Registration of pharmaceutical products in Nigeria Guidelines for the registration of pharmaceutical products in Nigeria QUALITY GUIDELINES FOR THE REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA  Lex Artifex 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. Acknowledgment  The Agency acknowledges the technical support of the World Health Organization (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. Objective This article provides guidance for the preparation of regulatory submission for the Registration of Medicines for Human Use in Nigeria in line with the widely accepted format and common requirements achieved through the processes of the International Council for Harmonization (ICH) 人類用Ich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 (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. 共同技術文件嘅透瓦霍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; Collaboration and information sharing among medicines regulatory agencies Provision of guidance on other technical and general requirements Elaborate on requirements for Active Pharmaceutical Ingredients (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; Promotion of a more transparent regulatory system LIST OF ABBREVIATIONS AIDS Acquired Immune Deficiency Syndrome API Active Pharmaceutical Ingredient APIMF Active Pharmaceutical Ingredient Master File .ATC Anatomical Therapeutical and Chemical Classification CEP Certificate of Suitability issued by the European Directorate for the Quality of Medicines and Healthcare (埃德QM) CPP Certificate of Pharmaceutical Product CTD Common Technical Document DMF Drug Master File ECOWAS Economic Community for West African States FPP Finished Pharmaceutical Products GMP Good Manufacturing Practices HIV Human Immunodeficiency Virus ICH International Council for Harmonisation of Technical Requirements for the Registration of Medicines for human use INN International Non-Proprietary Name MA Market Authorization NCE New Chemical Entities NMRA National Medicines Regulatory Authority OTC Over the Counter Medicines PIL Patient Information Leaflet POM Prescription-only Medicines SmPC Summary of Product Characteristics WAHO West African Health Organization WHO World Health Organization GENERAL PRINCIPLES FOR THE PRESENTATION OF APPLICATION FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA Language Applications for products seeking marketing authorization shall be submitted in English. In cases where there is the need to translate a document from its original language to  English, 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。.  Data Presentation Dossiers should be submitted in electronic form and should follow the CTD format. 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 ·         International standards for citing references in any parts of the dossier must be followed. 任何參考源嘅最新版本, 指定必須使用出版年. ·         Literature references should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 國際醫學期刊編輯委員會 (伊姆杰). ·         Acronyms and abbreviations should be defined the first time they are used in each module.  Where necessary, 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. ·         All in-house processes quoted in the documentation must have been validated and appropriate references cited.  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) guideline has been restated verbatim in these guidelines in bold text, 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)        “Drug substance” is replaced with “active pharmaceutical ingredient” or “API” b)        “Drug product” is replaced with “finished pharmaceutical product” or “FPP”. c)        “Application” is replaced with “product dossier” or “PD”. d)        “Combination product” is replaced with “fixed-dose combination” or “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, following the bold text reproduced from the M4Q (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指引嘅期望. 呢種方法嘅目的係便利呢啲準則中案文嘅肯定同來源 (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. Guidance on format The recommendations outlined in the WHO general filing guideline Guidelines on submission of documentation for a multisource (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成品建議:  The Open part (non-proprietary information) 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.  For an API from multiple manufacturers, 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. 1CTD-Q, 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優勢嘅信息. 應為每種FPP強度提供一份完整嘅PD副本.  For an FPP with multiple container-closure systems (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.  For an FPP supplied with reconstitution diluent(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.  STRUCTURE OF THE CTD FORMAT Information within the CTD is organized into a series of structured documents which are in turn organized into modules. 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.  TABLE 1: 共同技術文件中嘅主要章節標題 (CTD) FORMAT  Number Title and Main Section Headings     1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.A Module 1: Administrative and Product Information Cover Letter Table of Contents (Modules 1 to 5) Application Information Product Information Regional Summaries Electronic Review Documents Product Sample(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) Summaries CTD Table of Contents (Modules 2 to 5) CTD Introduction Quality Overall Summary Nonclinical Overview Clinical Overview Nonclinical Written and Tabulated Summaries Clinical Summary 3.1 3.2 3.3 Module 3: Quality Table of Contents of Module 3 Body of Data Literature References 4.1 4.2 4.3 Module 4: Nonclinical Study Reports Not required for Table of Contents of Module 4    generic products Study Reports Literature References 5.1 5.2 5.3 5.4 Module 5: Clinical Study Reports  Bioequivalence or Table of Contents of Module 5    Biowaiver required for generics as applicable Tabular Listing of All Clinical Studies Clinical Study Reports Literature References    MODULE 1 (行政和產品信息) 1.0     Cover letter: ·         A cover letter should accompany any data being submitted to the regulatory authority.  The cover letter should clearly state what is being submitted, 包括提及請求書 (if applicable) 同包裝嘅簡要說明. ·         The cover letter should not contain any scientific information. ·         Any cross-referenced regulatory document should be clearly stated in the cover letter, 以及以下信息應包含在內: •          Application type, 指定是否新, 續約或變更; •          NMRA application number (由NMRA發佈); •          Date of regulatory authorization if applicable. •          Brand name, Dci, 劑量, 表示, dosage form; •          Manufacturer’s name •          Applicant’s name •          Number of samples submitted A sample cover letter is provided in Annex B: 形式 1.1    Table of contents of the application including Module 1 (module 1-5) The Table of Contents (ToC) for the entire regulatory dossier should be placed in this section.  It should list all documents included in Modules 1-5.  A module-specific ToC Tocincluded with each Module. 1.2    應用程序信息 1.2.1   Application Letter 1.2.2   報名表 1.2.3   公司成立證書 1.2.4   授權書 1.2.5   Notarized Declaration of the applicant. (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   Power of Attorney /Contract Manufacturing Agreement 1.2.7   醫藥產品證書 1.2.8   Certificate of Good Manufacturing Practice 1.2.9   Manufacturing Authorization 1.2.10                Evidence of Trademark Registration 1.2.11                Superintendent Pharmacist’s Annual Licence to Practice 1.2.12                Certificate of Registration and Retention of Premises 1.2.13                Evidence of Previous Marketing Authorization (If applicable) 1.2.14                Invitation Letter for GMP Inspection 1.2.15                Copy of Certificate of Suitability of the European Pharmacopoeia (where applicable) 1.2.16                Letter of Access for APIMF(s) (where applicable) 1.2.17                Biowaiver Request in relation to conducting BCS-based bioavailability study 1.2.18                Biowaiver request in relation to conducting Additional Strength bioavailability study 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, an annotated version of the revised SmPC is required.  The annotations should identify all changes made, 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) ·         All container labels, 包括內部和外部標籤, 應在本節中提供. ·         This should include the labels for all strengths, 劑型和重組天拿水. ·         When additional revisions are requested during the course of the review, 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) ·         A copy of the Patient Information Leaflet (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.  Quality將放在本節中        Electronic Review Documents Electronic versions of applications are encouraged either in searchable Portable Document Format (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 ·         A sample of the product in the same packaging intended for commercial purposes should be submitted along with the application. 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) Summaries Module 2 包括以下內容 7 sections.   For multisource (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tents for Module 2 to 5 should be provided. 2.2      通用技術文檔The introduction should include proprietary name, 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              Quality Overall Summary The Quality Overall Summary (Qos) is a summary that follows the scope and the outline of the Body of Data in Module 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   Drug Substance For a drug product containing more than one drug substance, 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 (name, manufacturer) 包括糢塊3.2.S.1中嘅信息  2.3. S.2製造 (name, 物理地址, i.e., 網站)  Include information from Module 3.2.S.2 Information on the manufacturer, •              Provide the name, 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. •              A brief description of the manufacturing process (including, for example, 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. •              A flow diagram, 如3.2.S.2.2中提供; •              A description of the Source and Starting Material and raw materials of biological origin used in the manufacture of the API, 如3.2.S.2.3中所述; •              Highlight critical process intermediates, 如3.2.S.2.4中所述; •              A description of process validation and/or evaluation, 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, as described in 3.2.S.3.1, 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: •              Information on the manufacturer. •              A brief description of the manufacturing process and the controls that are intended to result in the routine and consistent production of product of appropriate quality. •              A flow diagram, 根據以下規定 3.2. P.3.3. •              A brief description of the process validation and/or evaluation, 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 如中所述), 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 (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 規範理由嘅簡要摘要  2.3. P.8 Stability (name, dosage form)  所進行的研究摘要 (conditions, batches, analytical procedures) 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,, 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 graphi表格演示文稿re 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.  區域信息  2.4. Non-Clinical Overview The Nonclinical Overview should 批次 an integrated overall analysis of the information in the Module 4. In general, 非臨床概述不應超過約 30 頁分析程序按以下順序顯示: •      Overview of the nonclinical testing strategy •      Pharmacology •      Pharmacokinetics •      Toxicology •      Integrated overview and conclusions •      List of literature references The In批准後穩定性協議ould clearly d在適當時用圖形表示utical as demonstrated by the nonclinical studies and arrive at logical, 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., 適用於標籤). ICH M4S (R2) Module 2.4 provides guidance for the contents of the Non-clinical Overview.  The non-clinical information in Module 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 Clinical Overview The Clinical Overview is intended to provide a critical analysis of the clinical data in the Common Technical Document. 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 Literature References ICH M4E (R1) Module 2.5 為臨床概述嘅內容提供指導.  Module 3: Quality The Quality module follows the structure and illustrative explanations that are outlined in ICH M4Q (R1).  Text is only duplicated from document in cases where emphasis is desired. 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 - Drug Substance The following information may be submitted as information for the API as applicable: Option 1 - Confirmation of API prequalification document Option 2-  A Certificate of Suitability of European Pharmacopeia (CEP) Option 3 - Active Pharmaceutical Ingredient Master File (APIMF) procedure Option 4 – Full Details in the Product Dossier For a drug product containing more than one drug substance, 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 Specification – the specifications of the FPP manufacturer including all tests and limits of the API manufacturer’s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer’s specifications such as polymorphs and/or particle size distribution. -       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 Stability – data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified 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 summarizedCep 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 the guidance 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申請人應在檔案中提供以下信息.E數據匯總喺QOS-PD中同CEP同Ph.Eur中未控制嘅任何附加測試和驗收標準. Monograph, 例如多態和/或顆粒大小分佈. 3.2. S.根據本節中嘅指南,溶解性同多態性FPP製造商使用嘅任何方法. Monograph. 3.2. S.4.4 Batch analysis – results from two batches 根據本節中嘅指南mpliance with the FPP manufacturer’s API specifications. 3.2. S.5 Reference sta專著 materials – information on the FPP manufacturer’s reference standards.  3.2.S.6 Container-closure system – specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closurS.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規範請人S.5參考標準或材料–有關FPP製造商參考標準嘅信息,應包含喺PD中.   Option 3: Active pharmaceutical ingredient master file (APIMF) procedure Full details of the chemistry, manufacturing process, quality controls during manufacturing and process validation for the API may be submitted as an APIMF by the API manufacturer In such cases, 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: General information S.1.1–S.1.3 Manufacture S.2                     Manufacturer(s) S.2.1                     Description of manufacturing process and process controls S.2.2   Controls of critical steps and intermediates S.2.4 Elucidation of structure and other characteristics S.3.1 Impurities S.3.2 Control of the API S.4.1–S.4.5 Reference standards or materials S.5 Container-closure system S.6 Stability S.7.1–S.7.3 It is the responsibility of the applicant to ensure that the complete 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"提供嘅指南嚟準備活性藥物成分主文件阿普伊姆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: Full details in the PD Information on the 3.2.S Active pharmaceutical ingredient sections, 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    Nomenclature (name, manufacturer) 應提供有關藥物物質名稱的信息. For  example: •              Recommended International Non-proprietary Name (酒店.); •              Compendial name if relevant; •              Chemical name(s); •              Company or laboratory code; •              Other non-proprietary name(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選項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 (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.  Physical description The physical description should include appearance, 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).  Solubilities and quantitative aqueous pH solubility profile The following should be provided for all options for the submission of API data. 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), 它醇二氯甲烷和丙酮dosage forms, 劑量/溶解度應根據公式確定:        Largest dosage strength (mg) Dose/solubility vo非專有信息                          The minimum concentration of the drug (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pH 1.2~6.8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). Polymorphism As recom毫升nded in ICH’s CTD-Q Questions and answers/location issues document (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), details should be included in 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.  Particle size distribution As recommended in ICH’s CTD-Q Questions and answers/location issues document (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).  Information from the literature Supportive data and results from specific studies or published literature can be included within or attached to this section. 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. 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 (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:  A flow diagram of the synthetic process(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.  A sequential procedural narrative of the manufacturing process should be submitted. 敘述應包括, 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).  Alternative processes should be explained and described with 例如vel of detail as the primary process. 應確定後處理步驟並證明其合理性. Any data to support this justification should be either referenced or filed in 3.2.S.2.5. 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對製造鎂程嘅詳細說明, 材料回收, if any, 應詳細描述它們被引入到流程中嘅步驟. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times of mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates. Where there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences. All solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; however, their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7. Where polymorphic or amorphous forms have been identified, the 標籤lting from the synthesis should be stated. Where particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (e.g. milling or micronization) should be described. Justification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2. It is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to NAFDAC according to the requirements of the NAFDAC variation guidelines. 3.2. S.2.3 Control of materials (name, manufacturer) Materials used in the manufacture of the API (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. 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, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future cha以下要求適用於提交API信息嘅第四个選項sh其中完整嘅細節喺檔案中提供S.2 there are occasions where a starting material for synthesis may also need to be defined. In general, the starting material for synthesis described in the PD should: a)            be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the race mate of a single enantiomer API, are not considered final intermediates; b)            be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (when applicable); c)            have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities; d)            be incorporated as a significant structural fragment into the structure of the API. Copies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, solvents, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD. The carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed. A letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies. When available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1. Reference documents: ICH Q6A. 3.2. S.2.4 Controls of critical steps and intermediates (name, manufacturer) Critical steps: Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided. 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, with the exception of information that is also relevant for the applicant. The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier. The critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral center or resulting in a major chemical transformation; 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. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected). 3.2. S.2.6 Manufacturing process development (name, manufacturer) A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production scale batches.  Reference should be made to the API data provided in Section 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 Characterization (name, manufacturer) 3.2. S.3.1 Elucidation of structure and other characteristics (name, manufacturer) Confirmation of structure based on, e.g. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included. Elucidation of structure The PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (e.g. whether the results support the proposed structure). For APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), ultraviolet (UV), nuclear magnetic resonance (N使用亞太基金基金程序嘅地方. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). For APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each of the proposed manufacturer(s) run concomitantly with an officially recognized pharmacopoeia reference standard. See section 3.2.S.5 for details on acceptable reference standards or materials.  Isomerism/stereochemistry When an API is chiral, 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. The identically of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, as appropriate. The API specification should include a test to ensure isomeric identity and purity. The potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed. When a single enantiomer of the API is claimed for non-pharmacopoeia APIs, unequivocal proof of absolute configuration of asymmetric centers should be provided, such as determined by X-ray of a single crystal. If, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect. Polymorphism Many APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrate紫外hic forms of the same chemical compound differ in internal solid-state structure and, therefore, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. 多態形式的意外外D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, e.g. 對於唔係BCS高可溶性嘅API. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions. A number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (e.g. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them. Decision tree 4 of ICH Q6A can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form. Polymorphism can also include solvation or hydration products (also known as pseudo polymorphs). If the API is used in a solvated form, the following information should be provided: ■ Specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor; ■ Specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits); ■ a description of the method used to prepare the solvate in 3.2. S.2.2. Particle size distribution For APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (e.g. delivery of inhalation products), achieving uniformity of content in low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions. If particle size distribution is an important parameter (e.g. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch (es) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch (es) used in the comparative bioavailability and biowaiver studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits: ▪        d10 not more than (NMT) 10% of total volume less than X µm; ▪        d50 XX µm–XXX µm; ▪        D90 not less than (NLT) 90% of total volume less than XXXX µm. Other controls on particle size distribution can be considered acceptable, if scientifically justified. 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, manufacture or degradation of the API. This should cover starting materials, by-products, intermedS.2.2, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeia APIs should not be limited to the impurities specified in the API monograph. The tables in the QOS-PD template should be used to summarize the information on the APIrelated and process-related impurities. In the QOSPD, the term “origin” refers to how and where the impurity was introduced (e.g. “Synthetic intermediate from Step 4 of the synthesis” or “Potential by-product due to rearrangement from Step 6 of the synthesis”). It should also be indicated if the impurity is a metabolite of the API. The ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included. It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. However, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (e.g. reporting, identification and qualification) could be extended to apply to APIs of semi-synthetic origin. As an illustrat報告le身份同資格認證e was derived from a fermentation process or a natural product of plant or animal origin, 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. Identification of impurities It is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. Furthermore, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendia monograph. As a result, each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (e.g. NMT 0.10% or 1.0 mg per day intake (whichever is lower) for APIs having an MDD ≤ 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendia monograph, which could potentially be higher than the applicable ICH limit. Qualification of impurities The ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs: The limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (e.g. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (e.g. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (e.g. samples of a similar age) to obtain a meaningful comparison of the impurity profiles. Levels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified. 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.  Basis for setting the acceptance criteria The basis for setting the acceptance criteria for the impurities should be provided. 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) and the concentration limits for process-related impurities (e.g. residual solvents) according to the applicable ICH guidelines (e.g. Q3A, Q3C). The qualified level should be considered as the maximum allowable limit. However, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason, the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results. If there are identified impurities specified in an official compendia monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (e.g. “Impurities D, E and F listed in The International Pharmacopoeia (Ph.Int.) Monograph are not potential impurities from the proposed route of synthesis used by manufacturer X”). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendia monograph at an acceptable level (e.g. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeia method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia. ICH class II solvent(s) used prior to the las中間體 manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option I) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API. For guidance on acceptable residual solvent limits refer to ICH Q3C. The limit for residues of trimethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option I or 3.2 mg/day on the basis of permitted daily exposure (PDE). The absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (e.g. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. 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) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment. Reference documents: ICH Q6A, Q3A, Q3C. 3.2. S.4 Control of the API (name, manufacturer) 3.2. S.4.1 Specification (name, manufacturer) The specification for the API should be provided. As defined in ICH’s Q6A guideline (6), 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.’’ Copies of the API specifications, 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, including specifications from each API manufacturer as well as those of the FPP manufacturer. The FPP manufacturer’s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods). ▪ The standard declared by the 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此外d indicate the kind of analytical procedure used (e.g. visual, IR, UV, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (e.g. BP, JP, and Ph.Eur. Ph.Int., USP or in-house) 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). Any non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing. The ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs. Reference documents: ICH Q6A, Q3A, Q3C and officially recognized pharmacopoeias. 3.2. S.4.2 Analytical procedures (name, manufacturer) The analytical procedures used for testing the API should be provided. Copies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should be provided. Unless modified it is not necessary to provide copies of officially recognized compendia analytical procedures. Tables for summarizing a number of the different analytical procedures and validation information (e.g. HPLC assay/impurity methods, gas chromatography (GC) 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 in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendia methods need not be summarized unless modifications have been made. 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. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, i.e. between 80 and 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities (e.g. 0.10%). The test for related substances in the Ph.Int. Monograph for lamivudine serves as a typical example. The system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. However, the choice of alternative peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int. Section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities). Reference documents: ICH Q2, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.4.3 Validation of analytical procedures (name, manufacturer) Analytical validation information, including experimental data for the analytical procedures used for testing the API, should be provided. Copies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, 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 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 validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOSPD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (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. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore, 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. 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, full validation of the method is expected with respect to those impurities. 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 specified impurities), 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. These data are used to establish the specifications and evaluate consistency in API quality. Analytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(es) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer’s test results should be summarized in the QOS-PD. 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. results not tested according to the proposed specification). Reference documents: ICH Q6A, Q3A, Q3C). 3.2. S.4.5 Justification of specification (name, manufacturer) Justification for the API specification should be provided. A discussion should be provided on the 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 of the modifications or replacement method(s) should be included. The justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (e.g. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided. Reference documents: ICH Q6A, Q3A, Q3C, and officially recognized pharmacopoeias. 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). These could be classified as primary or secondary reference standards. A suitable primary reference standard should be obtained from an officially recognized pharmacopoeia source (e.g. BP, JP, and Ph.Eur. Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeia standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeia sources do not need further structural elucidation. Otherwise a primary standard may be a batch of the API that has been fully characterized (e.g. by IR, UV, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary reference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, e.g. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents). A secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, e.g. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (e.g. if additional solvents are used during the additional purification process that are not used for routine purposes). Reference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance. Reference documents: ICH Q6A, WHO Technical Report Series, No. 943, Annex 3. 3.2. S.6 Container-closure system (name, manufacturer) A description of the container-closure system(s) should be provided, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should 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 do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.  The suitability should be discussed with respect to, 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. The WHO Guidelines on packaging for pharmaceutical products and the officially recognized pharmacopoeias should be consulted for recommendations on the packaging information for APIs. Primary packaging components are those that are in direct contact with the API or FPP. The specifications for the primary packaging components should be provided and should include a specific test for identification (e.g. IR). Copies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. In addition, the name and address of the manufacturer of the API should be stated on the container, regardless of whether relabeling is conducted at any stage during the API distribution process. 2. S.7 Stability (name, manufacturer) 3.2. S.7.1 Stability summary and conclusions (name, manufacturer) The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, for example, from forced degradation studies and stress conditions, as wellUvs conclusions with respect to storage conditions and retest date or shelf-life, 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, stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual API and the type of FPP involved. Stress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of WHO Technical Report Series, No. 953, Annex 2, as well as, "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. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition. The tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (e.g. temperatures, relative humiditS.5 參考標準或材料urations) and the observations for the various test parameters (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 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 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 aS.7穩定性t 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-app條件ility 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 section 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 NF (PH 102)”) and special technical 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 commer如果有嘅話 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 may influence both 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製造商ation 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 resources are 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製造工藝on 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 sco酌情ng 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 the dissolution 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 appro係iate for the type of dosage form. For extended-release FPPs, the testing conditions should be set to cover the entire time period of麻麻.release (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. Differences between the manufacturing processes (es) used to produce comparative bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can influence the performance of the product should be discussed. For products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (b) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety. The rationale for choosing the particular pharmaceutical product (e.g. Dosage form, delivery system) should be provided. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (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 contain材料選擇on防潮和防光age form and route of administration. The 包括吸附到容器和浸出quired 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 (including ophthalmics) Description of any additional × treatmentsa × ×        (sterilization dehydrogenation components) and of the Extraction studies – × × Interaction   studies – (migration/sorption) × × Moisture permeability      × (uptake) × (usually loss) × (usually loss) Light transmission ×b × × × Information should be submitted. – Information does not 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 o多態性ner-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), whenever the package provides 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 from the packaging components) should 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. The only exceptions are in the cases where the API cannot exist on its own. Similarly, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacture of the final product. Sites for such manufacturing steps should be listed in this section. A valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (Module 1, 1.2.2). For each site where the major production step(s) are carried out, when applicable, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (Module 1, 1.2.2). Justification for any differences to the product in the country or countries issuing the WHOtype certificate(s) When there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.  Regulatory situation in other countries A listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (Module 1, 1.2.2). Reference documents: WHO Technical Report Series, No. 961, Annex 3 and No. 957, Annex 5 3.2. P.3.2 Batch formula (name, dosage form) A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards. The tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch. All components used in the manufacturing process should be included, including those that may not be added to every batch (e.g. acid and alkali), those 的名稱 b地址ed同每個製造商嘅責任any others (e.g. nitrogen以及每個提議嘅生產場地或涉及製造和測試嘅工廠he製造所涉及的設施ed包裝1 kg of active ingredien如果某些公司只負責特定步驟verages should be clearly indicated 應該清楚地表明nding to 2%) overage of the API to compensate for manufacturing losses”). The components should be declared by their proper or comm涉及, 包括蚊ds (e.g. BP, JP, a而唔係行政辦公室, if applicable, their grades (e.g. “Microcrystalline cellulose NF (PH 102)”) and special technical characteristics (e.g. lyophilized, micronized, solubilized or emulsified). 3.2. P.3.3 Description of manufacturing process and process controls (name, dosage form) A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermedi包括 or final product controls are conducted should be identified. A narrative description of the manufacturing process, including packaging that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.  Steps in the process should have the appropriate process parameters identified, such as time, temperature, or ph. associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated. The maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 days. For an aseptically processed FPP, sterile filtration 天he bulk and filling into final containers should preferably be continuous; any holding time should be justified. Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3). The information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches. For the manufacture of sterile products, the class (e.g. A, B or C) of the areas should be stated for each activity (e.g. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization. Reference documents: ICH Q8, Q9, Q10. 3.2. P.3.4 Controls of critical steps and intermediates (name, dosage form) Critical steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.  Intermediates: Information on the quality and control of intermediates isolated during the process should be provided. Examples of applicable in-process controls include: Granulations: moisture (limits expressed as a range), blend uniformity (e.g. low-dose tablets), bulk and tapped densities and particle size distribution; Solid oral products: average weight, weight variation, hardness, thickness, friability, and disintegration checkedP.3製造hroughout compression, weight gain during coating; Semi-solids: viscosity, homogeneity, pH; Transdermal dosage forms: assay of API–adhesive mixture, weight per area of coated patch without backing; Metered dose inhalers: fill weight or volume, leak testing, valve delivery; Dry powder inhalers: assay of API–excipient blend, moisture, weight variation of individually contained doses such as capsules or blisters; Liquids: pH, 比重, clarity of solutions; Parenterals: appearance, clarity, fill volume or weight, pH, filter integrity tests, particulate matter, leak testing of ampoules, prefiltration and/or pre-sterilization bioburden testing. Reference documents: ICH Q2, Q6A, Q8, Q9, Q10, WHO Technical Report Series, No. 929, Annex 5. 3.2. P.3.5 Process validation and/or evaluation (name, dosage 包括承包商cumentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturin溫度e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided in 3.2A.2, if necessary. For products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below. The following information should be provided for all other products: 1.     a copy of the process validation protocol, specific to this FPP, described below; 2.     a commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the NAFDAC inspection team; 3.     if the process validation studies have already been conducted (e.g. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. and 2. 以上. One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. Thus, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analyzed statistically to verify the “normality” of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendia specifications. Similarly同樣ve sampling and testing may be performed with regard to any quality requirements. In addition, intermediate stages may be validated in the same way, e.g. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. Thus, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch. Where ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification. The process validation protocol should include, but not be limited to, the following: A reference to the current master production document; A discussion of the critical equipment; The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation; Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend); The testing parameters and acceptance criteria including in process and release specifications and comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies; The analytical procedures or a reference to appropriate section(s) of the dossier; The methods for recording and evaluating results; –  the proposed timeframe for completion of the protocol. The manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (e.g. a strictly controlled environment using highly reliable procedures and with appropriate inprocess controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following: Washing, 治療, sterilization and dehydrogenation of containers, closures and equipment; Filtration of solutions; Lyophilization process; Leaker test of filled and sealed ampoules; – final inspection of the product; – sterilization cycle. The sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (e.g. steam), dry heat, filtration, gaseous sterilization (e.g. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. Therefore, scientific justification for selecting any other method of sterilization should be provided. The sterilization process should be described in detail and evideP.3.3hould be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as the safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 °C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds. Any filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components. For the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current NA 個FDAC or WHO GMP guidelines for details. Reference documents: ICH Q8, Q9, Q10, WHO Technical Report Series, No. 961, Annex 3. 3.2. P.4 Control of excipients (name, dosage form) 3.2. P.4.1 Specifications (name, dosage form)  The specifications for excipients should be provided. The specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (e.g. acid and alkali), those that do not appear in the final FPP (e.g. solvents) and any others used in the manufacturing process (e.g. nitrogen or silicon for stoppers). If the standard claimed for an excipient is an officially recognized compendia standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendia monograph. If the standard claimed for an excipient is a non-compendia standard (e.g. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendia monograph, a copy of the specification for the excipient should be provided. For products submitted to NAFDAC for registration, only excipients with an officially recognized pharmacopoeia monograph should be used. Exceptions may be justified. For excipients of natural origin, microbial limit testing should be included in the specifications. Skiptesting is acceptable if justified (submission of acceptable results of five production batches). For oils of plant origin (e.g. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated. The colours permitted for use are limited to those listed in the “Japanese pharmaceutical excipients”, the European Union (EU) “List of permitted food colours”, and the FDA “Inactive ingredient guide”. For proprietary mixtures, the supplier’s product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer’s specifications for the product, including identification testing. For flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (e.g. USA or EU regulations). Information that is considered confidential may be submitted directly to the NAFDAC by the supplier who should make reference in the cover letter to the specific related product. Other certifications of at-risk components may be required on a case-by-case basis. If additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted. Reference documents: ICH Q6A. 3.2. P.4.2 Analytical procedures (name, dosage form) The analytical procedures used for testing the excipients should be provided, where appropriate. Copies of analytical procedures from officially recognized compendia monographs do not need to be submitted. Reference document: ICH Q2. 3.2. P.4.3 Validation of analytical procedures (name, dosage form) Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, where appropriate. Copies of analytical validation information are generally not submitted for the testing of excipients, with the exception of the validation of in-house methods where appropriate. Reference document: ICH Q2. 3.2. P.4.4 Justification of specifications (name, dosage form) Justification for the proposed excipient specifications should be provided, where appropriate. A discussion of the tests that are supplementary to those溶劑ng in the officially recognized compendia monograph should be provided. 3.2. P.4.5 Excipients of human or animal origin (name, dosage form) For excipients of human or animal origin, information should be provided regarding adventitious agents (e.g. sources, 規格, description of the testing performed, and viral safety data) (details in 3.2.A.2). The following excipients should be addressed in this section: gelatin, phosphates, stearic acid, magnesium stearate and other stearates. If the excipients are of plant origin a declaration to this effect will suffice. For excipients of animal origin, a letter of attestation should be provided confirming that the excipients used to manufacture the FPP are without risk of transmitting agents of animal spongiform encephalopathies. Materials of animal origin should be avoided whenever possible. When available a CEP demonstrating TSE-compliance should be provided. A complete copy of the CEP (including any annexes) should be provided in Module 1. Reference documents: ICH Q5A, Q5D, Q6B, WHO Technical Report Series, No. 908, Annex 1. 3.2. P.4.6 Novel excipients (name, dosage form) For excipient(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 declared by the 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, 視情況而定, identification and assay of antimicrobial or chemical preservatives (e.g. 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, melting point; 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 inCEP嘅完整副本 a包括任何附件ow應在模塊中提供s: at least every tenth batch and at least one batch 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 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. 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 summarizing a 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, related substances and dissolution of the FPP. 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. 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熔點 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 second batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 tablets or capsules) of穩定性posed strength of the FPP. These batches生產規模的批次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 (es) used in the comparative bioavailability or biowaiver studies. 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. The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as “all tests meet specifications”. The discussion should include ranges of analytical results, where relevant. For quantitative tests (e.g. individual and total impurity tests and assay tests), it should be ensured that actual numerical results are provided 另外. vague statements such as “within limits” or “conforms” (e.g. “levels of degradation product A ranged from 0.2 to 0.4 %”). Dissolution results shoul"e expressed, at a minimum, as both the average and the range of individual results. Recommendations for conducting and assessing comparative dissolution profiles can be found in Appendix 1. A discussion and justification should be provided for any incomplete analyses (e.g. for any parameters not tested according to the proposed specification). Reference documents: ICH Q3B, Q3C, Q6A. 3.2. P.5.5 Characterization of impurities (name, dosage form) 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 (e.g. residual solvents in the manufacturing 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 would not need 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 specifications should include descrip叶斯on 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 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 (e.g. 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. 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 thickness or area weight. Information to establish the suitability (e.g. qualification) of the conta主要包裝組件係嗰啲與API或FPP直接接觸嘅組件e warranted for certain changes in packaging components (e.g. a comparative delivery study (droplet size) for a change in manufacturer of dropper tips). 3.2. P.8 Stability (name, dosage form) 3.2. P.8.1 Stability summary and conclusions (name, dosage form) The types of studies conducted, 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 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 stability programme also includes the study of product related factors that influence 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, when the container-closure system is shown to be light protective. Additional 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) 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 相關情況bility guidelines for FPPs packaged in impermeable and semi-permeable containers and 因此ended 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 (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 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 scientificall自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, for example, after opening, reconstitution and/or dilution of any sterile and/or multidose products or after first opening of FPPs packed in bulk multidose con應提供les 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; 批號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 tests meet specifications”. The discussion should include ranges of analytical results 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 expresse批處理大小nimum, as both the average and range of individual results. Applicants should consult ICH’s Q1E guideline 在適當時on the evaluation and extrapolation of results from stability data (e.g. 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, but should not exceed the long-term data by mo但不應超過長期數據超過helf-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 pr應提供批准後穩定性協議和穩定性承諾itment 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 wrP.8穩定性ent (signed and dated) to continue long-term testing over the shelf-life period sh±ld 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 year of product manufactured in every strength and every container-closure system, if relevant, 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. 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 valid如果相關ese 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. 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 equipmenQ1Bot applQ1DblQ1Ei.e. not a biotech product). 3.2. A.2        Adventitious 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 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 (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 scale is generally, 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; ■ dispensing, processing and packaging sections with rel或ant 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, processing temperature range, granulation end-point and tablet machine speed ( expressed as target and range)); ■ list of in-process tests (e.g. appearance, pH, assay, blend uniformity, viscosity, particl粘度stribution, 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. Reference document: WHO Technical Report Series, No. 961. 3.2. R.2 Analytical procedures and validation information The tables presented in section 2.3.R.2 in the 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     Liter強度ferences  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. 假假地. M4S (R2) f在適用的情況下tail on the organization of Module 4 and for ICH references on study design 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 Pharmacodynami測定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   Distributio對於固體口服劑型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 pha如果適用,) 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 StuBies 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 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). 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 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 (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 produ劑型tive 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 avai名字lity 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 s然而e 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 biop即maceutics 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 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 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 cover 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 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 (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered 分鐘 (no calculations required). Oth否則 Similarity of the resulting comparative dissolution profiles should be calculated using the following equation thCt defines a similarity factor (f2): f2 = 50 LOG {[1+1/n ∑nt=1 (Rt−Tt) 2] −0.5 × 100} where Rt and Tt are 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 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 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 (和2) ICH Quality Guidelines 1.    ICH Q1A(R2) - Stability Testing of New Drug Substances and Products (2003) 2.    ICH QICH Q1Aility 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 - E目錄bility 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, Q5B, Q5C, Q5D  Quality of Biological Products [not needed for multisource (generic) pharmaceutical products] 10.  ICH Q6A - Specifications: Test Procedures and Acceptance Criteria for New Drug Subst例如.s 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 PharmacCtdical 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 CommiFppe on Phecifications 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 bioequivalence studies (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 on Bio waiver] Labelling Templates 1.    Patient information leaflet – Template 2.    Summary Product Characteristics (SmPC) Template 3.    Labelling Template ANNEX A: PRODUCT LABELLING GUIDANCE The Guidance and templates for product labelling shall be based on the NAFDAC Labelling Template guidance for the Package Leaflet, Summary of 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 SmPC document is to 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 M應包括ner 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 – product 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 Health Organization, registration will be via the Collaborative Procedu附錄he 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 is required 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 or pack sizes. On the other hand, separate applications shall be submitted for products that contain the same active ingredient(s) but of different salts, different strength, dosage form and proprietary or brand name. 1.4.1 Classes of Applications Applications shall be classified into three (3) •              New Applications •              Renewal of applications (i.e., registration) •              Variation of Applications ( i.e., of a registered product ) 1.4.2 New Applications Applications for the registration of a pharmaceutical product either submitted to the Director General NAFDAC and copy the Director Registration and Regulatory Affairs Directorate for the granting of market authorization. In addition to the dossier submitted, the applicant shall provide: 我.             A site master file of the plant in which the product was manufactured. (submitted in Module 3) 第二.            For NCEs and innovator products the pharmacovigilance plan shall be submitted. (Submitted in Module 1.2.8 (PSURs). 1.4.3 Applications for Renewal of Registration Applications for renewal of registration shall be made at least 3 months before the expiry of existing registration and shall follow the “GuidICH M4Sfor the Renewal of Marketing Authorisation Licence for a Pharmaceutical Product” 1.4.4 Application for Variation of a registered product Applications for variation to a registered product shall be made according to requirements “NAFDAC Variation Guidelines” 1.5 SUBMISSION OF APPLICATION Applications for the registration of products for market authorization shall be made to the Director General of NAFDAC and copy Director Registration and Regulatory Affairs NAFDAC in accordance with the approved format. For products meant for marketing authorization in a specific country, the application shall be sent to the Head of the NMRA in that country. 1.6 APPLICATION FEES AppR 2cation fees shall be paid for each application submitted. -This shall be as per the approved NAFDAC tariff. Others may be charged by various country MRAs as their legislation requires. 1.8 TIMELINES Complete applications for expedited registration (Locally manufactured and Priority Medicines only), Post Approval Variation and Renewal of registration will be processed唔係.ithin 9附件king day比較ving the applications.  Complete new applications will be processed within 12 months of receipt of the application. The applicant will be required to provide any requested additional data within 6 months. In case additional time is required, a formal request must be submitted. 1.9 WITHDRAWAL OF AN APPLICATION When the applicant fails to 月 written responses to queries within 6 months from the date of their issuance, it will例如: deemed that the applicant has withdrawn the application or if the queries have been reissued for a second time and the applicant provides unsatisfactory responses, the product will be disqualified and the application will be rejected. The applicant will be requirR1 to apply afresh. 1.10 VALIDITY OF REGISTRATION The registration of a pharmaceutical product shall be valid for five (5) years unless otherwise suspended or revoked by NAFDAC, or withdrawn by applicant. 1.11 APPEALS Any person aggrieved by a decision in relation to any application for marketing authorization of a pharmaceutical product may within two (2) months from the date of notice of the decision, make representations in writing to NAFDAC and submit additional data to support the appeal. Documentation in support of the manufacturer’s request to appeal a regulatory decision is placed in Module 1.1.5 of the CTD.  1.1.5 of the CTD. NAFDAC Templates Quality Templates 1.            Quality overall summary - product dossier (QOS-PD) 2.            Quality information summary (QIS) Bioequivalence Template 1.              Bioequivalence Trial Information Form (BTIF) 2.              Biowaiver Application Form ( BAF ) a.            NAFDAC BCS Biowaiver Template b.            NAFDAC Additional Strength Biowaiver Template. Labelling Templates 1.              Patient information leaflet  (PIL)– Template 2.              Summary Product Characteristics (SmPC) Template 3.              NAFDAC Label Template Administrative Templates 1.              Letter of Access for CEP 2.              Letter of Access for APIMF [1] The term “complicated FPP” includes sterile products, metered dose inhaler products, dry powder inhaler products and transdermal delivery systems. Other specific products under “complicated FPP” include ritonavir/lopinavir FDC tablets and FDCs containing rifampicin or an artemisinin. ABOUT LEX ARTIFEX LLP Lex Artifex LLP is the window for manufacturers, 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. We are a one-stop shop for legal compliance and due diligence services in Nigeria. We provide clients with legal guidance through every step of the trade process藥物more about the Lex Artifex LLP's F&D Helpdesk and how we can help you with your food and drug warehouse inspection by Nigerian’s NAFDAC, 請發送電子郵件: lexartifexllp@lexartifexllp.com; 叫 +234.803.979.5959.即。奇斯Btif必斯姆普克產品特性摘要糢塊通用as

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.

Acknowledgment

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

 

GENERAL PRINCIPLES FOR THE PRESENTATION OF APPLICATION FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS IN NIGERIA

語言

  • 申請營銷授權嘅產品應以英文提交.
  • In cases where there is the need to translate a document from its original language to English, 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

· International standards for citing references in any parts of the dossier must be followed. 任何參考源嘅最新版本, 指定必須使用出版年.
· Literature references should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 國際醫學期刊編輯委員會 (伊姆杰).
· Acronyms and abbreviations should be defined the first time they are used in each module. Where necessary, 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.
· All in-house processes quoted in the documentation must have been validated and appropriate references cited.
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) “Drug substance” is replaced with “active pharmaceutical ingredient” or “API”
B) “Drug product” is replaced with “finished pharmaceutical product” or “FPP”.
C) “Application” is replaced with “product dossier” or “PD”.
D) “Combination product” is replaced with “fixed-dose combination” or “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:
  • The Open part (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.
  • For an API from multiple manufacturers, 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.
  • For an FPP with multiple container-closure systems (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.
  • For an FPP supplied with reconstitution diluent(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.

STRUCTURE OF THE CTD FORMAT

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.

TABLE 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 generic products
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 Biowaiver required for
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

MODULE 1 (行政和產品信息)

1.0 Cover letter:

· A cover letter should accompany any data being submitted to the regulatory authority. The cover letter should clearly state what is being submitted, 包括提及請求書 (如果適用,) 同包裝嘅簡要說明.
· The cover letter should not contain any scientific information.
· Any cross-referenced regulatory document should be clearly stated in the cover letter, 以及以下信息應包含在內:
• Application type, 指定是否新, 續約或變更;
• NMRA application number (由NMRA發佈);
• Date of regulatory authorization if applicable.
• Brand name, Dci, 劑量, 表示, 劑型;
• Manufacturer’s name
• Applicant’s name
• Number of samples submitted
附件B提供了求職信樣本: 形式

1.1 Table of contents of the application including Module 1 (糢塊 1-5)

目錄 (Toc) for the entire regulatory dossier should be placed in this section. It should list all documents included in Modules 1-5. A module-specific ToC is included with each Module.
1.2 應用程序信息
1.2.1 Application Letter
1.2.2 報名表
1.2.3 公司成立證書
1.2.4 授權書
1.2.5 Notarized Declaration of the applicant. (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 Power of Attorney /Contract Manufacturing Agreement
1.2.7 醫藥產品證書
1.2.8 Certificate of Good Manufacturing Practice
1.2.9 Manufacturing Authorization
1.2.10 Evidence of Trademark Registration
1.2.11 Superintendent Pharmacist’s Annual Licence to Practice
1.2.12 Certificate of Registration and Retention of Premises
1.2.13 Evidence of Previous Marketing Authorization (如果適用,)
1.2.14 Invitation Letter for GMP Inspection
1.2.15 Copy of Certificate of Suitability of the European Pharmacopoeia (在適用的情況下)
1.2.16 Letter of Access for APIMF(s) (在適用的情況下)
1.2.17 Biowaiver Request in relation to conducting BCS-based bioavailability study
1.2.18 Biowaiver request in relation to conducting Additional Strength bioavailability study

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, an annotated version of the revised SmPC is required. The annotations should identify all changes made, 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)

· All container labels, 包括內部和外部標籤, 應在本節中提供.
· This should include the labels for all strengths, 劑型和重組天拿水.
· When additional revisions are requested during the course of the review, 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)

· A copy of the Patient Information Leaflet (必) 將放在本節中.
1.4. 區域摘要
1.4.1. Bioequivalence Trial Information Form (Btif)
1.4.2. Quality Information Summary (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
· A sample of the product in the same packaging intended for commercial purposes should be submitted along with the application. 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 sections. For multisource (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)

The table of contents for Module 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 Drug 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,
• Provide the name, 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.
• A brief description of the manufacturing process (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.
• A flow diagram, 如3.2.S.2.2中提供;
• A description of the Source and Starting Material and raw materials of biological origin used in the manufacture of the API, 如3.2.S.2.3中所述;
• Highlight critical process intermediates, 如3.2.S.2.4中所述;
• A description of process validation and/or evaluation, 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:
• Information on the manufacturer.
• A brief description of the manufacturing process and the controls that are intended to result in the routine and consistent production of product of appropriate quality.
• A flow diagram, 根據以下規定 3.2. P.3.3.
• A brief description of the process validation and/or evaluation, 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:
• Overview of the nonclinical testing strategy
• Pharmacology
• Pharmacokinetics
• Toxicology
• Integrated overview and conclusions
• List of literature references
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 provides guidance for the contents of the Non-clinical Overview. The non-clinical information in Module 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). Text is only duplicated from document in cases where emphasis is desired.

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- A Certificate of Suitability of European Pharmacopeia (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 Specification – the specifications of the FPP manufacturer including all tests and limits of the API manufacturer’s specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer’s specifications such as polymorphs and/or particle size distribution.
– 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 Stability – data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higher temperature or humidity to that of the prequalified 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 Container-closure system – specifications including descriptions and identification of primary packaging components except where the CEP specifies a container-closure system and the applicant declares the intent to use the same container-closure system.
  • 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
Description of manufacturing process and process controls S.2.2
Controls of critical steps and intermediates S.2.4 Elucidation of structure and other characteristics 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 General Information (名字, 製造商)
3.2. S.1.1 Nomenclature (名字, 製造商)
應提供有關藥物物質名稱的信息. For example:
• Recommended International Non-proprietary Name (酒店.);
• Compendial name if relevant;
• Chemical name(s);
• Company or laboratory code;
• Other non-proprietary name(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:
Largest dosage strength (鎂)
Dose/solubility volume =
The minimum concentration of the drug (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 Manufacture (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:
A flow diagram of the synthetic process(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.
A sequential procedural narrative of the manufacturing process should be submitted. 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).
Alternative processes should be explained and described with the same level of detail as the primary process. 應確定後處理步驟並證明其合理性. Any data to support this justification should be either referenced or filed in 3.2.S.2.5.
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. Recovery operations should be adequately controlled such that impurity levels do not increase over time. For recovery of solvents, any processing to improve the quality of the recovered solvent should be described. Regarding recycling of filtrates (mother liquors) to obtain second crops, information should be available on maximum holding times of mother liquors and maximum number of times the material can be recycled. Data on impurity levels should be provided to justify recycling of filtrates.
Where there are multiple manufacturing sites being used by one API manufacturer, a comprehensive list in tabular form should be provided comparing the processes at each of the sites and highlighting any differences.
All solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Solvents used in the final steps should be of high purity. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended; 然而, their use can be justified on presentation of sufficient data demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7.
Where polymorphic or amorphous forms have been identified, the form resulting from the synthesis should be stated.
Where particle size is considered a critical attribute (see 3.2.S.3.1 for details) the particle size reduction method(s) (例如:. milling or micronization) should be described.
Justification should be provided for use of alternative manufacturing processes. Alternative processes should be explained with the same level of detail as for the primary process. It should be demonstrated that batches obtained by the alternative processes have the same impurity profile as obtained by the principal process. If the impurity profile obtained is different it should be demonstrated to be acceptable according to the requirements described under S.3.2.
It is acceptable to provide information on pilot-scale manufacture, provided it is representative of production scale and scale-up is reported immediately to NAFDAC according to the requirements of the NAFDAC variation guidelines.

3.2. S.2.3 Control of Materials (名字, 製造商)

Materials used in the manufacture of the API (例如:. raw materials, starting materials, 溶劑, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided. 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, the name and address of the manufacturing site(s) of the manufacturer(s) should be indicated. A brief description of the preparation of the API starting material should be provided for each manufacturer, including the solvents, catalysts and reagents used. A single set of specifications should be proposed for the starting material that applies to material from all sources. Any future changes to the API starting material manufacturers, mode of preparation or specifications should be notified.
As indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may also need to be defined. 麻麻., the starting material for synthesis described in the PD should:
a) be a synthetic precursor of one or more synthesis steps prior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the race mate of a single enantiomer API, are not considered final intermediates;
B) be a well characterized, isolated and purified substance with its structure fully elucidated including its stereochemistry (在適用的情況下);
C) have well-defined specifications that include among others one or more specific identity tests and tests and limits for assay and specified, unspecified and total impurities;
D) be incorporated as a significant structural fragment into the structure of the API.
Copies of the specifications for the materials used in the synthesis, extraction, isolation and purification steps should be provided in the PD, including starting materials, reagents, 溶劑, catalysts and recovered materials. Confirmation should be provided that the specifications apply to materials used at each manufacturing site. A certificate of analysis of the starting material for synthesis should be provided. A summary of the information on starting materials should be provided in the QOS-PD.
The carry-over of impurities of the starting materials for synthesis into the final API should be considered and discussed.
A letter of attestation should be provided confirming that the API and the starting materials and reagents used to manufacture the API are without risk of transmitting agents of animal spongiform encephalopathies.
When available a CEP demonstrating compliance with recommendations on transmissible spongiform encephalopathy (TSE) 應提供. CEP嘅完整副本 (包括任何附件) 應在模塊中提供 1.
Reference documents: ICH Q6A.

3.2. S.2.4 Controls of critical steps and intermediates (名字, 製造商)

Critical steps: Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to ensure that the process is controlled should be provided.
Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.
使用亞太基金基金程序嘅地方, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD, with the exception of information that is also relevant for the applicant.
The following requirements apply to the fourth option for submission of API information where full details are provided in the dossier.
The critical steps should be identified. These can include: steps where significant impurities are removed or introduced; steps introducing an essential molecular structural element such as a chiral center or resulting in a major chemical transformation; 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.
Reference documents: 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, 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. If the API is prepared as sterile a complete description should be provided of the aseptic processing and/or sterilization methods. A description of the controls used to maintain the sterility of the API during storage and transportation should also be provided. Alternative processes should be justified and described (see guidance in 3.2.S.2.2 for the level of detail expected).

3.2. S.2.6 Manufacturing process development (名字, 製造商)

A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the API used in producing comparative bioavailability or biowaiver, scale-up, pilot, 和, if available, production scale batches.
Reference should be made to the API data provided in Section 3.2. S.4.4.
使用亞太基金基金程序嘅地方, a cross-reference to the Restricted part of the APIMF is considered sufficient for this section of the PD.

3.2. S.3 Characterization (名字, 製造商)

3.2. S.3.1 Elucidation of structure and other characteristics (名字, 製造商) Confirmation of structure based on, 例如:. synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.

Elucidation of structure

The PD should include quality assurance (QA) certified copies of the spectra, peak assignments and a detailed interpretation of the data from the studies performed to elucidate and/or confirm the structure of the API. The QOS-PD should include a list of the studies performed and a conclusion from the studies (例如:. whether the results support the proposed structure).
For APIs that are not described in an officially recognized pharmacopoeia, the studies carried out to elucidate and/or confirm the chemical structure normally include elemental analysis, infrared (IR), 紫外 (Uv), nuclear magnetic resonance (NMR) and mass spectra (MS) studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
For APIs that are described in an officially recognized pharmacopoeia it is generally sufficient to provide copies of the IR spectrum of the API from each of the proposed manufacturer(s) run concomitantly with an officially recognized pharmacopoeia reference standard. See section 3.2.S.5 for details on acceptable reference standards or materials.

Isomerism/stereochemistry

When an API is chiral, 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. The identically of the isomeric composition of the API to that of the API in the comparator product should be established. Information on the physical and chemical properties of the isomeric mixture or single enantiomer should be provided, 酌情. The API specification should include a test to ensure isomeric identity and purity.
The potential for interconversion of the isomers in the isomeric mixture, or racemization of the single enantiomer should be discussed.
When a single enantiomer of the API is claimed for non-pharmacopoeia APIs, unequivocal proof of absolute configuration of asymmetric centers should be provided, such as determined by X-ray of a single crystal.
If, based on the structure of the API, there is not a potential for stereoisomerism, it is sufficient to include a statement to this effect.

多態性

Many APIs can exist in different physical forms in the solid state. Polymorphism is characterized as the ability of an API to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water the solvates are also commonly known as hydrates.
Polymorphic forms of the same chemical compound differ in internal solid-state structure and, 因此, may possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These properties can have a direct impact on API processability, pharmaceutical product manufacturability and product quality and performance, including stability, dissolution and bioavailability. 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. In the absence of published data for APIs that are not BSC highly soluble, polymorphic screening will be necessary to determine if the API can exist in more than one crystalline form. Polymorphic screening is generally accomplished via crystallization studies using different solvents and conditions.
A number of methods can be used to characterize the polymorphic forms of an API. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. XRPD can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (例如:. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy (例如:. IR, Raman, and solid-state nuclear magnetic resonance (ssNMR)) are helpful for further characterization of polymorphic forms. Where polymorphism is a concern, the applicants or manufacturers of APIs should demonstrate that a suitable method, capable of distinguishing different polymorphs, is available to them.
Decision tree 4 of ICH Q6A can be used where screening is necessary and 4(2) can be used to investigate if different polymorphic forms have different properties that may affect performance, bioavailability and stability of the FPP and to decide whether a preferred polymorph should be monitored at release and on storage of the API. Where there is a preferred polymorph, acceptance criteria should be incorporated into the API specification to ensure polymorphic equivalence of the commercial material and that of the API batches used in the comparative bioavailability or biowaiver studies. The polymorphic characterization of the API batches used in comparative bioavailability or biowaiver studies by the above-mentioned methods should be provided. The method used to control polymorphic form should be demonstrated to be specific for the preferred form.
Polymorphism can also include solvation or hydration products (also known as pseudo polymorphs). If the API is used in a solvated form, the following information should be provided:
■ Specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic precursor; ■ Specifications for the solvated API including appropriate limits on the weight ratio of API to solvent (with data to support the proposed limits); ■ a description of the method used to prepare the solvate in 3.2. S.2.2.
顆粒大小分佈
For APIs that are not BCS highly soluble contained in solid FPPs, or liquid FPPs containing undissolved API, the particle size distribution of the material can have an effect on the in vitro and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage form performance (例如:. delivery of inhalation products), achieving uniformity of content in low-dose tablets (例如:. 2 mg or less), desired smoothness in ophthalmic preparations and stability of suspensions.
If particle size distribution is an important parameter (例如:. as in the above cases), results from an investigation of several batches of the API should be provided, including characterization of the batch (叶斯) used in the comparative bioavailability or biowaiver studies. API specifications should include controls on the particle size distribution to ensure consistency with the material in the batch (叶斯) used in the comparative bioavailability and biowaiver studies (例如:. limits for d10, d50 and d90). The criteria should be established statistically, based on the standard deviation of the test results from the previously mentioned studies. The following example is provided for illustrative purposes as possible acceptance criteria for particle size distribution limits:
▪ d10 not more than (NMT) 10% of total volume less than X µm;
▪ d50 XX µm–XXX µm;
▪ D90 not less than (NLT) 90% of total volume less than XXXX µm.
Other controls on particle size distribution can be considered acceptable, if scientifically justified.
Reference documents: 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, manufacture or degradation of the API. This should cover starting materials, by-products, 中間體, chiral impurities and degradation products and should include the chemical names, structures and origins of the impurities. The discussion of pharmacopoeia APIs should not be limited to the impurities specified in the API monograph.
The tables in the QOS-PD template should be used to summarize the information on the APIrelated and process-related impurities. In the QOSPD, the term “origin” refers to how and where the impurity was introduced (例如:. “Synthetic intermediate from Step 4 of the synthesis” or “Potential by-product due to rearrangement from Step 6 of the synthesis”). It should also be indicated if the impurity is a metabolite of the API.
The ICH thresholds for reporting, identification (used to set the limit for individual unknown impurities) and qualification are determined on the basis of potential exposure to the impurity, 例如:. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage forms and strengths having different MDD values, it is imperative that the thresholds and corresponding controls for each of the presentations be considered to ensure that the risks posed by impurities have been addressed. This is normally achieved by using the highest potential daily MDD, rather than the maintenance dose. For parenteral products the maximum hourly dose of the API should also be included.
It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH impurity guidelines. 然而, depending on the nature of the API and the extent of the chemical modification steps, the principles regarding the control of impurities (例如:. 報告, 身份同資格認證) could be extended to apply to APIs of semi-synthetic origin. As an illustrative example, an API whose precursor molecule was derived from a fermentation process or a natural product of plant or animal origin, 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

It is recognized by the pharmacopoeias that APIs can be obtained from various sources and thus can contain impurities not considered during the development of the monograph. 此外, a change in the production or source may give rise to additional impurities that are not adequately controlled by the official compendia monograph. As a result, each PD is assessed independently to consider the potential impurities that may arise from the proposed route(s) of synthesis. For these reasons the ICH limits for unspecified impurities (例如:. NMT 0.10% 或 1.0 mg per day intake (whichever is lower) for APIs having an MDD ≤ 2 g/day) are generally recommended, rather than the general limits for unspecified impurities that may appear in the official compendia monograph, which could potentially be higher than the applicable ICH limit.

Qualification of impurities

The ICH impurity guidelines should be consulted for options on the qualification of impurities. The limit specified for an identified impurity in an officially recognized pharmacopoeia is generally considered to be qualified. The following is an additional option for qualification of impurities in existing APIs:
The limit for an impurity present in an existing API can be accepted by comparing the results of tests for impurities found in the existing API with those observed in an innovator product using the same validated, stability-indicating analytical procedure (例如:. comparative (high-performance liquid chromatography (HPLC) studies). If samples of the innovator product are not available, the impurity profile may also be compared to a different prequalified FPP with the same route of administration and similar characteristics (例如:. tablet versus capsule). It is recommended that the studies be conducted on comparable samples (例如:. samples of a similar age) to obtain a meaningful comparison of the impurity profiles.
Levels of impurities generated from studies under accelerated or stressed storage conditions of the innovator or prequalified FPP are not considered acceptable/qualified.
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:. starting materials, by-products, 中間體, 人性雜質或降解產物) and the concentration limits for process-related impurities (例如:. residual solvents) according to the applicable ICH guidelines (例如:. Q3A, Q3C).
The qualified level should be considered as the maximum allowable limit. 然而, limits which are considerably wider than the actual manufacturing process capability are generally discouraged. For this reason, the acceptance criteria are also set taking into consideration the actual levels of impurities found in several batches of the API from each manufacturer, including the levels found in the batches used for the comparative bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual numerical results should be provided rather than vague statements such as “within limits” or “conforms”. In cases where a large number of batches have been tested it is acceptable to summarize the results of all the batches tested with a range of analytical results.
If there are identified impurities specified in an official compendia monograph that are not controlled by the proposed routine in-house analytical procedure, a justification for their exclusion from routine analyses should be provided (例如:. “Impurities D, E and F listed in The International Pharmacopoeia (Ph.Int.) Monograph are not potential impurities from the proposed route of synthesis used by manufacturer X”). If acceptable justification cannot be provided it should be demonstrated that the routine in-house method is capable of separating and detecting the impurities specified in the official compendia monograph at an acceptable level (例如:. 0.10%). If such a demonstration cannot be performed, a one-time study should be conducted applying the pharmacopoeia method to several recent batches to demonstrate the absence of the impurities listed in the pharmacopoeia.
ICH class II solvent(s) used prior to the last step of the manufacturing process may be exempted from routine control in API specifications if suitable justification is provided. Submission of results demonstrating less than 10% of the ICH Q3C limit (option I) of the solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches of the API or a suitable intermediate would be considered acceptable justification. The last step solvents used in the process should always be routinely controlled in the final API.
For guidance on acceptable residual solvent limits refer to ICH Q3C. The limit for residues of trimethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option I or 3.2 mg/day on the basis of permitted daily exposure (PDE).
The absence of known, established highly toxic impurities (genotoxic) used in the process or formed as a by-product should be discussed and suitable limits should be proposed. The limits should be justified by appropriate reference to available guidance (例如:. EMEA/CHMP/QWP/ 251344/2006 (13) or USFDA Guidance for Industry. 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) or metals that are used as a pharmaceutical excipient in the FPP (例如:. an iron oxide pigment). The guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000) or any equivalent approaches can be used to address this issue. The requirement normally does not apply to extraneous metal contaminants that are more appropriately addressed by GMP, good distribution practices (GDP) or any other relevant quality provision such as the heavy metal test in monographs of recognized pharmacopoeias that cover metal contamination originating from manufacturing equipment and the environment.
Reference documents: ICH Q6A, Q3A, Q3C.

3.2. S.4 Control of the API (名字, 製造商)

3.2. S.4.1 Specification (名字, 製造商)
The specification for the API should be provided.
As defined in ICH’s Q6A guideline (6), 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.’’
Copies of the API specifications, dated and signed by authorized personnel (例如:. the person in charge of the quality control or quality assurance department) should be provided in the PD, including specifications from each API manufacturer as well as those of the FPP manufacturer.
The FPP manufacturer’s API specification should be summarized according to the table in the QOS-PD template under the headings: tests, acceptance criteria and analytical procedures (including types, sources and versions for the methods).
▪ The standard declared by the applicant could be an officially recognized compendia standard (例如:. BP, JP, Ph.Eur. Ph.Int., USP) or an in-house (manufacturer’s) standard.
▪ The specification reference number and version (例如:. 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 (例如:. visual, IR, Uv, HPLC or laser diffraction), the source refers to the origin of the analytical procedure (例如:. BP, JP, and Ph.Eur. Ph.Int., USP or in-house) and the version (例如:. 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 (例如:. 喺殘留溶劑嘅情況下).
Any non-routine testing should be clearly identified as such and justified together with the proposal on the frequency of non-routine testing.
The ICH Q6A guideline (6) outlines recommendations for a number of universal and specific tests and criteria for APIs.
Reference documents: ICH Q6A, Q3A, Q3C and officially recognized pharmacopoeias.

3.2. S.4.2 Analytical procedures (名字, 製造商)

The analytical procedures used for testing the API should be provided.
Copies of the in-house analytical procedures used to generate testing results provided in the PD, as well as those proposed for routine testing of the API by the FPP manufacturer, 應提供. Unless modified it is not necessary to provide copies of officially recognized compendia analytical procedures.
Tables for summarizing a number of the different analytical procedures and validation information (例如:. HPLC assay/impurity methods, gas chromatography (GC) methods) can be found in the 2.3.R Regional information section of the QOS-PD (即. 2.3.R.2). These tables should be used to summarize the in-house analytical procedures of the FPP manufacturer for determination of the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (C) or 2.3.S.7.3 (B) of the QOS-PD. Officially recognized compendia methods need not be summarized unless modifications have been made.
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. Impurity standards may be obtained from pharmacopoeias (individual impurities or resolution mixtures), from commercial sources or prepared in-house. It is considered acceptable to use the API as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close to that of the API, 即. between 80 和 120%. In cases where the response factor is outside this range it may still be acceptable to use the API, provided a correction factor is applied. Data to support calculation of the correction factor should be provided for an in-house method. Unspecified impurities may be quantified using a solution of the API as the reference standard at a concentration corresponding to the limit established for individual unspecified impurities (例如:.
0.10%). The test for related substances in the Ph.Int. Monograph for lamivudine serves as a typical example.
The system suitability tests (SSTs) represent an integral part of the method and are used to ensure the satisfactory performance of the chosen chromatographic system. As a minimum, HPLC and GC purity methods should include SSTs for resolution and repeatability. For HPLC methods to control API-related impurities, this is typically done using a solution of the API with a concentration corresponding to the limit for unspecified impurities. Resolution of the two closest eluting peaks is generally recommended. 然而, the choice of alternative peaks can be used if justified (例如:. choice of a toxic impurity). In accordance with the Ph.Int. Section on Methods of analysis the repeatability test should include an acceptable number of replicate injections. HPLC assay methods should include SSTs for repeatability and in addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs should verify the ability of the system to separate and detect the analyte(s) (例如:. by applying a spot corresponding to the API at a concentration corresponding to the limit of unspecified impurities).
Reference documents: ICH Q2, WHO Technical Report Series, 唔係.. 943, 附件 3.

3.2. S.4.3 Validation of analytical procedures (名字, 製造商)

Analytical validation information, including experimental data for the analytical procedures used for testing the API, 應提供.
Copies should be provided of the validation reports for the analytical procedures used to generate testing results provided in the PD, 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 (例如:. HPLC assay and impurity methods, GC methods) can be found in the 2.3.R Regional information section of the QOS-PD (即. 2.3.R.2). These tables should be used to summarize the validation information of the analytical procedures of the FPP manufacturer for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the QOSPD. The validation data for other methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (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. Different sources of the same API or FPP can contain impurities and/or degradation products that were not considered during the development of the monograph. 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, full validation of the method is expected with respect to those impurities.
If an officially recognized compendia standard is claimed and an in-house method is used in lieu of the compendia method (例如:. for assay or for specified impurities), 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 (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, pilot, 擴大規模同, if available, 生產規模的批次.
These data are used to establish the specifications and evaluate consistency in API quality.
Analytical results should be provided from at least two batches of at least pilot scale from each proposed manufacturing site of the API and should include the batch(叶斯) used in the comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch.
Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP manufacturer, should be provided for the profiled batches and any company responsible for generating the test results should be identified. The FPP manufacturer’s test results should be summarized in the QOS-PD.
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 (例如:. 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 (例如:. results not tested according to the proposed specification).
Reference documents: ICH Q6A, Q3A, Q3C).

3.2. S.4.5 Justification of specification (名字, 製造商)

Justification for the API specification should be provided.
A discussion should be provided on the 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 of the modifications or replacement method(s) 應包括.
The justification for certain tests, analytical procedures and acceptance criteria may have been discussed in other sections of the PD (例如:. for impurities or particle size distribution) and does not need to be repeated here, although a cross-reference should be provided.
Reference documents: ICH Q6A, Q3A, Q3C, and officially recognized pharmacopoeias.

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). These could be classified as primary or secondary reference standards.
A suitable primary reference standard should be obtained from an officially recognized pharmacopoeia source (例如:. BP, JP, and Ph.Eur. Ph.Int., USP) where one exists, and the lot number should be provided. Where a pharmacopoeia standard is claimed for the API and/or the FPP, the primary reference standard should be obtained from that pharmacopoeia when available. Primary reference standards from officially recognized pharmacopoeia sources do not need further structural elucidation.
Otherwise a primary standard may be a batch of the API that has been fully characterized (例如:. by IR, Uv, NMR and mass spectrometry (MS) analyses). Further purification techniques may be needed to render the material acceptable for use as a chemical reference standard. The purity requirements for a chemical reference substance depend upon its intended use. A chemical reference substance proposed for an identification test does not require meticulous purification since the presence of a small percentage of impurities in the substance often has no noticeable effect on the test. On the other hand, chemical reference substances that are to be used in assays should possess a high degree of purity (such as 99.5% on the dried or water/solvent free basis). Absolute content of the primary reference standard must be declared and should follow the scheme: 100% minus organic impurities (quantified by an assay procedure, 例如:. HPLC or DSC) minus inorganic impurities minus volatile impurities by loss on drying (or water content minus residual solvents).
A secondary (or in-house) reference standard can be used by establishing it against a suitable primary reference standard, 例如:. by providing legible copies of the IR of the primary and secondary reference standards run concomitantly and by providing its certificate of analysis, including assay determined against the primary reference standard. A secondary reference standard is often characterized and evaluated for its intended purpose with additional procedures other than those used in routine testing (例如:. if additional solvents are used during the additional purification process that are not used for routine purposes).
Reference standards should normally be established for specified impurities. Refer to 3.2.S.4.2 for additional guidance.
Reference documents: ICH Q6A, WHO Technical Report Series, 唔係.. 943, 附件 3.

3.2. S.6 Container-closure system (名字, 製造商)

A description of the container-closure system(s) 應提供, including the identity of materials of construction of each primary packaging component, and their specifications. The specifications should include description and identification (and critical dimensions with drawings, 在適當時). Non-compendia methods (with validation) 應包括, 在適當時.
For non-functional secondary packaging components (例如:. those that do not provide additional protection), only a brief description should be provided. For functional secondary packaging components, additional information should be provided.
The suitability should be discussed with respect to, 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. The specifications for the primary packaging components should be provided and should include a specific test for identification (例如:. IR).
Copies of the labels applied on the secondary packaging of the API should be provided and should include the conditions of storage. 另外., the name and address of the manufacturer of the API should be stated on the container, regardless of whether relabeling is conducted at any stage during the API distribution process.

2. S.7穩定性 (名字, 製造商)

3.2. S.7.1 Stability summary and conclusions (名字, 製造商)
The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include results, 例如., from forced degradation studies and stress conditions, as well as conclusions with respect to storage conditions and retest date or shelf-life, 酌情.
The WHO guidelines Stability testing of active pharmaceutical ingredients and finished 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, humidity and light.”
The tables in the QOS-PD template should be used to summarize the results from the stability studies and related information (例如:. 條件, testing parameters, conclusions and commitments).

Stress Testing

As outlined in the ICH Q1A guidance document, stress testing of the API can help identify the likely degradation products which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used.
The nature of the stress testing will depend on the individual API and the type of FPP involved.
Stress testing may be carried out on a single batch of the API. For examples of typical stress conditions refer to section 2.1.2 of WHO Technical Report Series, 唔係.. 953, 附件 2, as well as, "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. For this reason the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition.
The tables in the QOS-PD template should be used to summarize the results of the stress testing and should include the treatment conditions (例如:. temperatures, relative humidity, concentrations of solutions and durations) and the observations for the various test parameters (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.

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 (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 WHO Technical Report Series, 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. 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 (例如:. 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 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 (%) Minimum time
period
(月)
Accelerated 40 ± 2 75 ± 5 6
Intermediate –a –a
Long-term 30 ± 2 65 ± 5 或 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, 唔係.. 953, 附件 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 (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).
Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, 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.

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(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.

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 (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 of WHO Technical Report Series, 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.
Reference documents: ICH Q1A, Q1B, Q1D, Q1E, WHO Technical Report Series, 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. For quantitative tests (例如:. 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, 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.:
Description of the dosage form
  • The description of the FPP should include the physical description, 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, debossed with ‘100’ on one side and plain on the other side.”
  • Composition, 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, and Ph.Eur. 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,
  • The container-closure used for the FPP (and accompanying reconstitution diluent, 如果適用,) should be briefly described, with further details provided under 3.2.P.7
  • Container-closure system, 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 of WHO Technical Report Series, 唔係.. 929, 附件 5 (21).
Reference documents: 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 of the WHO Guidelines for registration of fixed-dose combination medicinal products (WHO Technical Report Series, 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, 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. 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:. WHO Technical Report Series, 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. As an illustrative example, 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.
In vitro dissolution or drug release
A discussion should be included as to how the development of the formulation relates to development of the dissolution method(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.
Differences between the manufacturing processes (叶斯) used to produce comparative bioavailability or biowaiver batches and the process described in
3.2.P.3.3 that can influence the performance of the product should be discussed.
For products that meet the criteria of an established multisource product, in order to fulfil the requirements of section P.2.3, section P.2.3 (B) of the dossier and QOS-PD should be completed and a product quality review should be submitted as outlined in Appendix 2. The guidance that follows applies to all other products for which section P.2.3 should be completed in its entirety.
The rationale for choosing the particular pharmaceutical product (例如:.
Dosage form, delivery system) 應提供. The scientific rationale for the choice of the manufacturing, filling and packaging processes that can influence FPP quality and performance should be explained (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: One-time studies to establish the suitability of the container-closure system contact materials

Solid Products

Oral Liquid and Topical Products

Sterile Products

(including ophthalmics)

Description of any additional × treatmentsa
×
× (sterilization dehydrogenation components)
of
中。
Extraction studies –
×
×
Interaction studies –
(migration/sorption)
×
×
Moisture permeability ×
(uptake)
× (usually loss)
×
(usually loss)
Light transmission ×b
×
×
× Information should be submitted. – Information does not need to be submitted. a. 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 (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.
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 (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 (WHO Technical Report Series, 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 (WHO good distribution practices for 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. The only exceptions are in the cases where the API cannot exist on its own. 同樣, for a mixture of APIs, the blending of the APIs is considered to be the first step in the manufacture of the final product. Sites for such manufacturing steps should be listed in this section.
A valid manufacturing authorization for pharmaceutical production, as well as a marketing authorization, should be submitted to demonstrate that the product is registered or licensed in accordance with national requirements (糢塊 1, 1.2.2).
For each site where the major production step(s) are carried out, 在適用的情況下, attach a WHO-type certificate of GMP issued by the competent authority in terms of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce (糢塊 1, 1.2.2).
Justification for any differences to the product in the country or countries issuing the WHOtype certificate(s)
When there are differences between the product for which this application is submitted and that marketed in the country or countries which provided the WHO-type certificate(s), it is necessary to provide data to support the applicability of the certificate(s) despite the differences. Depending on the case, it may be necessary to provide validation data for example for differences in site of manufacture, specifications and formulation. Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.

Regulatory situation in other countries

A listing should be provided of the countries in which this product has been granted a marketing authorization, this product has been withdrawn from the market and/or this application for marketing has been rejected, deferred or withdrawn (糢塊 1, 1.2.2).
Reference documents: WHO Technical Report Series, 唔係.. 961, 附件 3 and No. 957, 附件 5

3.2. P.3.2 Batch formula (名字, 劑型)

A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.
The tables in the QOS-PD template should be used to summarize the batch formula of the FPP for each proposed commercial batch size and to express the quantity of each component on a per batch basis, including a statement of the total weight or measure of the batch.
All components used in the manufacturing process should be included, 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 kg of active ingredient base = 1.075 kg active ingredient hydrochloride”). All overages should be clearly indicated (例如:. “Contains 5 kg (corresponding to 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, and Ph.Eur. 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).
3.2. P.3.3 Description of manufacturing process and process controls (名字, 劑型) A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.
A narrative description of the manufacturing process, including packaging that represents the sequence of steps undertaken and the scale of production should also be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (例如:. tumble blender, in-line homogenizer) and working capacity, 相關情況.
Steps in the process should have the appropriate process parameters identified, such as time, 溫度, or ph. associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified in Section 3.2.P.3.4. In certain cases, environmental conditions (例如:. low humidity for an effervescent product) should be stated.
The maximum holding time for bulk FPP prior to final packaging should be stated. The holding time should be supported by the submission of stability data if longer than 30 天. For an aseptically processed FPP, sterile filtration of the bulk and filling into final containers should preferably be continuous; any holding time should be justified.
Proposals for the reprocessing of materials should be justified. Any data to support this justification should be either referenced or filed in this section (3.2.P.3.3).
The information above should be summarized in the QOS-PD template and should reflect the production of the proposed commercial batches. See Glossary (section 2) for definitions of pilot-scale and production-scale batches.
For the manufacture of sterile products, the class (例如:. A 個, B or C) of the areas should be stated for each activity (例如:. compounding, filling and sealing), as well as the sterilization parameters, including for equipment, container-closure system and terminal sterilization.
Reference documents: ICH Q8, Q9, Q10.

3.2. P.3.4 Controls of critical steps and intermediates (名字, 劑型)

Critical steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.
Intermediates: Information on the quality and control of intermediates isolated during the process should be provided.
Examples of applicable in-process controls include:
  • Granulations: moisture (limits expressed as a range), blend uniformity (例如:. low-dose tablets), bulk and tapped densities and particle size distribution;
  • Solid oral products: average weight, weight variation, hardness, thickness, friability, and disintegration checked periodically throughout compression, weight gain during coating;
  • Semi-solids: 粘度, homogeneity, Ph;
  • Transdermal dosage forms: assay of API–adhesive mixture, weight per area of coated patch without backing;
  • Metered dose inhalers: fill weight or volume, leak testing, valve delivery;
  • Dry powder inhalers: assay of API–excipient blend, moisture, weight variation of individually contained doses such as capsules or blisters;
  • Liquids: Ph, 比重, clarity of solutions;
  • Parenterals: appearance, clarity, fill volume or weight, Ph, filter integrity tests, particulate matter, leak testing of ampoules, prefiltration and/or pre-sterilization bioburden testing.
Reference documents: ICH Q2, Q6A, Q8, Q9, Q10, WHO Technical Report Series, 唔係.. 929, 附件 5.

3.2. P.3.5 Process validation and/or evaluation (名字, 劑型)

Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (例如:. validation of the sterilization process or aseptic processing or filling).
Viral safety evaluation should be provided in 3.2A.2, if necessary.
For products that meet the criteria of an established multisource product, a product quality review as outlined in Appendix 2 may be submitted in lieu of the information below.
The following information should be provided for all other products:
1. a copy of the process validation protocol, specific to this FPP, described below;
2. a commitment that three consecutive, production-scale batches of this FPP will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification after prequalification by the NAFDAC inspection team;
3. if the process validation studies have already been conducted (例如:. for sterile products), a copy of the process validation report should be provided in the PD in lieu of 1. 和 2. 以上.
One of the most practical forms of process validation, mainly for nonsterile products, is the final testing of the product to an extent greater than that required in routine quality control. It may involve extensive sampling, far beyond that called for in routine quality control and testing to normal quality control specifications and often for certain parameters only. 因此, for instance, several hundred tablets per batch may be weighed to determine unit dose uniformity. The results are then analyzed statistically to verify the “normality” of the distribution and to determine the standard deviation from the average weight. Confidence limits for individual results and for batch homogeneity are also estimated. Strong assurance is provided that samples taken at random will meet regulatory requirements if the confidence limits are well within compendia specifications.
同樣, extensive sampling and testing may be performed with regard to any quality requirements. 另外., intermediate stages may be validated in the same way, 例如:. dozens of samples may be assayed individually to validate mixing or granulation stages of low-dose tablet production by using the content uniformity test. Certain product characteristics may occasionally be skip-tested. 因此, subvisual particulate matter in parenteral preparations may be determined by means of electronic devices, or tablets or capsules tested for their dissolution profile if such tests are not performed on every batch.
Where ranges of batch sizes are proposed, it should be shown that variations in batch size would not adversely alter the characteristics of the finished product. It is envisaged that those parameters listed in the following validation scheme would need to be revalidated once further scale-up is proposed after prequalification.
The process validation protocol should include, but not be limited to, the following:
  • A reference to the current master production document;
  • A discussion of the critical equipment;
  • The process parameters that can affect the quality of the FPP (critical process parameters (CPPs)) including challenge experiments and failure mode operation;
  • Details of the sampling: sampling points, stages of sampling, methods of sampling and the sampling plans (including schematics of blender or storage bins for uniformity testing of the final blend);
  • The testing parameters and acceptance criteria including in process and release specifications and comparative dissolution profiles of validation batches against the batch(叶斯) used in the bioavailability or biowaiver studies;
  • The analytical procedures or a reference to appropriate section(s) of the dossier;
  • The methods for recording and evaluating results; – the proposed timeframe for completion of the protocol.
The manufacture of sterile FPPs needs to take place in a well-controlled manufacturing area (例如:. a strictly controlled environment using highly reliable procedures and with appropriate inprocess controls). A detailed description of these conditions, procedures and controls should be provided, together with actual copies of the standard operating procedures for the following:
  • Washing, 治療, sterilization and dehydrogenation of containers, closures and equipment;
  • Filtration of solutions;
  • Lyophilization process;
  • Leaker test of filled and sealed ampoules; – final inspection of the product; – sterilization cycle.
The sterilization process used to destroy or remove microorganisms is probably the single most important process in the manufacture of parenteral FPPs. The process can make use of moist heat (例如:. steam), dry heat, filtration, gaseous sterilization (例如:. ethylene oxide) or radiation. It should be noted that terminal steam sterilization, when practical, is considered to be the method of choice to ensure sterility of the final FPP. 因此, scientific justification for selecting any other method of sterilization should be provided.
The sterilization process should be described in detail and evidence should be provided to confirm that it will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as the safety of the FPP will not be affected. Details such as Fo range, temperature range and peak dwell time for an FPP and the container-closure system should be provided. Although standard autoclaving cycles of 121 °C for 15 minutes or more would not need a detailed rationale, such justifications should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. If ethylene oxide is used, studies and acceptance criteria should control the levels of residual ethylene oxide and related compounds.
Any filters used should be validated with respect to pore size, compatibility with the product, absence of extractables and lack of adsorption of the API or any of the components.
For the validation of aseptic processing of parenteral products that cannot be terminally sterilized, simulation process trials should be conducted. This involves filling containers with culture media under normal conditions, followed by incubation. Refer to current NAFDAC or WHO GMP guidelines for details.
Reference documents: ICH Q8, Q9, Q10, WHO Technical Report Series, 唔係.. 961, 附件 3.

3.2. P.4 Control of excipients (名字, 劑型)

3.2. P.4.1 Specifications (名字, 劑型)

The specifications for excipients should be provided.
The specifications from the applicant or the FPP manufacturer should be provided for all excipients, including those that may not be added to every batch (例如:. acid and alkali), those that do not appear in the final FPP (例如:. 溶劑) and any others used in the manufacturing process (例如:. nitrogen or silicon for stoppers).
If the standard claimed for an excipient is an officially recognized compendia standard, it is sufficient to state that the excipient is tested according to the requirements of that standard, rather than reproducing the specifications found in the officially recognized compendia monograph.
If the standard claimed for an excipient is a non-compendia standard (例如:. in-house standard) or includes tests that are supplementary to those appearing in the officially recognized compendia monograph, a copy of the specification for the excipient should be provided.
For products submitted to NAFDAC for registration, only excipients with an officially recognized pharmacopoeia monograph should be used. Exceptions may be justified.
For excipients of natural origin, microbial limit testing should be included in the specifications. Skiptesting is acceptable if justified (submission of acceptable results of five production batches).
For oils of plant origin (例如:. soy bean oil or peanut oil) the absence of aflatoxins or biocides should be demonstrated.
The colours permitted for use are limited to those listed in the “Japanese pharmaceutical excipients”, the European Union (EU) “List of permitted food colours”, and the FDA “Inactive ingredient guide”. For proprietary mixtures, the supplier’s product sheet with the qualitative formulation should be submitted, in addition to the FPP manufacturer’s specifications for the product, including identification testing.
For flavours, the qualitative composition should be submitted, as well as a declaration that the excipients comply with foodstuff regulations (例如:. USA or EU regulations).
Information that is considered confidential may be submitted directly to the NAFDAC by the supplier who should make reference in the cover letter to the specific related product.
Other certifications of at-risk components may be required on a case-by-case basis.
If additional purification is undertaken on commercially available excipients, details of the process of purification and modified specifications should be submitted.
Reference documents: ICH Q6A.

3.2. P.4.2 Analytical procedures (名字, 劑型)

The analytical procedures used for testing the excipients should be provided, 在適當時.
Copies of analytical procedures from officially recognized compendia monographs do not need to be submitted.
Reference document: ICH Q2.

3.2. P.4.3 Validation of analytical procedures (名字, 劑型)

Analytical validation information, including experimental data, for the analytical procedures used for testing the excipients should be provided, 在適當時.