ICH Q8(中英文).doc

ICH Q8（中英文）blueski推薦2009-12-20出處：Julia的blog作者：不詳INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE人用藥物注冊技術要求國際協(xié)調會議ICH Harmonised Tripartite Guideline ICH三方協(xié)調指南Pharmaceutical Development藥物開發(fā)Q8Recommended for Adoption at Step 4 of the ICH Process on 10 November 2005 by the ICH Steering Committee ICH指導委員會2005年11月10日ICH第四階段推薦采用This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 本指南根據ICH規(guī)程由合適的ICH專家工作組起草并經向法規(guī)部門咨詢。在規(guī)程的第4步，建議歐洲共同體、日本和美國的藥政部門采用其最終的草案。TABLE OF CONTENTS目錄1. INTRODUCTION簡介. 11.1 Objective of the Guideline指南目的. 11.2 Scope范圍. 12. PHARMACEUTICAL DEVELOPMENT藥物開發(fā). 12.1 Components of the Drug Product制劑產品的組分. 42.1.1 Drug Substance活性成分. 42.1.2 Excipients輔料. 42.2 Drug Product制劑. 52.2.1 Formulation Development配方開發(fā). 52.2.2 Overages超量. 62.2.3 Physicochemical and Biological Properties物化和生化性質. 72.3 Manufacturing Process Development制造工藝開發(fā). 72.4 Container Closure System容器系統(tǒng). 92.5 Microbiological Attributes微生物屬性. 92.6 Compatibility兼容性. 103. GLOSSARY術語. 11 1. INTRODUCTION 簡介1.1 Objective of Guideline 指南目的This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical Development) section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format. 本指南就 CTD 格式申請文件中第3.2.P.2 章：藥物開發(fā)需要敘述的內容給出了建議。 The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management (for definition, see ICH Q9) to the development of a product and its manufacturing process. It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product. The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided. 藥物開發(fā)一章給申請企業(yè)提供了一個機會，來闡述其應用科學的方法和風險管理手段，在產品及其生產工藝的開發(fā)過程中所獲得的知識。它既可以被用于原始的制劑上市申請，又可以經過更新后被用于支持產品生命周期內所獲得的新知識。本指導文件也說明了在什么情況下，藥物和生產方面的最大程度的理解可以形成靈活的藥政管理辦法的基礎。藥物開發(fā)一章旨在為審核官和檢查官就產品和生產工藝提供更詳盡的理解。 1.2 Scope 范圍 This guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH guideline M4). The guideline does not apply to contents of submissions for drug products during the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. This guideline might also be appropriate for other types of products. To determine the applicability of this guideline to a particular type of product, applicants can consult with the appropriate regulatory authorities. 本指導文件就 CTD 模塊3（ICH 標題 M4）中所定義的制劑的第3.2.P.2（藥物開發(fā)）一章中的內容提供了指南。本指導文件不適用于臨床研究階段制劑遞交文件的內容。然而，在這些階段對本指導文件中的原則進行考慮也是重要的。本指南可能也適用于其他一些類型的產品。申請者向合適的藥政管理當局進行咨詢來確定本指導文件是否適用于某一特定類型的產品。 2. PHARMACEUTICAL DEVELOPMENT 藥物開發(fā) The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. 藥物開發(fā)的目的在于設計符合質量要求的產品及符合重復生產模式的制造工藝。在藥物開發(fā)和研究過程中所獲得的信息和知識將為建立質量標準和生產控制提供科學的依據。 Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. 藥物開發(fā)研究過程中所獲得的信息是風險評估的基礎。質量是通過設計建立起來的，而不是通過對產品的檢測得來的，認識這一點是很重要的。開發(fā)過程中的配方和生產工藝的變更應當被看成是獲得更多額外知識的機會，以進一步支持設計空間的建立。包括從失敗實驗中獲得的知識也是有用的，也可以用于支持所選擇的產品及其生產工藝。The Pharmaceutical Development section should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and facilitate review. 藥物開發(fā)一章應當闡述為滿足申請中所規(guī)定的目的，建立所選擇的劑型和擬定的配方的知識基礎。在本章節(jié)中的每一個部分都應當要包括足夠的資料用以理解制劑及其生產工藝的開發(fā)。鼓勵使用表格和圖表進行概述。At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. 至少，應當要對關鍵的且能很大程度上影響產品質量的方面進行確定和討論，它們包括原料藥，賦形劑和生產工藝，這些方面也是需要檢測和控制的。通過評估它們的變化程度對制劑質量的影響可確定這些關鍵的配方屬性和工藝參數(shù)。 In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls. This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate: 此外，申請者也可以選擇進行一些其它的藥物開發(fā)研究以在更廣的物料屬性范圍，操作選項范圍和工藝參數(shù)范圍內對產品的性能有更深的了解。將這些更多的信息包括在本章節(jié)使得可以對生產工藝和過程控制有更高的理解。這樣的科學理解確立了設計空間。這些情況為建立更靈活的藥政管理辦法提供了可能，比如，便于： risk-based regulatory decisions (reviews and inspections); 基于風險管理的藥政決議（審核和現(xiàn)場檢查）； manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review; 生產工藝改進，在文件所述的已批準的設計空間范圍內，不需要進一步的藥政審核； reduction of post-approval submissions; 減少預審批呈遞 real-time quality control, leading to a reduction of end-product release testing. “實時”質量控制，導致最終產品的放行檢測的減少To realise this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. This understanding can be gained by application of, for example, formal experimental designs, process analytical technology (PAT), and/or prior knowledge. Appropriate use of quality risk management principles can be helpful in prioritising the additional pharmaceutical development studies to collect such knowledge. 為了實現(xiàn)這種靈活性，申請者應當要在物性（如：粒徑分布、水分、流動性），操作選項和工藝參數(shù)等的某一范圍內對產品性能進行更高層次的論述?？梢酝ㄟ^實行規(guī)范的實驗設計或工藝分析技術（PAT）來獲得這些知識。適當?shù)貞蔑L險管理原則，有助于按其優(yōu)先性進行排序額外的藥物開發(fā)研究，以獲得這些知識。The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation. 藥物開發(fā)研究的設計和實施應當要和其擬定的科學目的和產品開發(fā)階段相一致。需要認識到的是所獲知識的層次，而不是數(shù)據量，為科學的申請文件及其藥政評審提供了基礎。 2.1Components of the Drug Product制劑產品的組分 2.1.1Drug Substance活性成分 The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination. 應當要對原料藥的能對制劑的性質及其生產能力產生影響的，或是已被專門設計在原料藥方面的（如：晶體工程學）物化性質和生物學特性進行說明和討論。可能需要檢查的物化屬性和生物特性有：溶解性、水分、粒徑、晶體特性、生物活性、和滲透性等。這些性質可能相互之間是有聯(lián)系的，因此可能需要綜合起來考慮。有些性質會隨著時間而改變的，或是和供應商相關。 To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on drug product might be warranted. For example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances describes some of the circumstances in which drug product studies are recommended (e.g., Decision Tree #3 and #4 (Part 2). This approach applies equally for the ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification (3.2.S.4.5). 為了評估原料藥的物理化學性質對制劑產品性能的潛在影響，應當要提供制劑的研究資料。比如說，ICH Q6A 質量標準：新化學原料藥及新制劑的檢驗方法及合格標準中建議的一些情況下需要進行制劑研究（如決策樹#3 和#4（第2 部分）。對原料藥性質可能會對制劑性能產生的影響進行研究所獲得的知識，如果合適，可被用于論證原料藥的質量標準建立的原因（3.2.S.4.5）。 The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. 需討論原料藥與第 3.2.P.1 章中所列輔料的兼容性。對于含有多個原料藥的制劑，還應討論各原料藥間的兼容性。 2.1.2Excipients輔料The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification (3.2.P.5.6). 可以影響制劑產品的性能（例如，穩(wěn)定性和生物利用度）或是制劑產品的工藝性的輔料選擇，輔料的濃度和特性必須按各自的功效逐一討論。在相關的情況下（比如雙防腐劑系統(tǒng)中的防腐劑），還需確定各賦形劑間的兼容性。還應闡述各種輔料（如防氧化劑、穿透增強劑、分解質、釋放控制劑）在整個制劑保質期內實現(xiàn)其預期作用的能力?？蛇m當應用輔料性能方面的資料來論證輔料選擇及其質量特性的合理性，以支持制劑質量標準的合理性說明（3.2.P.5.6）。 Information to support the safety of excipients, when appropriate, should be cross-referenced (3.2.P.4.6).適當時，還應交叉引用相關資料以支持輔料的安全性論證（3.2.P.4.6）。2.2Drug Product制劑2.2.1Formulation Development處方開發(fā) A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product. 應綜述配方的開發(fā)過程，包括那些對制劑產品質量很重要的屬性，并考慮擬定用途和給藥途徑。 The summary should highlight the evolution of the formulation design from initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s). 該綜述應著重說明配方設計從最初概念到最終設計的發(fā)展過程。該綜述還應當要考慮各制劑組分的選擇（如：原料藥，賦形劑，包裝系統(tǒng)和相關劑型裝置），生產工藝和類似制劑產品開發(fā)過程中所獲得的經驗（如果合適的話）。 Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture. 正式的實驗設計所獲得的資料可用于確定關鍵的或有相互作用的變量，這些變量對于確保制劑產品的質量可能是重要的。在申請文件的此章節(jié)中應對批配方（3.2.P.3.2）中的輔料范圍進行合理性說明。通常，該合理性說明會建立在配方和生產工藝的開發(fā)所獲得的經驗這個基礎上。 A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. 應綜述在臨床安全性和有效性，生物利用度研究或生物等效性研究中所用到的所有配方。對于擬定的市售配方和臨床研究與穩(wěn)定性實驗所用批次的配方間的變更都應當進行明確地說明，并提供這些變更的合理性說明。 Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described in 3.2.P.1 should be summarized and a cross-reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process. 應綜述和市售配方（如3.2.P.1 中所描述）相關聯(lián)的對比性體外研究（如：溶出度）或對比性體內研究（如：生物等效性）所獲得的信息，并參引這些研究（研究序號）。如果已試圖確立體外實驗和體內實驗之間的相關性，則在此章節(jié)中應提供這些研究的結果并參引這些研究（研究序號）。成功的相關性有助于合適的溶出度可接受標準的選擇，并可能減少在產品和生產工藝出現(xiàn)變更的情況下，進一步進行生物等效性研究的需要。 Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use. 需應標明制劑的所有設計特性（如：藥片標記線、過度充填、反偽造措施），并提供使用他們的理由。應提供這些特性的適宜性的支持信息。2.2.2Overages超量In general, use of an overage of a drug substance to compensate for degradation during manufacture or a products shelf life, or to extend shelf life, is discouraged. 總體來說，不鼓勵加入過量原料藥以補償生產過程或產品存貯期中原料藥的降解，或用以延長保存期。Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3) justification for the amount of overage. The overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).對于制劑生產過程中出現(xiàn)的過量現(xiàn)象，無論其是否是出現(xiàn)在最終制劑中，都應當要從產品的安全性和有效性方面對其進行合理性說明。應提供如下信息：1）過量的量；2）過量的原因（如，補償生產過程中出現(xiàn)的損失）；3）超出量的合理性說明。在典型批配方（3.2.P.3.2）所列的原料藥量中應包括超出量。2.2.3Physicochemical and Biological Properties物化和生化性質The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes. Studies could include, for example, the development of a test for respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release, and the development and suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should cross-reference any relevant stability data in 3.2.P.8.3. 應確定和制劑產品的性能或工藝性能相關的物理化學特性和生物學特性，并對它們進行討論。可以包括如下配方屬性：pH 值、摩爾滲透壓濃度、離子濃度、親油性、溶出度、再分散作用、重構、粒徑分布、顆粒形狀、聚集作用、多晶形、流變性質、乳劑的顆粒尺寸、生物活性/功效、和/或免疫活性。配方屬性的生理性質如pH 值也應當要說明。需參引3.2.P.8.3 中的相關穩(wěn)定性資料。在申請文件中的此章節(jié)（3.2.P.2.2.3）中，應綜述為了研究物理化學特性和生物學性質對制劑的潛在影響及制劑可接受限度的合適性開展的開發(fā)研究。這些研究包括：比如，溶出度實驗或釋放度實驗的開發(fā)，吸入制劑的可吸入組分的實驗開發(fā)。應說明原料藥的生理適應性和配方屬性。比如說可以包括研究是否需要在制劑質量標準中加入多晶型的合格標準所獲得的信息。類似的，關于溶出度VS 崩解實驗或其他確保制劑釋放的方法的選擇，以支持配方和生產工藝的耐用性的信息也可以包括在該章節(jié)。也可參見ICH Q6A 質量標準：新原料藥和新制劑的測試方法和認可標準：化學物質。決策樹#4（Part 3）和決策樹#7（Part 1）。2.3Manufacturing Process Development制造工藝開發(fā)The selection, the control, and any improvement of the manufacturing process described in 3.2.P.3.3 (i.e., intended for commercial production batches) should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components. Appropriateness of the equipment used for the intended products should be discussed. Process development studies should provide the basis for process im