVC/aluminum foil unit dose blisters (in packages of 100s) (cards of 5 × 2, 10 cards per package).” Reference documents: ICH Q6A (6).

3.2. P.2 Pharmaceutical development (名字, 劑型)

The Pharmaceutical development section should contain information on the development studies conducted to establish that the dosage form, the formulation, 製造工藝, container-closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the product dossier. The studies described here are distinguished from routine control tests conducted according to specifications. Additionally, this section should identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality. Supportive data and results from specific studies or published literature can be included within or attached to the Pharmaceutical development section. Additional supportive data can be referenced to the relevant nonclinical or clinical sections of the product dossier.
Pharmaceutical development information should include, 假假地.:
  • the definition of the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering, 例如., the route of administration, 劑型, bioavailability, strength and stability;
  • identification of the potential critical quality attributes (CQAs) of the FPP so as to adequately control the product characteristics that could have an impact on quality;
  • discussion of the potential CQAs of the API(s), excipients and container-closure system(s) including the selection of the type, grade and amount to deliver drug product of the desired quality;
  • discussion of the selection criteria for the manufacturing process and the control strategy required to manufacture commercial lots meeting the QTPP in a consistent manner. These features should be discussed as part of the product development using the principles of risk management over the entire life-cycle of the product (ICH Q8).
For a discussion of additional pharmaceutical development issues specific to the development of FDCs reference should be made to section 6.3.2 世衛組織技術報告系列, 唔係.. 929, 附件 5 (21).
參考文檔: ICH Q6A, Q8, Q9, Q10.

3.2. P.2.1 Components of the FPP (名字, 劑型)

3.2. P.2.1.1 Active pharmaceutical ingredient (名字, 劑型)
The compatibility of the API with excipients listed in 3.2.P.1 should be discussed. Additionally, key physicochemical characteristics (例如:. water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed.
For FDCs, the compatibility of APIs with each other should be discussed.
Physicochemical characteristics of the API may influence both the manufacturing capability and the performance of the FPP.
Guidance on compatibility studies is provided in Appendix 3 的 世衛組織指南 固定劑量組合藥材註冊 (世衛組織技術報告系列, 唔係.. 929, 附件 5, 2005). In addition to visual examination, chromatographic results (測定, purity) are required to demonstrate API–API and API–excipient compatibility. 麻麻., API–excipient compatibility is not required to be established for specific excipients when evidence is provided (例如:. in the SmPC or product leaflet) that the excipients are present in the comparator product.
3.2. P.2.1.2 Excipients (名字, 劑型)
The choice of excipients listed in 3.2.P.1, their concentration and their characteristics that can influence the FPP performance should be discussed relative to their respective functions.
When choosing excipients those with a compendia monograph are generally preferred and may be required in certain jurisdictions. Other resources are available for information on acceptable excipients and their concentrations, 如 美國食品和藥物 管理 (FDA) inactive ingredient guide (IIG) 列表手冊 藥物輔料. Use of excipients in concentrations outside established ranges is discouraged and generally requires justification. 另外., available guidelines should be referenced which discuss particular excipients to be avoided, for example azocolourants as listed in the EMA Guideline CPMP/463/00. Other guidance such as the WHO Guidelines on development of paediatric medicines: points to consider in formulation (32) may provide useful general guidance in this regard.
Ranges in concentrations or alternatives for excipients are normally not accepted unless supported by appropriate process validation data. Where relevant, compatibility study results (例如:. on compatibility of a primary or secondary amine API with lactose) should be included to justify the choice of excipients. Specific details should be provided where necessary (例如:. on use of potato or corn starch).
Where antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.
Antimicrobial preservatives are discussed in 3.2. P.2.5.

3.2. P.2.2 Finished pharmaceutical product (名字, 劑型)

3.2. P.2.2.1 Formulation development (名字, 劑型)
A brief summary describing the development of the FPP should be provided, taking into consideration the proposed route of administration and usage. The differences between the comparative bioavailability or biowaiver formulations and the formulation (即. composition) described in 3.2.P.1 should be discussed. Results from comparative in vitro studies (例如:. dissolution) or comparative in vivo studies (例如:. bioequivalence) should be discussed, when appropriate.
An established multisource product is one that has been marketed by the applicant or manufacturer associated with the dossier for at least five years and for which at least 10 production batches were produced over the previous year or, if less than 10 batches were produced in the previous year, not less than 25 batches were produced in the previous three years. For products that meet the criteria of an established multisource product, all sections of P.2.2.1 of the dossier and QOS-PD should be completed with the exception of P.2.2.1 (a). 另外., a product quality review should be provided as outlined in Appendix 2.
The requirements for bioequivalence studies should be taken into consideration, 例如., when formulating multiple strengths and/or when the product(s) may be eligible for a biowaiver. WHO reference documents (例如:. 世衛組織技術報告系列, 唔係.. 937, 附件 7) should be consulted.
Product scoring may be recommended or required, 例如., when scoring is specified in the listing of recommended comparator products, or when division into fractional doses may be necessary according to approved posology.
If the proposed FPP is a functionally scored tablet a study should be undertaken to ensure the uniformity of dose in the tablet fragments. The data provided in the PD should include a description of the test method, individual values, mean and relative standard deviation (RSD) of the results. Uniformity testing (即. content uniformity for split portions containing less than 5 mg or less than 5% of the weight of the dosage unit portion, or mass uniformity for other situations) should be performed on each split portion from a minimum of 10 randomly selected whole tablets. 作為一個說明性嘅例子, the number of units (即. the splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) 或 10 quarters for quadrisect tablets (one quarter of each tablet is retained for the test). At least one batch of each strength should be tested. Ideally the study should cover a range of the hardness values. The splitting of the tablets should be performed in a manner that would be representative of that used by the consumer (例如:. manually split by hand). The uniformity test on split portions can be demonstrated on a one-time basis and does not need to be added to the FPP specification(s). The tablet description in the FPP specification and in the product information (例如:. 斯姆普克, labelling and package leaflet) should reflect the presence of a score.
If splitting of a tablet is intended for preparation of a paediatric dose a demonstration of content uniformity of tablet fragments may be required.
Where relevant, labelling should state that the score line is only to facilitate breaking for ease of swallowing and not to divide the tablet into equal doses.
體外溶解或藥物釋放
應討論該提法的發展與解散方法的發展有何關係(s) and the generation of the dissolution profile.
The results of studies justifying the choice of in vitro dissolution or drug release conditions (例如:. apparatus, rotation speed and medium) 應提供. Data should also be submitted to demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients and particle size where relevant. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters. Use of a single point test or a dissolution range should be justified based on the solubility and/ or biopharmaceutical classification of the API.
For slower dissolving immediate-release products (例如:. Q = 80% 係 90 分鐘), a second time point may be warranted (例如:. Q = 60% 係 45 分鐘).
Modified-release FPPs should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vitro–in vivo correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form.
For extended-release FPPs, the testing conditions should be set to cover the entire time period of expected release (例如:. at least three test intervals chosen for a 12-hour release and additional test intervals for longer duration of release). One of the test points should be at the early stage of drug release (例如:. within the first hour) to demonstrate absence of dose dumping. At each test point, upper and lower limits should be set for individual units. Generally, the acceptance range at each intermediate test point should not exceed 25% or ± 12.5% of the targeted value. Dissolution results should be submitted for several lots, including those lots used for pharmacokinetic and bioavailability or biowaiver studies. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.
3.2. P.2.2.2 Overages (名字, 劑型)
Any overages in the formulation(s) described in 3.2.P.1 should be justified.
Justification of an overage to compensate for loss during manufacture should be provided, including information on the step(s) where the loss occurs, the reasons for the loss and batch analysis release data (assay results).
Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable.
3.2. P.2.2.3 Physicochemical and biological properties (名字, 劑型)
Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, 多態性, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.
3.2. P.2.3 Manufacturing process development (名字, 劑型)
The selection and optimization of the manufacturing process described in 3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.
Where relevant, justification for the selection of aseptic processing or other sterilization methods over terminal sterilization should be provided.
製造工藝之間嘅差異 (叶斯) 用于生產比較生物可用性或生物豁免批次和過程描述在
3.2.應討論能夠影響產品性能嘅P.3.3.
For products that meet the criteria of an established multisource product, 為咗滿足第2.3節嘅要求, 第2.3節 (B) 應完成檔案和QOS-PD,並提交附錄中概述的產品質量審查 2. 以下指南適用於應完整完成P.2.3節嘅所有其他產品.
選擇特定藥物產品嘅理由 (例如:.
劑型, 交付系統) 應提供. 選擇製造業嘅科學依據, 應解釋可能影響FPP質素同性能嘅灌裝同包裝流程 (例如:. wet granulation using high shear granulator). API stress study results may be included in the rationale. Any developmental work undertaken to protect the FPP from deterioration should also be included (例如:. protection from light or moisture).
The scientific rationale for the selection, optimization and scale-up of the manufacturing process described in 3.2.P.3.3 should be explained, in particular the critical aspects (例如:. rate of addition of granulating fluid, massing time and granulation end-point). A discussion of the critical process parameters (Cpp), controls and robustness with respect to the QTPP and CQA of the product should be included (ICH Q8).

3.2. P.2.4 Container-closure system (名字, 劑型)

The suitability of the container-closure system (described in 3.2.P.7) used for the storage, 運輸 (航運) and use of the FPP should be discussed. This discussion should consider, 例如:. 材料選擇, 防潮和防光, compatibility of the materials of construction with the dosage form (包括吸附到容器和浸出) safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the FPP).
Testing requirements to verify the suitability of the container-closure system contact material(s) depend on the dosage form and route of administration. The pharmacopoeias provide standards that are required for packaging materials, 包括, 例如., the following: – glass containers:
plastic containers:
rubber/elastomeric closures:
Table 2 outlines the general recommendations for the various dosage forms for one-time studies to establish the suitability of the container-closure system contact materials.

Table 2: 一次過研究,以確定容器閉合系統接觸材料嘅適用性

固體P滾管

口服液和局部產品

無菌產品

(including ophthalmics)

任何額外×治療嘅描述a
×
× (sterilization dehydrogenation components)
中。
提取研究–
×
×
互動研究–
(migration/sorption)
×
×
濕氣滲透性×
(uptake)
× (usually loss)
×
(usually loss)
光傳輸×B
×
×
應提交×信息. – Information does not need to be submitted. a. G。. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules or vials. B如果產品已證明係可拍照嘅,則不需要.
For solid oral dosage forms and solid APIs, compliance with regulations on plastic materials coming into contact with food (例如. (EU) 唔係.. 10/2011 (40)) can be considered acceptable.
The suitability of the container-closure system used for the storage, 運輸 (航運) and use of any intermediate or in-process products (例如:. premixes or bulk FPP) should also be discussed.
A device is required to be included with the container-closure system for administration of oral liquids or solids (例如:. solutions, emulsions, suspensions and powders or granules), whenever the package provides for multiple doses.
按照 Ph.Int. General chapter Liquid preparations for oral use:
‘‘Each dose from a multi-dose container is administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes or, for oral drops, 一個合適嘅滴水器。
對於伴隨多劑量容器嘅設備, the results of a study should be provided demonstrating the reproducibility of the device (例如:. consistent delivery of the intended volume), generally at the lowest intended dose.
A sample of the device should be provided with Module 1.

3.2. P.2.5 Microbiological attributes (名字, 劑型)

Where appropriate, the microbiological attributes of the dosage form should be discussed, 包括, 例如., the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container-closure system to prevent microbial contamination should be addressed.
Where an antimicrobial preservative is included in the formulation, the amount used should be justified by submission of results of studies on the product formulated with different concentrations of the preservative(s) to demonstrate the least necessary but still effective concentration. The effectiveness of the agent should be justified and verified by appropriate studies (例如:. USP or Ph.Eur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, the effectiveness of the agent should be established with a batch of the FPP containing a concentration of the antimicrobial preservative corresponding to the lower proposed acceptance criteria.
As outlined in the WHO stability guidelines (世衛組織技術報告系列, 唔係.. 953, 附件 2, 2009), a single primary stability batch of the FPP should be tested for effectiveness of the antimicrobial preservative (in addition to preservative content) at the proposed shelf-life for verification purposes, regardless of whether there is a difference between the release and shelflife acceptance criteria for preservative content.

3.2. P.2.6 Compatibility (名字, 劑型)

The compatibility of the FPP with reconstitution diluent(s) or dosage devices (例如:. precipitation of API in solution, sorption on injection vessels, 穩定性) should be addressed to provide appropriate and supportive information for the labelling.
Where a device is required for oral liquids or solids (例如:. solutions, emulsions, suspensions and powders or granules for such reconstitution) that are intended to be administered immediately after being added to the device, the compatibility studies mentioned in the following paragraphs are not required.
Where sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution proposed in the labelling. These studies should preferably be conducted on aged samples. Where the labelling does not specify the type of containers, compatibility (with respect to parameters such as appearance, Ph, 測定, levels of individual and total degradation products, sub visible particulate matter and extractables from the packaging components) should be demonstrated in glass, PVC and polyolefin containers. 然而, if one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated only in the specified containers.
Studies should cover the duration of storage reported in the labelling (例如:. 24 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling specifies co-administration with other FPPs, compatibility should be demonstrated with respect to the principal FPP as well as the co-administered FPP (即. in addition to other aforementioned parameters for the mixture, the assay and degradation levels of each co-administered FPP should be reported).

3.2. P.3製造 (名字, 劑型)

3.2. P.3.1 Manufacturer(s) (名字, 劑型)
的名稱, 地址, 同每個製造商嘅責任, 包括承包商, 以及每個提議嘅生產場地或涉及製造和測試嘅工廠.
製造所涉及的設施, 包裝, labelling and testing should be listed. 如果某些公司只負責特定步驟 (例如:. manufacturing of an intermediate), 應該清楚地表明 (世衛組織良好嘅派做法 藥物).
The list of manufacturers or companies should specify the actual addresses of production or manufacturing site(s) 涉及 (包括蚊(s) and unit(s)), 而唔係行政辦公室.
For a mixture of an API with an excipient, the blending of the API with the excipient is considered to be the first step in the manufacture of the final product and, 因此, the mixture does not fall under the definition of an API. 唯一嘅例外係喺API本身無法存在嘅情況下. 同樣, 用于API嘅混合物, ABI嘅混合被認為係製造最終產品嘅第一步. 此類製造步驟的站點應列在本節中.
藥品生產嘅有效製造授權, 以及營銷授權, 應提交以證明產品係按照國家要求註冊或許可嘅 (糢塊 1, 1.2.2).
對於主要生產步驟嘅每個站點(s) 執行, 在適用的情況下, 附上世衛組織主管當局頒發嘅關於國際商務中藥品質量嘅世衛組織型GMP認證 (糢塊 1, 1.2.2).
喺簽發WHOtype證書嘅國家/地區對產品產生任何差異嘅理由(s)
当提交此申請嘅產品與提供世衛組織類型證書緊嘅國家/地區銷售嘅產品之間存在差異時(s), 有必要提供數據,以支持證書嘅適用性(s) 儘管存在分歧. 視情況而定, 可能需要提供驗證數據,例如製造地點嘅差異, 規格同配方. 請注意,只有細微嘅差異至有可能被受落. 容器標籤嘅差異通常唔需要合理.

其他國家/地區嘅監管情況

應提供本產品已獲得營銷授權嘅國家/地區嘅列表, 本產品已退出市場和/或此營銷申請已被拒絕, 推遲或撤回 (糢塊 1, 1.2.2).
參考文檔: 世衛組織技術報告系列, 唔係.. 961, 附件 3 和否. 957, 附件 5

3.2. P.3.2批次公式 (名字, 劑型)

應提供批量公式,包括用于製造過程嘅劑型嘅所有組件列表, 每批金額, including overages, and a reference to their quality standards.
QOS-PD糢闆中嘅表應用於匯總每個建議嘅商業批次大小嘅FPP批次公式,並按每個批次表示每個組件嘅數量, 包括批次總重量或量嘅陳述.
應包括製造過程中使用嘅所有組件, including those that may not be added to every batch (例如:. acid and alkali), those that may be removed during processing (例如:. 溶劑) and any others (例如:. nitrogen or silicon for stoppers). If the FPP is formulated using an active moiety, then the composition for the active ingredient should be clearly indicated (例如:. "1公斤活性成分基數= 1.075 千克活性成分鹽酸化物"). All overages should be clearly indicated (例如:. 朕包含 5 公斤 (對應 2%) overage of the API to compensate for manufacturing losses”).
The components should be declared by their proper or common names, quality standards (例如:. Bp, Jp, 同博士. Ph.Int, Usp, in-house) 和, 如果適用,, their grades (例如:. 迨微晶纖維素NF (PH 102)") and special technical characteristics (例如:. lyophilized, micronized, solubilized or emulsified).
3.2. P.3.3 製造工藝和工藝控制描述 (名字, 劑型) 應顯示流程圖,說明流程嘅步驟,並顯示材料進入流程嘅位置. 過程控制嘅關鍵步驟同啲, 應確定中間測試或最終產品控制.
製造過程嘅敘述性描述, 仲應提供代表所採取步驟順序和生產規模嘅包裝. 應更詳細地描述直接影響產品質素的新工藝或技術和包裝操作. 設備應, 假假地, 按類型識別 (例如:. 翻滾攪拌機, 內聯同質化器) 同工作能力, 相關情況.
過程中的步驟應確定適當的過程參數, 如時間, 溫度, 或電話. 相關嘅數值可以作為預期範圍呈現. 關鍵步驟嘅數字範圍應喺第3.2.P.3.4節中合理. 在某些情況下, 環境條件 (例如:. 發泡產品嘅低濕度) should be stated.
應說明最終包裝前批量FPP嘅最大持有時間. 如果超過 30 天. 對於無能處理嘅FPP, 散裝物嘅無菌過濾同填充到最終容器最好係連續嘅; 任何持有時間都應該係合理嘅.
關於材料後處理的建議應有理有據. 支持此理由嘅任何數據都應喺本節中引用或歸檔 (3.2.P.3.3).
上述信息應喺QOS-PD糢闆中總結,並應反映擬議商業批次嘅生產情況. 請參閱詞彙表 (部分 2) 試點規模和生產規模批次嘅定義.
用于制造無菌產品, 類 (例如:. A 個, B或C) 每個活動應說明嘅區域 (例如:. 復合, 填充和密封), 以及滅菌參數, 包括設備, 集裝箱關閉系統同碼頭消毒.
參考文檔: ICH Q8, Q9, Q10.

3.2. P.3.4關鍵步驟和中間體的控制 (名字, 劑型)

關鍵步驟: 應提供測試和驗收標準 (有理有據, 包括實驗數據) 喺製造工藝3.2.P.3.3中肯定嘅關鍵步驟執行, 確保過程得到控制.
中間體: 應提供在此過程中隔離嘅中間體嘅質素同控制信息.
適用嘅流程控制示例包括:
  • 顆粒: 水分 (以範圍表示嘅限制), 混合均勻性 (例如:. 低劑量片劑), 散裝和挖掘密度和顆粒大小分佈;
  • 固體口服產品: 平均重量, 重量變化, 硬度, 厚度, 易碎性, 和解體檢查定期喺成個壓縮, 塗層過程中體重增加;
  • 半固體: 粘度, 均勻, Ph;
  • 透皮劑量表: API-粘合混合物的檢測, 塗層貼片嘅每個區域嘅重量,無後盾;
  • 計量劑量吸入器: 填充重量或體積, 洩漏測試, 閥門交付;
  • 乾粉吸入器: API-興奮混合的檢測, 水分, 單獨包含的劑量(如膠囊或水泡)的重量變化;
  • 液體: Ph, 比重, 解決方案嘅清晰性;
  • 家長: 外觀, 清晰, 填充體積或重量, Ph, 過濾器完整性測試, 顆粒物, 安培洩漏測試, 過濾前和/或滅菌前生物負擔測試.
參考文檔: ICH第2季度, Q6A, Q8, Q9, Q10, 世衛組織技術報告系列, 唔係.. 929, 附件 5.

3.2. P.3.5過程驗證和/或評估 (名字, 劑型)

描述, 文檔, 應提供驗證和/或評估研究嘅結果,用于製造過程中嘅關鍵步驟或關鍵檢測 (例如:. 絕育過程或無菌處理或填充的驗證).
病毒安全評估應喺3.2A.2中提供。, 如有必要.
For products that meet the criteria of an established multisource product, 附錄中概述嘅產品質量審查 2 可以代替以下信息提交.
應為所有其他產品提供以下信息:
1. 過程驗證協議嘅副本, 具體到此FPP, 如下所述;
2. 承諾,連續三個, 本FPP嘅生產規模批次將按照上述協議進行預期驗證. 申請人應提交書面承諾,NAFDAC檢査組資格預審之後緊,這些研究提供的信息將供核實。;
3. 如果過程驗證研究已經進行 (例如:. 無菌產品), 流程驗證報告嘅副本應喺PD中提供,以代替 1. 和 2. 以上.
過程驗證最實用嘅形式之一, 主要用于非無菌產品, 係產品嘅最終測試,在一定程度上大於常規質量控制所需嘅水平. 它可能涉及廣泛嘅採樣, 遠遠超出常規質量控制和測試中要求嘅正常質量控制規範,並且通常僅針對某些參數. 因此, 例如, 每批幾百片可以稱量以確定單位劑量均勻性. 然後對結果進行統計分析,以驗證分布嘅"正常性",並肯定標準偏離平均權重. 仲估計個人結果同批次同質性嘅信心限制. 提供強有力嘅保證,如果信心限制完全喺簡編規範範圍內,隨機採集嘅樣品將符合監管要求.
同樣, 可針對任何質素要求進行廣泛嘅抽樣同測試. 另外., 中間階段可以以同樣嘅方式驗證, 例如:. 数十个樣品可以單獨檢測,透過內容均勻性測試嚟驗證低劑量片劑生產嘅混合或造粒階段. 某些產品特性偶爾可能會跳過測試. 因此, 親子製劑中嘅亞視覺顆粒物可以透過電子設備肯定, 或片劑或膠囊測試其解散配置文件,如果此類測試唔執行每批.
建議批次大小嘅範圍, 應該表明,批量大小嘅變化唔會對成品嘅特性產生不利影響. 據設想,一旦喺資格預審後提議進一步擴大,以下驗證計劃中列出嘅參數將需要驗證番。.
過程驗證協議應包括, but not be limited to, the following:
  • 當前主生產文檔嘅引用;
  • 關鍵設備嘅討論;
  • 可能影響FPP質素嘅過程參數 (關鍵過程參數 (Cpps)) 包括挑戰實驗和故障模式操作;
  • 抽樣詳情: 採樣點, 抽樣階段, 抽樣方法同抽樣計劃 (包括攪拌機或儲物箱嘅示意圖,用于最終混合物嘅均勻性測試);
  • 測試參數和驗收標準,包括驗證批次嘅流程和發佈規格及相對溶解配置文件(叶斯) 用于生物可用性或生物豁免研究;
  • 分析程序或引用適當嘅部分(s) 檔案;
  • 記錄和評估結果嘅方法; – 完成協議的擬議時間框架.
無菌FP嘅製造需要喺控制良好嘅製造領域進行 (例如:. 使用高度可靠嘅程序同適當嘅處理控制嘅嚴格控制環境). 呢啲條件嘅詳細描述, 應提供程序和控制, 以及以下標準操作程序嘅實際副本:
  • 洗, 治療, 容器嘅滅菌同脫氫, 關閉和設備;
  • 過濾解決方案;
  • 嗜酸過程;
  • 填充同密封安培嘅洩漏測試; – 產品的最後檢查; – 滅菌周期.
用于破壞或去除微生物嘅滅菌過程可能係製造父性FP嘅單一最緊要過程. 呢個過程可以利用潮濕嘅熱量 (例如:. 蒸汽), 乾熱, 過濾, 氣態滅菌 (例如:. 乙烯氧化物) 或輻射. 應當指出,終端蒸汽滅菌, 實用時, 被認為係確保最終FPP不育嘅首選方法. 因此, 應提供選擇任何其他絕育方法的科學理由.
滅菌過程應詳細描述,並提供證據,以確認其將生產具有高度可靠性的無菌產品,並且不會影響FPP的物理和化學性質以及安全性。. 詳細信息,如Fo範圍, 應提供FPP同容器關閉系統嘅溫度範圍同峰值停留時間. 雖然標準自動拍手周期 121 °C用于 15 分鐘或更多將不需要一個詳細的理由, 應為降低溫度周期或降低暴露時間嘅溫度周期提供此類理由. 如果使用氧化乙烯, 研究和驗收標準應控制殘留嘅乙烯氧化物和相關化合物嘅水平.
使用嘅任何過濾器都應根據毛孔尺寸進行驗證, 與產品嘅兼容性, 缺乏可提取物和缺乏API或任何組件的吸附.
用于驗證無法絕育嘅無菌處理父產品, 應進行模擬過程試驗. 涉及到喺正常條件下用文化介質填充容器, 其次係孵化. 有關詳細信息,請參閱當前嘅NAFDAC或世衛組織GMP指南.
參考文檔: ICH Q8, Q9, Q10, 世衛組織技術報告系列, 唔係.. 961, 附件 3.

3.2. P.4對輔料的控制 (名字, 劑型)

3.2. P.4.1規格 (名字, 劑型)

應提供輔料的規格.
應向所有備件提供申請人或FPP製造商嘅規格, including those that may not be added to every batch (例如:. acid and alkali), 嗰啲冇出現喺最後嘅FPP (例如:. 溶劑) 以及製造過程中使用嘅任何其他設備 (例如:. nitrogen or silicon for stoppers).
如果要求為輔料提供嘅標準係官方認可嘅簡編標準, 足以說明,根據該標準嘅要求對輔料進行測試, 而唔係複製官方認可嘅簡編專著中發現嘅規格.
如果為輔料索賠嘅標準是非合成標準 (例如:. 內部標準) 或包括與官方認可嘅編目專著中出現嘅測試相補充嘅測試, 應提供供不應求的規格副本.
提交NAFDAC註冊嘅產品, 只有具有官方認可嘅藥典專著嘅輔料才應該使用. 例外可能係合理嘅.
對於自然來源嘅輔料, 微生物限量測試應包含喺規範中. 跳過測試係可以接受嘅,如果合理嘅話 (提交五個生產批次嘅可接受結果).
植物原產油 (例如:. 大豆油或花生油) 應證明沒有黃曲黴毒素或生物去除蟲劑.
允許使用嘅顏色僅限於"日本藥品輔料"中列出嘅色水, 歐盟 (EU) "允許食物顏色列表", 同FDA"非活性成分指南". 對於專有混合物, 應提交具有定性配方嘅供應商產品表, 除了FPP製造商嘅產品規格, 包括身份識別測試.
對於口味, 應提交定性組合, 以及一個聲明,即輔料符合食品法規 (例如:. 美國或歐盟法規).
被視為機密嘅信息可由供應商直接提交畀NAFDAC,供應商應求職信中提及特定緊嘅相關產品.
可能需要根據個案對風險組件進行其他認證.
如果對商業上可用的輔料進行額外的淨化, 應提交淨化和修改規格過程嘅詳細信息.
參考文檔: ICH Q6A.

3.2. P.4.2分析程序 (名字, 劑型)

應提供用于測試輔料嘅分析程序, 在適當時.
無需提交官方認可嘅簡編專著嘅分析程序副本.
參考文檔: ICH第2季度.

3.2. P.4.3分析程序嘅驗證 (名字, 劑型)

分析驗證信息, 包括實驗數據, 對於用于測試嘅分析程序,應提供輔料, 在適當時.
分析驗證信息副本一般唔提交用于檢測輔料, 除在適當情況下驗證內部方法外.
參考文檔: ICH第2季度.

3.2. P.4.4規格嘅理由 (名字, 劑型)

應提供擬議嘅次要規格嘅理由, 在適當時.
應提供對官方認可嘅簡編專著中所述測試嘅補充嘅討論.

3.2. P.4.5 人類或動物起源的起源 (名字, 劑型)

人類或動物起源嘅摘要, 應提供有關冒險代理人嘅信息 (例如:. 來源, 規格, 所執行測試嘅描述, 同病毒安全數據) (詳情在3.2.A.2).
本節應處理以下要點: 明膠, 磷酸鹽, 硬脂酸, 石酸鎂同其他石板. 如果輔料是植物來源,則為此申報就足夠了.
動物起源嘅輔料, 應提供證明信,確認用于制造FPP嘅輔料冇傳播動物海綿狀腦病劑的風險.
應儘可能避免動物來源嘅材料.
在可用時,應提供展示TSE合規性嘅CEP. CEP嘅完整副本 (包括任何附件) 應在模塊中提供 1.
參考文檔: ICH Q5A, Q5D, Q6B, 世衛組織技術報告系列, 唔係.. 908, 附件 1.

3.2. P.4.6新奇嘅輔料 (名字, 劑型)

對於輔料(s) used for the first time in an FPP or by a new route of administration, full details of manufacture, characterization, and controls, with cross-references to supporting safety data (non-clinical and/or clinical) should be provided according to the API and/or FPP format (details in 3.2.A.3).
Novel excipients are not accepted by NAFDAC. For the purpose of these guidelines, a novel excipient is one that has not been used (at a similar level and by the same route of administration) in a product approved by an SRA or by WHO.

3.2. P.5 Control of FPP (名字, 劑型)

3.2. P.5.1 Specification(s) (名字, 劑型)
The specification(s) for the FPP should be provided.
正如ICH嘅Q6A指南所定義嘅, 規範係:
‘‘a list of tests, 參考分析程序和適當的接受標準, 這是數值限制, 範圍, 或所述測試的其他標準. 它規定咗API或FPP應符合嘅一套標準,呢啲標準被認為係可接受嘅,用于預期用途. “Conformance to specifications” means that the API and/or FPP, 根據列出嘅分析程序進行測試時, 符合所列驗收標準. 規格係關鍵嘅質量標準,由製造商提出並證明其合理性,並經監管機構批准。
FPP規範嘅副本(s) from the applicant (as well as the company responsible for the batch release of the FPP, if different from the applicant), 日期同由授權人員簽署 (即. 質檢總局、質檢部門負責人) 應在PD中提供. Two separate sets of specifications may be set out: after packaging of the FPP (release) and at the end of the shelf-life.
The specifications should be summarized according to the tables in the QOS-PD template including the tests, 驗收標準和分析程序 (listing types, 方法嘅來源同版本).
  • The standard declared by the applicant could be an officially recognized compendia standard (例如:. Bp, Jp, 欧尔博士. Ph.Int, Usp) 或內部 (製造商嘅) 標準.
  • The specification reference number and version (例如:. 修訂編號和/或日期) 應提供用于版本控制目的.
  • For the analytical procedures, 類型應表示所使用的分析過程的類型 (例如:. 視覺, 紅外, UV or HPLC); 來源係指分析程序嘅起源 (例如:. Bp, Jp, 欧尔博士. Ph.Int, Usp, in-house) 同版本 (例如:. code number/version/ date) 應提供用于版本控制目的.
ICH’s Q6A guideline outlines recommendations for a number of universal and specific tests and criteria for FPPs. Specifications should include, 假假地., tests for appearance, 識別, 測定, purity, performance tests (例如:. dissolution), physical tests (例如:. loss on drying, 硬度, friability and particle size), uniformity of dosage units, 和, 視情況而定, identification and assay of antimicrobial or chemical preservatives (例如:. antioxidants) and microbial limit tests.

The following information provides guidance on specific tests that are not addressed by ICH’s Q6A guideline:

▪ fixed-dose combination FPPs (FDC-FPPs):

  • Analytical methods that can distinguish each API in the presence of the other API(s) should be developed and validated,
  • Acceptance criteria for degradation products should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, its acceptance limits should in general be calculated with reference to the worst case (the API with the smaller area under the curve). Alternatively the content of such impurities could be calculated in relation to their reference standards,
  • A test and limit for content uniformity is required for each API present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit,
  • For the API(s) present at ≥ 5 mg and ≥ 5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing;
  • Modified-release products: a meaningful API release method;
  • Inhalation and nasal products: consistency of delivered dose (throughout the use of the product), particle or droplet size distribution profiles (comparable to the product used in in vivo studies where applicable) and if applicable for the dosage form, moisture content, leak rate, microbial limits, preservative assay, sterility and weight loss;
  • Suppositories: uniformity of dosage units, 熔點;
  • 透皮劑量表: peel or shear force, mean weight per unit area and dissolution. Unless there is appropriate justification, the acceptable limit for the API content of the FPP in the release specifications is ± 5% of the label claim (即. 95.0–105.0%).
For products such as tablets, capsules and suppositories where a test for uniformity of single-dose preparations is required, a test and limit for content uniformity is required when the API is present in the FPP at less than 5 mg or less than 5% of the weight of the dosage unit. 否則, the test for mass uniformity may be applied.
Skip-testing is acceptable for parameters such as identification of colouring materials and microbial limits, when justified by the submission of acceptable supportive results for five production batches. When justification for skip-testing has been accepted the specifications should include a footnote, stating, 假假地., the following skip-testing requirements: at least every tenth batch and at least one batch annually is tested. 另外., for stability indicating parameters such as microbial limits, testing will be performed at release and at the end of shelf-life during stability studies.
Any differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. Note that such differences for parameters such as dissolution are normally not accepted.
參考文檔: ICH Q3B, 第3季度, Q6A.

3.2. P.5.2 Analytical procedures (名字, 劑型)

The analytical procedures used for testing the FPP should be provided.
Copies of the in-house analytical procedures used during pharmaceutical development (if used to generate testing results provided in the PD) as well as those proposed for routine testing should be provided. Unless modified it is not necessary to provide copies of analytical procedures described in officially recognized compendia.
總結若干不同分析過程和驗證信息嘅表格 (例如:. HPLC檢測和雜質方法) 可在QOS-PD嘅2.3.R區域信息部分搵到 (即. 2.3.R.2). These tables should be used to summarize the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.
Refer to section 3.2.S.4.2 of these guidelines for additional guidance on analytical procedures.
參考文檔: ICH第2季度 (16).

3.2. P.5.3 Validation of analytical procedures (名字, 劑型)

分析驗證信息, 包括實驗數據, for the analytical procedures used for testing the FPP, 應提供.
Copies of the validation reports for the in-house analytical procedures used during pharmaceutical development (if used to support testing results provided in the PD) as well as those proposed for routine testing should be provided.
用于總結若干不同分析程序和驗證信息嘅表格 (例如:. HPLC檢測和雜質方法, and GC methods) can be found in the 2.3.R Regional information section of the QOSPD (即. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures used for determination of the assay, related substances and dissolution of the FPP.
監管部門和藥典本身都承認咗啲, 可能需要對簡編方法進行驗證. 已發佈嘅簡編方法通常基於來自特定製造商嘅API或FPP進行驗證. The same API or FPP obtained from different sources can contain impurities and/or degradation products or excipients that were not considered during the development of the monograph. 因此, the monograph and compendia method(s) should be demonstrated suitable for the control of the proposed FPP.
For officially recognized compendia FPP assay methods, verification should include a demonstration of specificity, accuracy and repeatability (method precision). If an officially recognized compendia method is used to control related substances that are not specified in the monograph, full validation of the method is expected with respect to those related substances.
如果聲稱有官方認可嘅簡編標準,並且使用內部方法代替簡編方法 (例如:. for assay or for related compounds), 應證明內在和簡編方法的等價性. 可以透過透過兩種方法對一個樣本進行重複分析並提供研究結果嚟實現。. For methods for the determination of related compounds, the sample analyzed should be the placebo spiked with related compounds at concentrations equivalent to their specification limits.
參考文檔: ICH第2季度.

3.2. P.5.4 Batch analyses (名字, 劑型)

A description of batches and results of batch analyses should be provided.
Information on relevant FPP batches used to establish the specifications and evaluate consistency in manufacturing should be provided and should include strength and batch number, 批處理大小, date and site of production and use (例如:. used in comparative bioavailability or biowaiver studies, preclinical and clinical studies (如果相關), 穩定性, 飛行員, scale-up and, 如果可用, 生產規模的批次).
Analytical results generated by the company responsible for the batch release of the FPP (generally the applicant or the FPP manufacturer, if different from the applicant) should be provided for not less than two batches of at least pilot scale, or in the case of an uncomplicated[1] Fpp (例如:. immediate-release solid FPPs (with noted exceptions), or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (例如:. for solid oral dosage forms, 25 000 或 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
The results should include those of tests on the batch (叶斯) 用于比較生物可用性或生物豁免研究. Copies of the certificates of analysis for these batches should be provided in the PD and the company responsible for generating the testing results should be identified.
對結果嘅討論應側重於為各種測試所記錄嘅觀察結果, 而唔係報告評論,如"所有測試符合規範". The discussion should include ranges of analytical results, 相關情況. 用于定量測試 (例如:. 個人和總雜質測試和檢測測試), 應確保提供實際的數字結果,而不是模糊的陳述,如"限度內"或"符合" (例如:. “levels of degradation product A ranged from 0.2 自 0.4 %"). Dissolution results should be expressed, 假假地., as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1.
對於任何唔完整嘅分析,應提供討論和理由 (例如:. for any parameters not tested according to the proposed specification).
參考文檔: ICH Q3B, 第3季度, Q6A.

3.2. P.5.5 Characterization of impurities (名字, 劑型)

Information on the characterization of impurities should be provided, if not previously provided in “3.2.S.3.2 Impurities”.
A discussion should be provided of all impurities that are potential degradation products (including those among the impurities identified in 3.2.S.3.2 as well as potential degradation products resulting from interaction of the API with other APIs (FDCs), excipients or the container-closure system) and FPP process-related impurities (例如:. residual solvents in the manufacturing process for the FPP).
參考文檔: ICH Q3B, 第3季度, Q6A.

3.2. P.5.6 Justification of specification(s) (名字, 劑型)

Justification for the proposed FPP specification(s) 應提供.
A discussion should be provided on the omission or inclusion of certain tests, 測試嘅演變, 分析程序和驗收標準, 與官方認可嘅簡編標準嘅差異(s). If the officially recognized compendia methods have been modified or replaced, a discussion should be included.
某些測試嘅理由, 分析程序和驗收標準 (例如:. degradation products or dissolution method development) may have been discussed in other sections of the PD and would not need to be repeated here, 雖然應該提供交叉引用.
ICH Q6A should be consulted for the development of specifications for FPPs.

3.2. P.6 Reference standards or materials (名字, 劑型)

Information on the reference standards or reference materials used for testing of the FPP should be provided, if not previously provided in “3.2.S.5 Reference standards or materials”.
See section 3.2.S.5 for information that should be provided on reference standards or materials. Information should be provided on reference materials of FPP degradation products, where not included in 3.2.S.5.
參考文檔: ICH Q6A (6), 世衛組織技術報告系列, 唔係.. 943, 附件 3.

3.2. P.7 Container-closure system (名字, 劑型)

A description of the container-closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. 規範應包括描述和標識 (and critical dimensions, with drawings where appropriate). 非合成方法 (與驗證) 應包括, 在適當時.
對於非功能性二次包裝組件 (例如:. those that neither provide additional protection nor serve to deliver the product), 只應提供簡短嘅描述. 用于功能二次包裝組件, 應提供其他信息.
Suitability information should be located in 3.2.P.2.
The WHO Guidelines on packaging for pharmaceutical products (18) and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for FPPs.
Descriptions, materials of construction and specifications (of the company responsible for packaging the FPP, generally the FPP manufacturer) should be provided for the packaging components that are:
  • In direct contact with the dosage form (例如:. container, closure, liner, desiccant and filler);
  • Used for drug delivery (including the device(s) for multidose solutions, emulsions, suspensions and powders or granules for reconstitution into solution, emulsion or suspension;
  • Used as a protective barrier to help ensure stability or sterility; ▪ necessary to ensure FPP quality during storage and shipping.
主要包裝組件係嗰啲與API或FPP直接接觸嘅組件.
The specifications for the primary packaging components should include a specific test for identification (例如:. 紅外). Specifications for film and foil materials should include limits for thickness or area weight.
Information to establish the suitability (例如:. qualification) of the container closure system should be discussed in section 3.2.P.2. Comparative studies may be warranted for certain changes in packaging components (例如:. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips).

3.2. P.8穩定性 (名字, 劑型)

3.2. P.8.1 Stability summary and conclusions (名字, 劑型)
所進行的研究類型, 使用嘅協議, 研究結果應總結. The summary should include, 例如., conclusions with respect to storage conditions and shelf-life, 和, 如果適用,, in-use storage conditions and shelf-life.
The WHO stability guidelines Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (19) 應徵求關於核心穩定性嘅建議
ABI同FP資格預審所需嘅數據包.
As outlined in the WHO stability guidelines, the purpose of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product related factors that influence the quality of the API or FPP, 例如., interaction of API with excipients, container-closure systems and packaging materials.

壓力測試

As outlined in the WHO stability guidelines, photo stability testing should be conducted on at least one primary batch of the FPP if appropriate. If “protect from light” is stated in one of the officially recognized pharmacopoeias for the API or FPP it is sufficient to state “protect from light” on labelling, in lieu of photo stability studies, when the container-closure system is shown to be light protective. Additional stress testing of specific types of dosage forms may be appropriate (例如:. cyclic studies for semi-solid products or freeze–thaw studies for liquid products).

Accelerated, intermediate (如有必要) 同長期測試

穩定性數據必須證明藥用產品喺目標國家普遍存在嘅氣候條件下喺成個訂保質期內嘅穩定性. Merely applying the same requirements applicable to other markets could potentially lead to substandard products if stability studies are conducted at the storage conditions for countries in Climatic Zone I/II when the products are supplied in countries in Climatic Zones III and IV. Refer to WHO Technical Report Series, 唔係.. 953, 附件 2, 附錄 1 (7) for information on climatic zones. Effective as of September 2011, the required longterm storage conditions for the WHO Prequalification of Medicines Programmed are 30 ºC ± 2 ºC/75% ± 5% RH, and after this date the long-term data submitted in the PD (see Table 3) should be at these conditions. The use of alternative long-term conditions will need to be justified and should be supported with appropriate evidence.
Other storage conditions are outlined in the WHO stability guidelines for FPPs packaged in impermeable and semi-permeable containers and those intended for storage in a refrigerator and in a freezer. FPPs intended for storage below −20 °C should be treated on a case-by-case basis.

Table 3: Minimum data required at the time of submitting the dossier (in the general case)

Storage Temperature

(ºC)

Relative Humidity

(%)

Minimum Time Period

(月)

Accelerated 40 ± 2
75 ± 5
6
中間
不適用
不適用
長期 30 ± 2
75 ± 5
6
a長期條件喺邊度 30 ºC ± 2 ºC/75% ± 5% RH, there is no intermediate condition. Refer to WHO Technical Report Series, 唔係.. 953, 附件 2 (19) for further information regarding the storage conditions.
To establish the shelf-life, data should be provided on not less than two batches of at least pilot scale, or in the case of an uncomplicated FPP (例如:. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale and a second batch which may be smaller (例如:. for solid oral dosage forms, 25 000 或 50 000 tablets or capsules) of each proposed strength of the FPP. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
The stability testing programme should be summarized and the results of stability testing should be reported in the dossier and summarized in the tables in the QOS-PD. Bracketing and matrixing of proportional strengths can be applied if scientifically justified.
For sterile products, sterility should be reported at the beginning and end of shelf-life. For parenteral products, sub visible particulate matter should be reported frequently, but not necessarily at every test interval. Bacterial endotoxins need only be reported at the initial test point. Weight loss from plastic containers should be reported over the shelf-life.
Any in-use period and associated storage conditions should be justified with experimental data, 例如., after opening, reconstitution and/or dilution of any sterile and/or multidose products or after first opening of FPPs packed in bulk multidose containers (例如:. bottles of 1000s). 如果適用,, the inuse period and storage conditions should be stated in the product information.
有關穩定性研究嘅信息應包括詳細信息,例如
  • 存儲條件;
  • 強度;
  • 批號, including the API batch number(s) and manufacturer(s);
  • 批處理大小;
  • a container-closure system including orientation (例如:. erect, inverted, on-side) 在適用的情況下;
  • completed (and proposed) test intervals.
對結果嘅討論應側重於為各種測試所記錄嘅觀察結果, 而唔係報告評論,如"所有測試符合規範". The discussion should include ranges of analytical results and any trends that were observed. 用于定量測試 (例如:. individual and total degradation product tests and assay tests) actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. Dissolution results should be expressed, 假假地., as both the average and range of individual results.
Applicants should consult ICH’s Q1E guideline (23) for details on the evaluation and extrapolation of results from stability data (例如:. if significant change was not observed within 6 months at accelerated condition and the data show little or no variability, the proposed shelf-life could be up to twice the period covered by the long-term data, 但不應超過長期數據超過 12 月).
建議嘅存儲聲明同保質期
提議嘅存儲聲明同保質期 (and in-use storage conditions and in-use period, 如果適用,) for the FPP should be provided.
The recommended labelling statements for use based on the stability studies, are provided in the WHO stability guidelines.
參考文檔: 世衛組織技術報告系列, 唔係.. 953, 附件 2, ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q3B, Q6A.

3.2. P.8.2 Post-approval stability protocol and stability commitment (名字, 劑型)

應提供批准後穩定性協議和穩定性承諾.

初級穩定性研究承諾

当關於初級批次長期穩定嘅現有數據唔包括喺評估PD時授予嘅擬議保質期時, a commitment should be made to continue the stability studies in order to firmly establish the shelf-life. A written commitment (signed and dated) to continue long-term testing over the shelf-life period should be included in the dossier.

承諾穩定性研究

承諾批次嘅長期穩定性研究應喺成個建議嘅保質期內對每個集裝箱封閉系統中每個強度至少三個生產批次進行. Where stability data were not provided for three production batches of each strength, a written commitment (signed and dated) should be included in the dossier.

正在進行的穩定性研究

如世衛組織穩定準則所述, an ongoing stability programme is established to monitor the product over its shelf-life and to determine that the product remains and can be expected to remain within specifications under the storage conditions on the label. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every container-closure system, 如果相關, should be included in the stability programme (unless none is produced during that year). Bracketing and matrixing may be applicable. A written commitment (signed and dated) to this effect should be included in the dossier.
Any differences between the stability protocols used for the primary batches and those proposed for the commitment batches or ongoing batches should be scientifically justified.
參考文檔: ICH Q1A.

3.2. P.8.3 Stability data (名字, 劑型)

Results of the stability studies should be presented in an appropriate format (例如:. tabular, graphical, and narrative). Information on the analytical procedures used to generate the data and validation of these procedures should be included.
Information on characterization of impurities is located in 3.2. P.5.5.
The actual stability results and reports used to support the proposed shelf-life should be provided in the PD. 用于定量測試 (例如:. individual and total degradation product tests and assay tests), actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”.
Dissolution results should be expressed, 假假地., as both the average and range of individual results.
參考文檔: ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q2.

3.2. A Appendices

3.2. A.1設施和設備
不適用 (即. not a biotech product).
3.2. A.2 Adventitious agent’s safety evaluation
3.2. A.3新奇嘅輔料
唔接受新奇嘅輔料.
3.2. R Regional information
3.2. R.1 Production documentation
3.2. R.1.1已執行的生產文檔
至少兩批至少試點規模, or in the case of an uncomplicated FPP (例如:. immediate-release solid FPPs (with noted exceptions) or non-sterile solutions), at least one batch of at least pilot scale (the batch used in comparative bioavailability or biowaiver studies) and a second batch which may be smaller (例如:. for solid oral dosage forms, 25 000 或 50 000 tablets or capsules), should be manufactured for each strength. These batches should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
對於固體口服劑型, pilot scale is generally, 假假地., one-tenth that of full production scale or 100 000 tablets or capsules, whichever is the larger.
Copies of the executed production documents should be provided for the batches used in the comparative bioavailability or biowaiver studies. Any notations made by operators on the executed production documents should be clearly legible.
If not included in the executed batch records through sufficient in process testing, data should be provided for the batch used in comparative bioavailability or biowaiver studies that demonstrate the uniformity of this batch. The data to establish the uniformity of the bio batch should involve testing to an extent greater than that required in routine quality control.
English translations of executed records should be provided where relevant.

3.2.R.1.2主生產文檔

應為每個提議嘅強度提供FPP主生產文件嘅副本, commercial batch size and manufacturing site.
The details in the master production documents should include, but not be limited to, the following:
■ master formula;
■ dispensing, processing and packaging sections with relevant material and operational details;
■ relevant calculations (例如:. if the amount of API is adjusted based on the assay results or on the anhydrous basis);
■ identification of all equipment by, 假假地., type and working capacity (including make, model and equipment number, where possible);
■ process parameters (例如:. mixing time, mixing speed, milling screen size, processing temperature range, granulation end-point and tablet machine speed ( expressed as target and range));
■ list of in-process tests (例如:. 外觀, Ph, 測定, 混合均勻性, 粘度, particle size distribution, loss on drying, 重量變化, 硬度, disintegration time, 塗層過程中體重增加, leaker test, minimum fill, clarity and filter integrity checks) and specifications;
■ sampling plan with regard to the:
– steps at which sampling should be done (例如:. 乾燥, lubrication and compression),
– number of samples that should be tested (例如:. for blend uniformity testing of low-dose FPPs, blend drawn using a sampling thief from x positions in the blender),
– frequency of testing (例如:. weight variation every x minutes during compression or capsule filling);
■ precautions necessary to ensure product quality (例如:. temperature and humidity control and maximum holding times);
■ for sterile products, reference to standard operating procedures ( SOPs) in appropriate sections and a list of all relevant SOPs at the end of the document;
■ theoretical and actual yield;
■ compliance with the GMP requirements.
參考文檔: 世衛組織技術報告系列, 唔係.. 961.

3.2. R.2分析程序和驗證信息

應使用QOS-PD糢闆中第2.3.R.2節中顯示嘅錶來匯總第3.2.S.4.2節嘅分析過程同驗證信息, 3.2.S.4.3,
2.3.S.4.4 (C),
2.3. S.7.3 (B), 3.2.P.5.2 and 3.2.P.5.3 where relevant.
4.3 文獻參考
適當時,應喺PD嘅一節中包括與API同FPP相關嘅科學文獻.

糢塊 4: 非臨床摘要

此糢塊通常不需要用于多源 (通用) 藥物. It deals with the toxicity testing intended to justify the stability and safety of the product. The module is included for completeness to indicate the appropriate format and placement of the nonclinical data.
Refer to ICH M4S (R 2) for additional detail on the organization of Module 4 and for ICH references on study design and data content.
4.1 目錄 (糢塊 4)
4.2 學習報告
研究報告應按下列順序提交:
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)
4.2.2.2 Absorption
4.2.2.3 Distribution 4.2.2.4 Metabolism
4 2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity (in order by species, by route)
4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by duration; including supportive toxicokinetics evaluations)
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo (supportive toxicokinetics evaluations)
4.2.3.4 Carcinogenicity (including supportive toxicokinetics evaluations)
4.2.3.4.1 Long-term studies (in order by species; including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)
4.2.3.4.2 Short- or medium-term studies (including range-finding studies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)
4.2.3.4.3 Other studies
4.2.3.5 Reproductive and Developmental Toxicity
4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including maternal function
4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated.
4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (如果可用)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 其他
4.3 文獻參考

糢塊 5: 臨床摘要

對於多源 (通用) 藥物, only Module 5.3.1 Reports of Biopharmaceutical Studies would normally be needed. 然而, all parts of the module are included for completeness to indicate the appropriate format and placement of the nonclinical data.
ICH E3 provides guidance on the organisation of clinical study reports, other clinical data, and references within a Common Technical Document (Ctd).
糢塊 5 provides the recommended organization for the placement of clinical study reports and related information to simplify preparation and review of dossiers and to ensure completeness. The placement of a report should be determined by the primary objective of the study. Each study report should appear in only one section. Where there are multiple objectives, the study should be cross-referenced in the various sections. An explanation such as “not applicable” or “no study conducted” should be provided when no report or information is available for a section or subsection.
Refer to ICH M4E (R 2) for additional detail on the organization of Module 5 and for additional ICH references on study design and data content.
5.1 目錄 (糢塊 5)
A Table of Contents for study reports should be provided.
5.2 Tabular Listing of Clinical Studies
5.3 臨床研究報告
5.3.1 生物製藥研究報告
Bioavailability (BA) studies evaluate the rate and extent of release of the active substance from the medicinal product. Comparative BA or bioequivalence (BE) studies may use Pharmacokinetic (PK), Pharmacodynamic (PD), clinical or in vitro dissolution endpoints, and may be either single dose or multiple doses. When the primary purpose of a study is to assess the PK of a drug, but also includes BA information, the study report should be submitted in Section 5.3.1, and referenced in Sections 5.3.1.1 and/or 5.3.1.2.
5.3.1.1 Bioavailability (BA) 學習報告
本部分嘅學士學位研究應包括
·把藥物物質由固體口服劑量形式嘅釋放和系統可用性與靜脈注射或作為口服液體劑型給予的藥物物質嘅系統可用性進行比較嘅研究
·劑量形式相稱性研究, 和
·食物效應研究.
5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) 學習報告
本節嘅研究比較咗類似藥物產品釋放藥物嘅速度同程度 (例如., tablet to tablet, tablet to capsule). 比較學士學位或BE研究可能包括比較
·臨床研究中用於支持有效性和待銷藥物產品的藥物產品,
• the drug product used in clinical studies supporting effectiveness and the drug product used in stability batches, 和
·來自不同製造商嘅類似藥物產品.
5.3.1.3 體外體內相關性研究報告
提供BA信息嘅體外溶解研究, including studies used in seeking to correlate in vitro data with in vivo correlations, should be placed in this section. Reports of in vitro dissolution tests used for batch quality control and/or batch release should be placed in the Quality section (糢塊 3) of the CTD.
5.3.1.4 人類研究生物分析方法報告
生物製藥研究或體外溶解研究的生物分析和/或分析方法通常應在個別研究報告中提供. Where a method is used in multiple studies, the method and its validation should be included once in Section 5.3.1.4 and referenced in the appropriate individual study reports.
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies References
5.3.5.3 Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses
5.3.5.4 Other Clinical Study Reports
5.3.6 營銷後經驗報告
對於目前銷售的產品, reports that summarize marketing experience (including all significant safety observations) 應包括.
5.3.7 Case Report Forms and Individual Patient Listings (when submitted)
Case report forms and individual patient data listings that are described as appendices in the ICH or WHO clinical study report guideline should be placed in this section when submitted in the same order as the clinical study reports and indexed by study.
5.4 文獻參考
引用文檔嘅副本, including important published articles, official meeting minutes, or other regulatory guidance or advice should be provided here. This includes copies of all references cited in the Clinical Overview, and copies of important references cited in the Clinical Summary or in the individual technical reports that were provided in Module 5, Only one copy of each reference should he provided. Copies of references that are not included here should be immediately available on request.

附錄 1

關於進行和評估比較解散概況嘅建議
兩個FP嘅解散測量 (例如:. test and reference (比較) or two different strengths) should be made under the same test conditions. A minimum of three time-points (zero excluded) 應包括, the time-points for both reference (比較) and test product being the same. The sampling intervals should be short for a scientifically sound comparison of the profiles (例如:. 5, 10, 15, 20, 30, 45 (60, 90, 120) 分鐘). 15分鐘嘅時間啲對於肯定產品是否非常迅速溶解同肯定f2 必須計算. For extended release FPPs, the time-points should be set to cover the entire duration of expected release, 例如:. 1, 2, 3, 5 和 8 hours for a 12-hour release and additional test intervals for longer duration of release.
Studies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, Ph 4.5 buffer and pH 6.8 buffer. International Pharmacopoeia buffers are recommended; other pharmacopoeia buffers with the same pH and buffer capacity are also accepted. Water may be considered as an additional medium, especially when the API is unstable in the buffered media to the extent that the data are unusable.
If both the test and reference (比較) products show more than 85% dissolution in 15 分鐘, the profiles are considered similar (no calculations required). 否則:
▪ Similarity of the resulting comparative dissolution profiles should be calculated using the following equation that defines a similarity factor (F2):
F2 = 50 LOG {[1+1/n ∑nt=1 (Rt-Tt) 2] +0.5 × 100}
其中Rt 同Tt 是平均百分比API溶解參考 (比較) and test product, 分別, at each time-point. 一個f2 價值之間 50 和 100 suggests that the two dissolution profiles are similar.
▪ A maximum of one time-point should be considered after 85% dissolution of the reference (比較) product has been reached. In the case where 85% dissolution cannot be reached due to poor solubility of the API, the dissolution should be conducted until an asymptote (plateau) has been reached.
▪ At least 12 units should be used for determination of each profile. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the percentage coefficient of variation at the first time-point should be not more than 20% and at other time-points should be not more than 10%.
▪ When delayed-release products (例如:. enteric coated) are being compared, the recommended conditions are acid medium (Ph 1.2) 適用於 2 hours and buffer pH 6.8 medium.
▪ When comparing extended-release beaded capsules, where different strengths have been achieved solely by means of adjusting the number of beads containing the API, one condition (normally the release condition) will suffice.
▪ Surfactants should be avoided in comparative dissolution testing. A statement that the API is not soluble in any of the media is not sufficient and profiles in the absence of surfactant should be provided. The rationale for the choice and concentration of surfactant should be provided. The concentration of the surfactant should be such that the discriminatory power of the test will not be compromised.
REFERENCES:
ICH Common Technical Document References (http://www.ich.org)
1. ICH M4Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (2016)
2. ICH M4E(R 2) – Common Technical Document for the Registration of Pharmaceuticals for Human Use: Efficacy (2016)
3. ICH M4Q(R1) – Common Technical Document for the Registration of Pharmaceuticals for Human Use: 質量 (2002)
4. ICH M4S(R 2) – 人類藥品註冊通用技術文件
使用: Safety (2002)
ICH Quality Guidelines
1. ICH Q1A(R 2) – Stability Testing of New Drug Substances and Products (2003)
2. ICH Q1B Stability Testing: Photo stability Testing of New Drug Substances and Products (1996)
3. ICH Q1D – 新藥物質穩定性測試嘅支架和矩阵設計
產品 (2002)
4. ICH Q1EEvaluation for Stability Data (2003)
5. ICH第2季度(R1) – Validation of Analytical Procedures: Text and Methodology (2005) [combines the previous Q2A and Q2B Guidelines]
6. ICH Q3A(R 2) – Impurities in New Drug Substances (2006)
7. ICH Q3B(R 2) – Impurities in New Drug Products (2206)
8. ICH Q3C(R6) – Impurities: Guideline For Residual Solvents Q3C(2016)
9. ICH Q5A, Q5B, Q5C, Q5D Quality of Biological Products [not needed for multisource (通用) 藥物]
10. ICH Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (1999)
11. ICH Q6B Specifications: 生物技術/生物的測試程序和驗收標準
產品 (1999) [not needed for multisource (通用) 藥物]
World Health Organization Guidelines
1. Guidelines on packaging for pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, 世界衛生組織, 2002
( 世衛組織技術報告系列, 唔係.. 902), 附件 9
2. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva,
世界衛生組織, 2009 (世衛組織技術報告系列, 唔係.. 953), 附件 2. [Together with
2015 update table Stability Conditions for WHO Member States by Region]
3. Guideline on submission of documentation for a multisource (通用) finished pharmaceutical product (Fpp): quality part, In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, 世界衛生組織, 2012 (世衛組織技術報告系列, 唔係.. 970), 附件 4
4. Multisource (通用) 藥物: guidelines on registration requirements to establish interchangeability, In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-ninth report. . 世界衛生組織, 2015 (世衛組織技術報告系列, 唔係.. 992), 附件 7.
5. Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (通用) 世衛組織規格專家委員會嘅產品
藥品製劑: Forty-ninth report. 世界衛生組織, (世衛組織技術
報告系列, 唔係.. 992), 附件 8 2015
6. Guidance for organizations performing in vivo bioequivalence studies (revision), In WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fiftieth report.
7. 世衛組織技術報告系列, 唔係.. 996, 附件 9, 2016
World Health Organization Templates
[https://extranet.who.int/prequal/content/who-medicines-prequalification-guidance]
Quality Templates
1. Quality overall summaryproduct dossier (QOS-PD)
2. Quality information summary (奇斯)
Bioequivalence Template
1. Bioequivalence trail information form (Btif)
2. Biowaiver Application Form (BAF)
3. 參考世衛組織生物可用性和生物等價研究指南以及世衛組織
生物豁免糢闆]
Labelling Templates
1. Patient information leaflet – Template
2. Summary Product Characteristics (斯姆普克) Template
3. 標籤糢闆

附件A: 產品標籤指南

產品標籤指南同糢闆應基於包裝傳單嘅NAFDAC標籤糢闆指南,
可由NAFDAC網站獲得嘅產品特徵同標籤摘要: https://extranet.who.int/prequal/content/contents-and-structure-whopar.

糢塊 1.3.1 產品特性摘要 (斯姆普克)

The format of the SmPC document is to be consistent with the NAFDAC SmPC Template. The information should be provided in English language.
參閱北美自由貿易協定
使用纳夫达克斯姆PC糢闆
糢塊 1.3.2 患者信息傳單
PIL嘅格式應與NAFDAC PIL糢闆保持一致. 信息應以英文提供
參考北美自由貿易協定PIL指南
使用纳夫达克PIL糢闆
糢塊 1.3.3 Container Labelling (Inner and Outer Labels)
The primary and secondary packaging must include the following information in a legible, understandable and indelible manner. The information should be provided in English.
The Container Labelling is to be consistent with the WHO template.
參考北美自由貿易協定標籤指南

附件B: 糢闆

請參閱此處搵到嘅NAFDAC糢闆
質量總體摘要–產品檔案 (QOS-PD)
Quality information Summary (奇斯)

ANNEX C: 申請管理和標準操作程序

已獲得世界衛生組織資格預審嘅藥品, registration will be via the Collaborative Procedure for the Accelerated Registration of WHO Prequalified medicines and vaccines.
As for other products, including those for specific or neglected tropical diseases, a complete application will be required.

1.4 應用總體政策

每個產品需要單獨嘅應用程序. For purposes of clarification, one application could be submitted for products containing the same active ingredients and the same strength made by the same manufacturer at the same manufacturing site, to the same specifications and dosage form, but differing only in packing or pack sizes. 另一方面, 對於含有相同活性成分嘅產品,應單獨提交申請(s) 但不同嘅鹽, 不同嘅強度, 劑型和專有或品牌名稱.

1.4.1 應用類

申請應分為三類 (3)
·新應用
·申請續訂 (即。, 註冊)
·應用變化 ( 即。, 註冊產品嘅 )
1.4.2 新應用
藥品註冊申請一係提交畀國家食品藥品監督管理局,一係抄襲主任註冊監管事務局,授予市場授權. 除了提交的檔案, 申請人應提供:
我. 生產該產品嘅工廠嘅站點主文件. (在糢塊中提交 3)
第二. 對於NCEs同創新產品,應提交藥監計劃. (在糢塊中提交 1.2.8 (普蘇斯).
1.4.3 註冊續期申請
至少應提出續簽登記嘅申請 3 在現有註冊期滿前幾個月,應遵循《市場授權許可證續期指南》。
藥品桎梏
1.4.4 註冊產品變更申請
註冊產品嘅變更申請應按照"NAFDAC"嘅要求進行
變化指南"

1.5 提交申請

產品市場授權登記申請,應當按照核准格式向國家食品藥品監督管理局總幹事提出,並抄送國家食品藥品監督管理局註冊監管司司長。. 用于特定國家/地區嘅營銷授權產品, 申請應發送畀該国嘅NMRA負責人.

1.6 申請費

提交的每份申請均應支付申請費. -應按照核准嘅北美自由貿易協定關稅.
其他國家MRA可能會根據其立法要求向其他國家MR收取費用.

1.8 時間表

完成快速註冊申請 (僅本地製造和優先藥物), 註冊後審批變更和續簽將在 90 收到申請的工作日. 完整嘅新申請將在內部處理 12 收到申請嘅月份. 申請人將被要求提供任何要求嘅其他數據內 6 月.
如果需要額外嘅時間, 必須提交正式請求.

1.9 撤回申請

當申請人未能提交書面答覆查詢內 6 自其發行之日起嘅幾個月, 將被視為申請人已撤回申請,抑或如果查詢已第二次發出番,並且申請人提供唔滿意嘅答覆, 產品將被取消資格,申請將被拒絕. 申請人必須重新申請.

1.10 註冊有效性

藥品註冊有效期為五 (5) 年,除非否則暫停或撤銷NAFDAC, 或由申請人撤回.

1.11 上訴

因任何藥品嘅營銷授權申請而受害嘅任何人,可在兩項範圍內 (2) 決定通知之日起數月, 以書面形式向NAFDAC提出陳述,並提交其他數據以支持上訴.
支持製造商對監管決定提出上訴請求嘅文件已放入糢塊中 1.1.5 of the CTD.
1.1.5 of the CTD.
北美自由貿易協定糢闆
Quality Templates
1. Quality overall summaryproduct dossier (QOS-PD)
2. Quality information summary (奇斯)
Bioequivalence Template
1. 生物等價試驗信息表 (Btif)
2. Biowaiver Application Form ( BAF )
a. 纳夫达克BCS生物豁免糢闆
B. 纳夫达克額外強度生物豁免糢闆.
Labelling Templates
1. 患者信息傳單 (必)– 模板
2. Summary Product Characteristics (斯姆普克) Template
3. 北美自由貿易協定標籤糢闆
管理糢闆
1. CEP嘅訪問權限
2. APIMF嘅訪問權限
[1] 術語"複雜嘅FPP"包括無菌產品, 計量劑量吸入器產品, 乾粉吸入器產品和皮下輸送系統. 徜徉複雜FPPx下嘅其他特定產品包括利托纳维尔/洛皮纳维尔FDC片劑和含有利福匹辛或青黴素嘅FDC.

 

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