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ICH-Q7a(中英文對照稿)——FDA 原料藥GMP 指南

2019-6-26 作者:不詳   來源:網絡 我要評論1
Tags: FDA  ICH-Q7a  

FDA 原料藥GMP 指南

Table of Contents 目錄
1. INTRODUCTION 1. 簡介
1.1 Objective 1.1 目的
1.2 Regulatory Applicability 1.2 法規的適用性
1.3 Scope 1.3 范圍
2. QUALITY MANAGEMENT 2.質量管理
2.1 Principles 2.1 總則
2.2 Responsibilities of the Quality Unit(s) 2.2 質量部門的責任
2.3 Responsibility for Production Activities 2.3 生產作業的職責
2.4 Internal Audits (Self Inspection) 2.4 內部審計(自檢)
2.5 Product Quality Review 2.5 產品質量審核
3. PERSONNEL 3. 人員
3.1 Personnel Qualifications 3.人員的資質
3.2 Personnel Hygiene 3.2 人員衛生
3.3 Consultants 3.3 顧問
4. BUILDINGS AND FACILITIES 4. 建筑和設施
4.1 Design and Construction 4.1 設計和結構
4.2 Utilities 4.2 公用設施
4.3 Water 4.3 水
4.4 Containment 4.4 限制
4.5 Lighting 4.5 照明
4.6 Sewage and Refuse 4.6 排污和垃圾
4.7 Sanitation and Maintenance 4.7 衛生和保養
5. PROCESS EQUIPMENT 5. 工藝設備
5.1 Design and Construction 5.1 設計和結構
5.2 Equipment Maintenance and Cleaning 5.2 設備保養和清潔
5.3 Calibration 5.3 校驗
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5.4 Computerized Systems 5.4 計算機控制系統
6. DOCUMENTATION AND RECORDS 6. 文件和記錄
6.1 Documentation System and Specifications 6.1 文件系統和質量標準
6.2 Equipment cleaning and Use Record 6.2 設備的清潔和使用記錄
6.3 Records of Raw Materials, Intermediates, API
Labeling and Packaging Materials
6.3 原料、中間體、原料藥的標簽和包裝材料的記錄
6.4 Master Production Instructions (Master Production
and Control Records)
6.4 生產工藝規程(主生產和控制記錄)
6.5 Batch Production Records (Batch Production and
Control Records)
6.5 批生產記錄(批生產和控制記錄)
6.6 Laboratory Control Records 6.6 實驗室控制記錄
6.7 Batch Production Record Review 6.7 批生產記錄審核
7. MATERIALS MANAGEMENT 7. 物料管理
7.1 General Controls 7.1 控制通則
7.2 Receipt and Quarantine 7.2 接收和待驗
7.3 Sampling and Testing of Incoming Production
Materials
7.3 進廠物料的取樣與測試
7.4 Storage 7.4 儲存
7.5 Re-evaluation 7.5 復驗
8. PRODUCTION AND IN-PROCESS CONTROLS 8. 生產和過程控制
8.1 Production Operations 8.1 生產操作
8.2 Time Limits 8.2 時限
8.3 In-process Sampling and Controls 8.3 工序取樣和控制
8.4 Blending Batches of Intermediates or APIs 8.4 中間體或原料藥的混批
8.5 Contamination Control 8.5 污染控制
9. PACKAGING AND IDENTIFICATION LABELING
OF APIs AND INTERMEDIATES
9. 原料藥和中間體的包裝和貼簽
9.1 General 9.1 總則
9.2 Packaging Materials 9.2 包裝材料
9.3 Label Issuance and Control 9.3 標簽發放與控制
9.4 Packaging and Labeling Operations 9.4 包裝和貼簽操作
10. STORAGE AND DISTRIBUTION 10.儲存和分發
10.1 Warehousing Procedures 10.1 入庫程序
10.2 Distribution Procedures 10.2 分發程序
11. LABORATORY CONTROLS 11.實驗室控制
11.1 General Controls 11.1 控制通則
11.2 Testing of Intermediates and APIs 11.2 中間體和原料藥的測試
11.3 Validation of Analytical Procedures 11.3 分析方法的驗證
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11.4 Certificates of Analysis 11.4 分析報告單
11.5 Stability Monitoring of APIs 11.5 原料藥的穩定性監測
11.6 Expiry and Retest Dating 11.6 有效期和復驗期
11.7 Reserve/Retention Samples 11.7 留樣
12. VALIDATION 12.驗證
12.1 Validation Policy 12.1 驗證方針
12.2 Validation Documentation 12.2 驗證文件
12.3 Qualification 12.3 確認
12.4 Approaches to Process Validation 12.4 工藝驗證的方法
12.5 Process Validation Program 12.5 工藝驗證的程序
12.6 Periodic Review of Validated Systems 12.6 驗證系統的定期審核
12.7 Cleaning Validation 12.7 清洗驗證
12.8 Validation of Analytical Methods 12.8 分析方法的驗證
13. CHANGE CONTROL 13.變更的控制
14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用
14.1 Rejection 14.1 拒收
14.2 Reprocessing 14.2 返工
14.3 Reworking 14.3 重新加工
14.4 Recovery of Materials and Solvents 14.4 物料與溶劑的回收
14.5 Returns 14.5 退貨
15. COMPLAINTS AND RECALLS 15.投訴與召回
16. CONTRACT MANUFACTURERS (INCLUDING
LABORATORIES)
16.協議生產商(包括實驗室)
17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS,
REPACKERS, AND RELABELLERS
17.代理商、經紀人、貿易商、經銷商、重新
包裝者和重新貼簽者
17.1 Applicability 17.1 適用性
17.2 Traceability of Distributed APIs and Intermediates 17.2 已分發的原料藥和中間體的可追溯性
17.3 Quality Management 17.3 質量管理
17.4 Repackaging, Relabeling, and Holding of APIs and
Intermediates
17.4 原料藥和中間體的重新包裝、重新貼簽
和待檢
17.5 Stability 17.5 穩定性
17.6 Transfer of Information 17.6 信息的傳達
17.7 Handling of Complaints and Recalls 17.7 投訴和召回的處理
17.8 Handling of Returns 17.8 退貨的處理
18. Specific Guidance for APIs Manufactured by Cell
Culture/Fermentation
18. 用細胞繁殖/發酵生產的原料藥的特殊
指南
18.1 General 18.1 總則
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18.2 Cell Bank Maintenance and Record Keeping 18.2 細胞庫的維護和記錄的保存
18.3 Cell Culture/Fermentation 18.3 細胞繁殖/發酵
18.4 Harvesting, Isolation and Purification 18.4 收取、分離和精制
18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/滅活步驟
19. APIs for Use in Clinical Trials 19. 用于臨床研究的原料藥
19.1 General 19.1 總則
19.2 Quality 19.2 質量
19.3 Equipment and Facilities 19.3 設備和設施
19.4 Control of Raw Materials 19.4 原料的控制
19.5 Production 19.5 生產
19.6 Validation 19.6 驗證
19.7 Changes 19.7 變更
19.8 Laboratory Controls 19.8 實驗室控制
19.9 Documentation 19.9 文件
20. Glossary 20. 術語
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Q7a GMP Guidance for APIs
Q7a 原料藥的GMP 指南
1. INTRODUCTION 1. 簡介
1.1 Objective 1.1 目的
This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented,to possess.
本文件旨在為在合適的質量管理體系下制造活性藥用成分(以下稱原料藥)提供有關優良藥品生產管理規范(GMP)提供指南。它也著眼于幫助確保原料藥符合其旨在達到或表明擁有的質量與純度要求。

In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging,labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such
approach satisfies the requirements of the applicable statues. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.
本指南中所指的“制造”包括物料接收、生產、包裝、重新包裝、貼簽、重新貼簽、質量控制、放行、原料藥的儲存和分發及其相關控制的所有操作。本指南中,“應當”一詞表示希望采用的建議,除非證明其不適用或者可用一種已證明有同等或更高質量保證水平的供選物來替代。本指
南中的“現行優良生產管理規范(cGMP)”和“優良生產管理規范(GMP)”是等同的。

The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.
本指南在總體上未涉及生產人員的安全問題,亦不包括環保方面的內容。這方面的管理是生產者固有的責任,也是國家法律規定的。

This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met.

本指南未規定注冊/歸檔的要求、或修改藥典的要求。本指南不影響負責藥政審理部門在原料藥上市/制造授權或藥品申請方面建立特定注冊/歸檔要求的能力。注冊/歸檔的所有承諾必須做到。

1.2 Regulatory Applicability 1.2 法規的適用性
Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.
在世界范圍內對原料藥的法定定義是各不相同的。當某種物料在其制造或用于藥品的地區或國家被稱為原料藥,就應該按照本指南進行生產。

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1.3 Scope 1.3 范圍
This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.

本文件適用于人用藥品(醫療用品)所含原料藥的生產。它適用于無菌原料藥在滅菌前的步驟。本指南不包括無菌原料藥的消毒和滅菌工藝,但是,應當符合地方當局所規定的藥品(醫療用品)生產的GMP指南。

This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section

18.
本文件適用于通過化學合成、提取、細胞培養/發酵,通過從自然資源回收,或通過這些工藝的結合而得到的原料藥。通過細胞培養/發酵生產的原料藥的特殊指南則在第18 章論述。

This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materials. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-packaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals.

本指南不包括所有疫苗、完整細胞、全血和血漿、全血和血漿的衍生物(血漿成分)和基因治療的原料藥。但是卻包括以血或血漿為原材料生產的原料藥。值得注意的是細胞培養基(哺乳動物、植物、昆蟲或微生物的細胞、組織或動物源包括轉基因動物)和前期生產可能應遵循GMP
規范,但不包括在本指南之內。另外,本指南不適用于醫用氣體、散裝的制劑藥(例如,散裝的片劑和膠囊)和放射性藥物的生產。

Section 19 contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials (investigational medicinal products).
第19 章的指南只適用于用在藥品(醫療用品)生產中的原料藥制造,特別是臨床實驗用藥(研究用醫療產品)的原料藥制造。

An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement,or produced in-house. API starting materials normally have defined chemical properties and structure.

“原料藥的起始物料”是指一種原料、中間體或原料藥,用來生產一種原料藥,或者以主要結構單元的形式被結合進原料藥結構中。原料藥的起始物料可能是在市場上有售、能夠通過合同或商業協議從一個或多個供應商處購得,或由生產廠家自制。原料藥的起始物料一般來說有特定的
化學特性和結構。
The company should designate and document the rationale for the 生產廠商要指定并用書面文件說明原料

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point at which production of the API begins. For synthetic processes,this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction,purification), this rationale should be established on a case-by-case basis. Table 1 gives guidance on the point at which the API starting material is normally introduced into the process.

藥的生產從何處開始的理論依據。對于合成工藝而言,就是“原料藥的起始物料”進入工藝的那一點。對其他工藝(如:發酵,提取,純化等)可能需要具體問題具體對待。表1 給出了原料藥的起始物料從哪一點引入工藝過程的指導原則。
From this point on, appropriate GMP as defined in this guidance should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a company chooses to validate a process step does not necessarily define that steps as critical.

從這步開始,本指南中的有關GMP 規范應當應用在這些中間體和/或原料藥的制造中。這包括對原料藥質量有影響的關鍵工藝步驟的驗證。但是,值得注意的是廠商選擇某一步驟進行驗證,并不一定將該步驟定為關鍵步驟。
The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps,purification, and packaging. Physical processing of APIs, such as
granulation, coating or physical manipulation of particle size (e.g.,milling, micronizing) should be conducted according to this guidance.
本文件的指南通常適用于表1 中的灰色步驟。但在表中體現的所有步驟并不是將應用GMP 管理的所有步驟全部體現出來了。原料藥生產中的GMP 要求應當隨著工藝的進行,從原料藥的前幾步到最后幾步,精制和包裝,越來越嚴格。原料藥的物理加工,如制粒、包衣或顆粒度的物理處理(例如制粉、微粉化)應當按本指南的標準進行。
This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.
本GMP 指南不適用于引入定義了的“原料藥的起始物料”以前的步驟。
Table 1: Application of this Guidance to API Manufacturing
Type of Manufacturing 
Application of this guidance to steps (shown in gray) used in this type of manufacturing
Chemical manufacturing
Production of the API 
Starting material
Introduction of the API
starting material into
process
Production of
Intermediate(s)
Isolation and
purification
Physical processing, and
packaging
API derived from
animal sources
Collection of organ,
fluid, or tissue
Cutting, mixing, and/or
initial processing
Introduction of the API
starting material into
process
Isolation and
purification
Physical processing, and
packaging
API extracted from
plant sources
Collection of plant Cutting and initial
extraction(s)
Introduction of the API
starting material into
process
Isolation and
purification
Physical processing, and
packaging
Herbal extracts used
as API
Collection of plants Cutting and initial
extraction
Further
extraction
Physical processing, and packaging
API consisting of comminuted or powdered herbs Collection of plants and/or cultivation and harvesting
Cutting/comminuting Physical processing, and packaging

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Biotechnology:
fermentation/cell
culture
Establishment of
master cell bank and
working cell bank
Maintenance of working
cell bank
Cell culture and/or
fermentation
Isolation and
purification
Physical processing, and
packaging
“Classical”
fermentation to
produce an API
Establishment of cell
bank
Maintenance of the cell
bank
Introduction of the cells
into fermentation
Isolation and
purification
Physical processing, and
packaging
表 1: 本指南在原料藥生產中的應用
生產類型本指南在用于各類生產的工藝步驟(灰色背景)中的應用
化學品的生產原料藥起始物料的生產
原料藥起始物料引入工藝過程
中間體的生產分離和純化物理加工和包裝
動物源原料藥器官、分泌物或組織的收集
切割、混合和/或初步加工原料藥起始物料引入工藝過程分離和純化物理加工和包裝從植物源提取的原料藥
植物的收集切割和初步提取原料藥起始物料引入工藝過程,分離和純化物理加工和包裝
草藥提取物用作原料藥
植物的收集切割和初步提取進一步提取物理加工和包裝
由粉碎的或粉末狀草藥組成的原料藥
植物的收集和/或培養和收獲
切割/粉碎物理加工和包裝
生物技術:發酵/細胞培養
主細胞庫和工作細胞庫的建立
工作細胞庫的維護細胞培養和/或發酵分離和純化物理加工和包裝
“經典” 發酵生產原料藥
細胞庫的建立細胞庫的維護細胞引入發酵分離和純化物理加工和包裝
Increasing GMP requirements
GMP 的要求增加
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2. QUALITY MANAGEMENT 2.質量管理
2.1 Principles 2.1 總則
2.10 Quality should be the responsibilities of all persons involved
in manufacturing.
2.10 參與原料藥生產的每一個人都應當對
質量負責。
2.11 Each manufacturer should establish, document, and implement
an effective system for managing quality that involves the active
participation of management and appropriate manufacturing
personnel.
2.11 每一個生產商都應當建立并執行一套有
管理人員和有關員工積極參與的有效的質量
管理體系,并使其文件化。
2.12 The system for managing quality should encompass the
organizational structure, procedures, process and resources, as well
as activities to ensure confidence that the API will meet its intended
specifications for quality and purity. All quality-related activities
should be defined and documented.
2.12 質量管理體系應當包括組織機構、規程、工藝和資源,以及確保原料藥會符合其預期的質量與純度要求所必需的活動。所有涉及質量管理的活動都應當明確規定,并使其文件化。
2.13 There should be a quality unit(s) that is independent of
production and that fulfills both quality assurance (QA) and quality
control (QC) responsibilities. The quality unit can be in the form of
separate QA and QC units or a single individual or group,
depending upon the size and structure of the organization.
2.13 應當設立一個獨立于生產部門的質量部門,同時履行質量保證(QA)和質量控制(QC)的職責。依照組織機構的大小,可以是分開的QA 和QC 部門,或者只是一個人或小組。
2.14 The persons authorized to release intermediates and APIs
should be specified.
2.14 應當指定授權發放中間體和原料藥的人員。
2.15 All quality-related activities should be recorded at the time
they are performed.
2.15 所有有關質量的活動應當在其執行時就記錄。
2.16 Any deviation from established procedures should be
documented and explained. Critical deviations should be
investigated, and the investigation and its conclusions should be
documented.
2.16 任何偏離既定規程的情況都應當有文字記錄并加以解釋。對于關鍵性偏差應當進行調查,并記錄調查經過及其結果。
2.17 No materials should be released or used before the satisfactory
completion of evaluation by the quality unit(s) unless there are
appropriate systems in place to allow for such use (e.g., release
under quarantine as described in Section 10 or the use of raw
materials or intermediates pending completion of evaluation).
2.17 在質量部門對物料完成滿意的評價之前,任何物料都不應當發放或使用,除非有合適的系統允許此類使用(如10.20 條款所述的待檢情況下的使用,或是原料或中間體在等待評價結束時的使用)。
2.18 Procedures should exist for notifying responsible management
in a timely manner of regulatory inspections, serious GMP
deficiencies, product defects and related actions (e.g.,
quality-related complaints, recalls, and regulatory actions).
2.18 應當有規程能確保公司的責任管理部門能及時得到有關藥政檢查、嚴重的GMP缺陷、產品缺陷及其相關活動(如質量投訴,召回,藥政活動等)的通知。
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2.2 Responsibilities of the Quality Unit(s) 2.2 質量部門的責任
2.20 The quality unit(s) should be involved in all quality-related
matters.
2.20 質量部門應當參與所有與質量有關的事物。
2.21 The quality unit(s) should review and approve all appropriate
quality-related documents.
2.21 所有與質量有關的文件應當由質量部門審核批準。
2.22 The main responsibilities of the independent quality unit(s)
should not be delegated. These responsibilities should be described
in writing and should include, but not necessarily be limited to:
1. Releasing or rejecting all APIs. Releasing or rejecting
intermediates for use outside the control of the manufacturing
company
2. Establishing a system to release or reject raw materials,
intermediates, packaging, and labeling materials
3. Reviewing completed batch production and laboratory control
records of critical process steps before release of the API for
distribution
4. Making sure that critical deviations are investigated and
resolved
5. Approving all specifications and master production instructions
6. Approving all procedures affecting the quality of intermediates
or APIs
7. Making sure that internal audits (self-inspections) are
performed
8. Approving intermediate and API contract manufacturers
9. Approving changes that potentially affect intermediate or API
quality
10. Reviewing and approving validation protocols and reports
11. Making sure that quality-related complaints are investigated
and resolved
12. Making sure that effective systems are used for maintaining
and calibrating critical equipment
13. Making sure that materials are appropriately tested and the
results are reported
14. Making sure that there is stability data to support retest or
expiry dates and storage conditions on APIs and/or
intermediates, where appropriate
15. Performing product quality reviews (as defined in Section 2.5)
2.22 獨立的質量部門的主要職責不應當委派給他人。這些責任應當以文字形式加以說明,而且應當包括,但不限于:
1. 所有原料藥的放行與否。用于生產商控制范圍以外的中間體的放行與否;
2. 建立一個放行與拒收原材料、中間體、包裝材料和標簽的系統;
3. 在供銷售的原料藥放行前,審核已完成的關鍵步驟的批生產記錄和實驗室檢驗記錄;
4. 確保已對重大偏差進行了調查并已解決;
5. 批準所有的規格標準和主生產指令;
6. 批準所有可能影響原料藥和中間體質量的規程;
7. 確保進行內部審計(自檢);
8. 批準中間體或原料藥的委托生產商;
9. 批準可能影響到中間體或原料藥質量的變更;
10. 審核并批準驗證方案和報告;
11. 確保調查并解決質量問題的投訴;
12. 確保用有效的體系來維護和校驗關鍵設備;
13. 確保物料都經過了適當的檢驗并報告結果;
14. 確保有穩定性數據支持中間體或原料藥的復驗期或有效期和儲存條件;
15. 開展產品質量審核(詳見 2.5 節)。
2.3 Responsibility for Production Activities 2.3 生產作業的職責
The responsibility for production activities should be described in
writing and should include, but not necessarily be limited to:
生產作業的職責應當以文字形式加以說明,并應當包括,但不限于以下內容:
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1. Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures
2. Producing APIs and, when appropriate, intermediates according to pre-approved instructions
3. Reviewing all production batch records and ensuring that these are completed and signed
4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded
5. Making sure that production facilities are clean and, when appropriate, disinfected
6. Making sure that the necessary calibrations are performed and records kept
7. Making sure that the premises and equipment are maintained and records kept
8. Making sure that validation protocols and reports are reviewed and approved
9. Evaluating proposed changes in product, process or equipment
10. Making sure that new and, when appropriate, modified
facilities and equipment are qualified
1. 按書面程序起草、審核、批準和分發中間體或原料藥的生產指令;
2. 按照已批準的指令生產原料藥或者中間體;
3. 審核所有的批生產記錄確保其完整并有簽名;
4. 確保所有的生產偏差都已報告、評價,對關鍵的偏差已做了調查,并記錄結論;
5. 確保生產設施的清潔,必要時要消毒;
6. 確保進行必要的校驗,并有記錄;
7. 確保對廠房和設備進行保養,并有記錄;
8. 確保驗證方案和報告的審核與批準;
9. 對產品、工藝或設備擬作的變更進行評估;
10. 確保新的或已改進的生產設施和設備經過了確認。
2.4 Internal Audits (Self Inspection) 2.4 內部審計(自檢)
2.40 To verify compliance with the principles of GMP for APIs,
regular internal audits should be performed in accordance with an
approved schedule.
2.40 為確實符合原料藥GMP 原則,應當按照批準的計劃進行定期的內部審計。
2.41 Audit findings and corrective actions should be documented
and brought to the attention of responsible management of the firm.
Agreed corrective actions should be completed in a timely and
effective manner.
2.41 審計結果及整改措施應當形成文件,并引起公司責任管理人員的重視。獲準的整改措施應當及時、有效地完成。
2.5 Product Quality Review 2.5 產品質量審核
2.50 Regular quality-reviews of APIs should be conducted with the
objective of verifying the consistency of the process. Such reviews
should normally be conducted and documented annually and
should include at least:
● A review of critical in-process control and critical API test
results
● A review of all batches that failed to meet established
specification(s)
● A review of all critical deviations or nonconformances
and related investigations
2.50 原料藥的定期質量審核應當以證實工藝的一致性為目的來進行。此種審核通常應當每年進行一次,并記錄,內容至少應當包括:
● 關鍵工藝控制以及原料藥關鍵測試結果的審核;
● 所有不符合既定質量標準的產品批號的審核;
● 所有關鍵的偏差或違規行為及有關調查的審核;
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● A review of any changes carried out to the processes or
analytical methods
● A review of results of the stability monitoring program
● A review of all quality-related returns, complaints and
recalls
● A review of adequacy of corrective actions
● 任何工藝或分析方法變動的審核;
● 穩定性監測的審核;
● 所有與質量有關的退貨、投訴和召回的審核;
● 整改措施的適當性的審核。
2.51 The results of this review should be evaluated and an
assessment made of whether corrective action or any revalidation
should be undertaken. Reasons for such corrective action should be
documented. Agreed corrective actions should be completed in a
timely and effective manner.
2.51 應當對質量審核結果進行評估,并做出是否需要整改或做任何再驗證的評價。此類整改措施的理由應當文件化。獲準的整改措施應當及時、有效地完成。
3. PERSONNEL 3. 人員
3.1 Personnel Qualifications 3.1 員工的資質
3.10 There should be an adequate number of personnel qualified by
appropriate education, training, and/or experience to perform and
supervise the manufacture of intermediates and APIs.
3.10 應當有足夠數量的員工具備從事和監
管原料藥和中間體生產的教育、培訓和/或經
歷等資格。
3.11 The responsibilities of all personnel engaged in the
manufacture of intermediates and APIs should be specified in
writing.
3.11 參與原料藥和中間體生產的所有人員的職責應當書面規定。
3.12 Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee’s functions. Records of training should be maintained. Training should be periodically assessed.
3.12 應當由有資格的人員定期進行培訓,內容至少應當包括員工所從事的特定操作和與其職能有關的GMP。培訓記錄應當保存,并應當定期對培訓進行評估。
3.2 Personnel Hygiene 3.2 員工的衛生
3.20 Personnel should practice good sanitation and health habits. 3.20 員工應當養成良好的衛生和健康習慣。
3.21 Personnel should wear clean clothing suitable for the
manufacturing activity with which they are involved and this
clothing should be changed, when appropriate. Additional
protective apparel, such as head, face, hand, and arm coverings,
should be worn, when necessary, to protect intermediates and APIs
from contamination.
3.21 員工應當穿著適合其所從事生產操作的干凈服裝,必要時應當更換。其它保護性用品如頭、臉、手和臂等遮護用品必要時也應當佩帶,以免原料藥和中間體受到污染。
3.22 Personnel should avoid direct contact with intermediates and
APIs.
3.22 員工應當避免與中間體或原料藥的直接接觸。
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3.23 Smoking, eating, drinking, chewing and the storage of food
should be restricted to certain designated areas separate from the
manufacturing areas.
3.23 吸煙、吃、喝、咀嚼及存放食品僅限于與生產區隔開的指定區域。
3.24 Personnel suffering from an infectious disease or having open
lesions on the exposed surface of the body should not engage in
activities that could result in compromising the quality of APIs.
Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions
should be excluded from activities where the condition could
adversely affect the quality of the APIs until the condition is
corrected or qualified medical personnel determine that the
person’s inclusion would not jeopardize the safety or quality of the
APIs.
3.24 患傳染性疾病或身體表面有開放性創傷的員工不應當從事危及原料藥質量的生產活動。在任何時候(經醫學檢驗或監控檢查)任何患有危及到原料藥質量的疾病或創傷的人員都不應當參與作業,直到健康狀況已恢復,或者有資格的醫學人員確認該員工不會危及到原料藥的安全性和質量。
3.3 Consultants 3.3 顧問
3.30 Consultants advising on the manufacture and control of
intermediates or APIs should have sufficient education, training,
and experience, or any combination thereof, to advise on the
subject for which they are retained.
3.30 中間體或原料藥生產和控制的顧問應當有足夠的學歷,受訓和經驗,能勝任所承擔的工作。
3.31 Records should be maintained stating the name, address,
qualifications, and type of service provided by these consultants.
3.31 顧問的姓名、地址、資格和提供服務的類型都應當有文字記錄。
4. BUILDINGS AND FACILITIES 4. 建筑和設施
4.1 Design and Construction 4.1 設計和結構
4.10 Buildings and facilities used in the manufacture of
intermediates and APIs should be located, designed, and
constructed to facilitate cleaning, maintenance, and operations as
appropriate to the type and stage of manufacture. Facilities should
also be designed to minimize potential contamination. Where
microbiological specifications have been established for the
intermediate or API, facilities should also be designed to limit
exposure to objectionable microbiological contaminants, as
appropriate.
4.10 用于中間體和原料藥生產的廠房和設施的選址、設計和建造應當便于清潔,維護和適應一定類型和階段的生產操作。設施的設計應盡量減少潛在的污染。如果中間體或原料藥的生產有微生物限度要求,那么設施設計應相應的限制有害微生物的污染。
4.11 Buildings and facilities should have adequate space for the
orderly placement of equipment and materials to prevent mix-ups
and contamination.
4.11 廠房和設施應有足夠空間,以便有秩序地放置設備和物料,防止混淆和污染。
4.12 Where the equipment itself (e.g., closed or contained system)
provides adequate protection of the material, such equipment can
be located outdoors.
4.12 自身能對物料提供足夠保護的設備(如關閉的或封閉的系統),可以在戶外放置。
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4.13 The flow of materials and personnel through the building or
facilities should be designed to prevent mix-ups and contamination.
4.13 通過廠房和設施的物流和人流的設計應當能防止混雜和污染。
4.14 There should be defined areas or other control systems for the
following activities:
● Receipt, identification, sampling, and quarantine of incoming
materials, pending release or rejection
● Quarantine before release or rejection of intermediates and
APIs
● Sampling of intermediates and APIs
● Holding rejected materials before further disposition (e.g.,
return, reprocessing or destruction)
● Storage of released materials
● Production operations
● Packaging and labeling operations
● Laboratory operations
4.14 以下活動應當有指定區域或其它控制系統:
● 來料的接收、鑒別、取樣和待驗,等待放行或拒收;
● 中間體和原料藥放行或拒收前的待驗;
● 中間體和原料藥的取樣
● 不合格物料處理(如退貨、返工或銷毀)前的貯存;
● 已放行物料的貯存;
● 生產操作;
● 包裝及貼標簽操作;
● 實驗室操作。
4.15 Adequate and clean washing and toilet facilities should be
provided for personnel. These facilities should be equipped with
hot and cold water, as appropriate, soap or detergent, air dryers, or
single service towels. The washing and toilet facilities should be
separate from, but easily accessible to, manufacturing areas.
Adequate facilities for showering and/or changing clothes should
be provided, when appropriate.
4.15 應當為員工提供足夠和清潔的盥洗設施。這些盥洗設施應當裝有冷熱水(視情況而定)、肥皂或洗滌劑,干手機和一次性毛巾。盥洗室應當與生產區隔離,但要便于達到。應當根據情況提供足夠的淋浴和/或更衣設施。
4.16 Laboratory areas/operations should normally be separated
from production areas. Some laboratory areas, in particular those
used for in-process controls, can be located in production areas,
provided the operations of the production process do not adversely
affect the accuracy of the laboratory measurements, and the
laboratory and its operations do not adversely affect the production
process, intermediate, or API.
4.16 實驗室區域/操作通常應當與生產區隔離。有些實驗室區域,特別是用于中間控制的,可以位于生產區內,只要生產工藝操作對實驗室測量的準確性沒有負面影響,而且,實驗室及其操作對生產過程,或中間體,或原料藥也沒有負面影響。
4.2 Utilities 4.2 公用設施
4.20 All utilities that could affect product quality (e.g., steam, gas,
compressed air, heating, ventilation, and air conditioning) should
be qualified and appropriately monitored and action should be
taken when limits are exceeded. Drawings for these utility systems
should be available.
4.20 對產品質量會有影響的所有公用設施(如蒸汽,氣體,壓縮空氣和加熱,通風及空調)都應當確認合格,并進行適當監控,在超出限度時應當采取相應措施。應當有這些公用設施的系統圖。
4.21 Adequate ventilation, air filtration and exhaust systems should
be provided, where appropriate. These systems should be designed
and constructed to minimize risks of contamination and
4.21 應當根據情況,提供足夠的通風、空氣過濾和排氣系統。這些系統應當根據相應的生產階段,設計和建造成將污染和交叉污染
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cross-contamination and should include equipment for control of
air pressure, microorganisms (if appropriate), dust, humidity, and
temperature, as appropriate to the stage of manufacture. Particular
attention should be giving to areas where APIs are exposed to the
environment.
降至最低限度,并包括控制氣壓、微生物(如果適用)、灰塵、濕度和溫度的設備。特別值得注意的是原料藥暴露的區域。
4.22 If air is recirculated to production areas, appropriate measures
should be taken to control risks of contamination and
cross-contamination.
4.22 如果空氣再循環到生產區域,應當采取適當的控制污染和交叉污染的風險。
4.23 Permanently installed pipework should be appropriately
identified. This can be accomplished by identifying individual
lines, documentation, computer control system, or alternative
means. Pipework should be located to avoid risks of contamination
of the intermediate or ApI.
4.23 永久性安裝的管道應當有適宜的標識。這可以通過標識每根管道、提供證明文件、計算機控制系統,或其它替代方法來達到。管道的安裝處應當防止污染中間體或原料藥。
4.24 Drains should be of adequate size and should be provided with
an air break or a suitable device to prevent back-siphonage, when
appropriate.
4.24 排水溝應當有足夠的尺寸,而且應當根據情況裝有空斷器或適當的裝置,防止倒虹吸。
4.3 Water 4.3 水
4.30 Water used in the manufacture of APIs should be
demonstrated to be suitable for its intended use.
4.30 原料藥生產中使用的水應當證明適合于其預定的用途。
4.31 Unless otherwise justified, process water should, at a
minimum, meet World Health Organization (WHO) guidelines for
drinking (portable) water quality.
4.31 除非有其它理由,工藝用水最低限度應當符合世界衛生組織(WHO)的飲用水質量指南。
4.32 If drinking (portable) water is insufficient to ensure API
quality and tighter chemical and/or microbiological water quality
specifications are called for, appropriate specifications for
physical/chemical attributes, total microbial counts, objectionable
organisms, and/or endotoxins should be established.
4.32 如果飲用水不足以確保原料的質量,并要求更為嚴格的化學和/或微生物水質規格標準,應當指定合適的物理/化學特性、微生物總數、控制菌和/或內毒素的規格標準。
4.33 Where water used in the process is treated by the manufacturer
to achieve a defined quality, the treatment process should be
validated and monitored with appropriate action limits.
4.33 在工藝用水為達到規定質量由制造商進行處理時,處理工藝應當經過驗證,并用合適的處置限度來監測。
4.34 Where the manufacturer of a nonsterile API either intends or
claims that it is suitable for use in further processing to produce a
sterile drug (medicinal) product, water used in the final isolation
and purification steps should be monitored and controlled for total
microbial counts, objectionable organisms, and endotoxins.
4.34 當非無菌原料藥的制造商打算或者聲稱該原料藥適用于進一步加工生產無菌藥品(醫療用品)時,最終分離和精制階段的用水應當進行微生物總數、致病菌和內毒素方面的監測和控制。
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4.4 Containment 4.4 限制
4.40 Dedicated production areas, which can include facilities, air
handling equipment and/or process equipment, should be employed
in the production of highly sensitizing materials, such as penicillins
or cephalosprins.
4.40 在高致敏性物質,如青霉素或頭孢菌素類的生產中,應當使用專用的生產區,包括設施、空氣處理設備和/或工藝設備。
4.41 The use of dedicated production areas should also be
considered when material of an infectious nature or high
pharmacological activity or toxicity is involved (e.g., certain
steroids or cytotoxic anti-cancer agents) unless validated
inactivation and/or cleaning procedures are established and
maintained.
4.41 當涉及具有感染性、高藥理活性或毒性的物料時(如,激素類或抗腫瘤類),也應當考慮專用的生產區,除非已建立并維持一套經驗證的滅活和/或清洗程序。
4.42 Appropriate measures should be established and implemented
to prevent cross-contamination from personnel and materials
moving from one dedicated area to another.
4.42 應當建立并實施相應的措施,防止由于在各專用區域間流動的人員和物料而造成的交叉污染。
4.43 Any production activities (including weighing, milling, or
packaging) of highly toxic nonpharmaceutical materials, such as
herbicides and pesticides, should not be conducted using the
buildings and/or equipment being used for the production of APIs.
Handling and storage of these highly toxic nonpharmaceutical
materials should be separate from APIs.
4.43 劇毒的非藥用物質,如除草劑、殺蟲劑的任何生產活動(包括稱重、研磨或包裝)都不應當使用生產原料藥所使用的廠房和/或設備。這類劇毒非藥用物質的處理和儲存都應當與原料藥分開。
4.5 Lighting 4.5 照明
4.50 Adequate lighting should be provided in all areas to facilitate
cleaning, maintenance, and proper operations.
4.50 所有區域都應當提供充足的照明,以便于清洗、保養或其它操作。
4.6 Sewage and Refuse 4.6 排污和垃圾
4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or
gaseous by-products from manufacturing) in and from buildings
and the immediate surrounding area should be disposed of in a safe,
timely, and sanitary manner. Containers and/or pipes for waste
material should be clearly identified.
4.60 進入和流出廠房及鄰近區域的污水、垃圾和其它廢物(如生產中的固態、液態或氣
態的副產物),應當安全、及時、衛生的處理。廢物的容器和/或管道應當顯著地標明。
4.7 Sanitation and Maintenance 4.7 衛生和保養
4.70 Buildings used in the manufacture of intermediates and APIs
should be properly maintained and repaired and kept in a clean
condition.
4.70 生產中間體和原料藥的廠房應當適當地保養、維修并保持清潔。
4.71 Written procedures should be established assigning
responsibility for sanitation and describing the cleaning schedules,
methods, equipment, and materials to be used in cleaning buildings
and facilities.
4.71 應當制定書面程序來分配衛生工作的職責,并描述用于清潔廠房和設施的清潔的計劃、方法、設備和材料。



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