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fda指南

英文简历模板 时间:2020-06-05

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FDA无菌生产指南 中英文对照版
篇一:fda指南

Translated from / 译自:

Guidance for Industry

Sterile Drug Products

Produced by Aseptic Processing — Current Good Manufacturing Practice

行业指南

无菌加工生产的无菌药品

—现行的生产质量管理规范(cGMP)

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

Office of Regulatory Affairs (ORA)

September 2004 Pharmaceutical CGMPs

Guidance for Industry

Sterile Drug Products

Produced by Aseptic Processing — Current Good Manufacturing Practice

Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573

or

Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

(Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

Office of Regulatory affairs (ORA)

September 2004 Pharmaceutical CGMPs

TABLE OF CONTENTS

I.

INTRODUCTION............................................................................................................. 1

简介

II.

BACKGROUND ............................................................................................................... 2

背景

A. Regulatory Framework ................................................................................................................. 2 法规架构

B. Technical Framework .................................................................................................................... 3

技术架构

III.

SCOPE ............................................................................................................................... 4

适用范围

IV.

BUILDINGS AND FACILITIES .................................................................................... 6

厂房和建筑

A. Critical Area – Class 100 (ISO 5) ................................................................................................. 8 关键区域– 100级 (ISO 5)

B. Supporting Clean Areas .............................................................................................................. 11 辅助洁净区域

C. Clean Area Separation ................................................................................................................ 11 净化区的隔离

D. Air Filtration ................................................................................................................................ 12

空气过滤

1. Membrane ...................................................................................................................................... 13 膜过滤

2. High-Efficiency Particulate Air (HEPA) ....................................................................................... 14 高效颗粒空气过滤器(HEPA)

E. Design ............................................................................................................................................ 16

设计

V.

PERSONNEL TRAINING, QUALIFICATION, & MONITORING ........................ 20

人员的培训,资格认定和监控 A. Personnel ....................................................................................................................................... 21 人员

B. Laboratory Personnel .................................................................................................................. 25 实验室人员

C. Monitoring Program .................................................................................................................... 25

监控程序

VI.

COMPONENTS AND CONTAINER/CLOSURES .................................................... 27

药品成分和容器/密封

A. Components .................................................................................................................................. 27

B. Containers/Closures ..................................................................................................................... 30 容器/密封

1. Preparation .................................................................................................................................... 30 准备

2. Inspection of Container Closure System ........................................................................................ 32 容器密封系统的检查 内毒素控制 时间限制

VII. ENDOTOXIN CONTROL ............................................................................................. 34 VIII. TIME LIMITATIONS ................................................................................................... 36 IX.

VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION .................. 37

无菌加工和灭菌的验证

A. Process Simulations ..................................................................................................................... 37 工艺模拟

1. Study Design ................................................................................................................................. 38 研究设计

2. Frequency and Number of Runs .................................................................................................... 40 运行频率和次数 3. Duration of Runs ............................................................................................................................ 41 运行时间

4. Size of Runs .................................................................................................................................... 42 批量

5. Line Speed ...................................................................................................................................... 43 运行速度

6. Environmental Conditions ............................................................................................................. 43 环境质量fda指南。

7. Media ............................................................................................................................................ 43 培养基

8. Incubation and Examination of Media-Filled Units ...................................................................... 44 培养基灌装单位的培养和检查

9. Interpretation of Test Results ......................................................................................................... 47 试验结果解释

B. Filtration Efficacy ........................................................................................................................ 49 过滤功效

C. Sterilization of Equipment, Containers, and Closures ............................................................. 51 设备、容器和密封的灭菌

1. Qualification and Validation ......................................................................................................... 52 确认和验证

2. Equipment Controls and Instrument Calibration .......................................................................... 54 设备控制和仪器校准

X.

LABORATORY CONTROLS ...................................................................................... 56

实验室控制

A. Environmental Monitoring ......................................................................................................... 58

1. General Written Program ............................................................................................................. 58 书面程序

2. Establishing Levels and a Trending Program ............................................................................... 59 建立监测标准和趋势分析程序

3. Disinfection Efficacy ...................................................................................................................... 60 消毒功效

4. Monitoring Methods...................................................................................................................... 61 监测方法

B. Microbiological Media and Identification ................................................................................. 63 微生物培养基及微生物的鉴定

C. Prefiltration Bioburden ............................................................................................................... 64 过滤前的生物负荷

D. Alternate Microbiological Test Methods ................................................................................... 64 可替代的微生物测试方法 E. Particle Monitoring ...................................................................................................................... 65

颗粒监测

XI.

STERILITY TESTING .................................................................................................. 66

无菌试验

A. Microbiological Laboratory Controls ........................................................................................ 68 微生物实验室控制

B. Sampling and Incubation ............................................................................................................ 68 取样和培养

C. Investigation of Sterility Positives .............................................................................................. 69

无菌试验阳性结果的调查 批生产纪录审核:工艺控制文件化

XII. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION ........ 74 APPENDIX 1: ASEPTIC PROCESSING ISOLATORS ....................................................... 76

附录 1: 无菌隔离装置

APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY.......................................................... 83

附录2: 吹-灌-封技术

APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS .... 87

附录3:灌装和密封前的工艺

REFERENCES ............................................................................................................................ 90

参考文献

RELEVANT GUIDANCE DOCUMENTS............................................................................... 91

相关指南文件

GLOSSARY................................................................................................................................. 92

术语表

FDA 行业指南 中英对照 待完成
篇二:fda指南

Guidance for Industry

Container Closure Systems for Packaging Human Drugs and Biologics

Chemistry, Manufacturing and Controls Documentation

行业指南

人用药品及生物制品的包装容器和封装系统:化学,生产和控制文件

指南发布者:美国FDA下属的CDER及CBER

发布日期:May 1999

TABLE OF CONTENTS目录

I. II. 介绍 背景

A.

B.

C.

III. Definitions 定义 CGMP, CPSC and USP Requirements on Containers and Closures. CGMP, CPSC和USP对容器和密封的要求 Additional Considerations 其他需要考虑的事项 包装组件的合

格要求以及质量控制

A.

B.

C.

D.

E.

F.

G.

H.

IV. V. Introduction 介绍 General Considerations 通常要求 Information That Should Be Submitted in Support of an Original Application for Any Drug Product 为支持任何药品的原始申请所必须提供的信息 Inhalation Drug Products 吸入性药品 Drug Products for Injection and Ophthalmic Drug Products 注射剂和眼科用药 Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems 液体口服和外用药品和外用给药系统 Solid Oral Dosage Forms and Powders for Reconstitution 口服固体剂型和待重新溶解的粉末 Other Dosage Forms 其他剂型 批准后的包装变更 药品主文件 第III类

A.

B.

VI. A.fda指南。

B. General Comments 总体评述 Information in a Type III DMF 第III类DMF中包括的信息 Containers for Bulk Drug Substances 用于原料药的容器 Containers for Bulk Drug Products 用于散装药品的容器 大包装容器

附件A

REGULATORY REQUIREMENTS 药政要求

附件B

COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING 关于包装,所适用的政策指南 附件C

EXTRACTION STUDIES “提取性”研究 ATTACHMENT D 附件D

ABBREVIATIONS 缩略语 附件E

REFERENCES 参考文献

GUIDANCE FOR INDUSTRY

Container Closure Systems for Packaging Human Drugs and Biologics

Chemistry, Manufacturing and Controls Documentation

I. INTRODUCTION 介绍

This document is intended to provide guidance on general principles for submitting information on packaging materials used for human drugs and biologics. This guidance supersedes the FDA Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics , issued in February 1987 and the packaging policy statement issued in a letter to industry dated June 30, 1995 from the Office of Generic Drugs. This guidance is not intended to describe the information that should be provided about packaging operations associated with drug product manufacture. 本文件目的是为递交人用药品和生物制品的包装信息提供总体原则指南。本文件替代了FDA在1987年2月发布的另一份指南,以及替代了仿制药办公室在1995年6月30日向行业内发布的包装政策声明信。本指南不描述药品的包装操作。

Approaches which differ from those described in this guidance may be followed, but the

applicant is encouraged to discuss significant variations in advance with the appropriate CDER chemistry review staff or CBER review staff. This is to prevent applicants or sponsors from

spending unnecessary time and effort in preparing a submission that the FDA may later 43

determine to be unacceptable. 可以采取与本指南的内容不一致的措施,但是我们建议申请人就明显的差异预先与CDER或CBER的审核人员进行讨论。这样做的目的是为了避免申请人或发起人花费不必要的时间和努力准备申报资料,而这种申报资料经FDA认定是不可接受的。 II. BACKGROUND 背景

The Federal Food, Drug, and Cosmetic Act (the Act) mandates the need for adequate

information related to packaging materials. Section 501(a)(3) of the Act states that a drug is deemed to be adulterated "if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health...." In addition, section 502 of the Act states that a drug is considered misbranded if there are packaging omissions. Also, section 505 of the Act requires a full description of the methods used in, and the facilities and controls used for, the packaging of drugs (see Attachment A). 联邦食品、药品和化妆品法案(简称“法案”)要求必须提供包装材料的充分信息。法案的第501(a)(3)部分规定,如果某个药品的包装材料含有有毒、有害的物质,导致药品损坏健康,那么该药品为劣药。另外,法案的第502部分规定,如果某药品在包装方面有缺失,则被认为是贴错标签。还有,法案第505部分要求详细描述包装药品时所用的方法,所用的设施和控制措施(见附件A)。

Section 505(b)(1)(D) of the Act states that an application shall include a full description of the methods used in, the manufacturing, processing and packing of such drug. This includesfda指南。

facilities and controls used in the packaging a drug product. 法案的第505(b)(1)(D)部分规定,申请人必须完整描述该药品的生产、加工和包装。其中包括包装药品时的设施和控制措施。

A. Definitions 定义

Materials of construction refer to the substances (e.g., glass, high density polyethylene (HDPE) resin, metal) used to manufacture a packaging component. 组成材料是指用来生产包装组件的物质(例如玻璃,HDPE树脂,金属)

A packaging component means any single part of a container closure system. Typical components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube liners), closures (e.g., screw caps, stoppers), closure liners, stopper overseals,

container inner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps, administration accessories, and container labels. A primary packaging

component means a packaging component that is or may be in direct contact with the dosage form. A secondary packaging component means a packaging component that is not and will not be in direct contact with the dosage form. 包装组件是指一个容器/封装系统的任何单独部分。通常的组件有容器(例如安瓿,西林瓶,瓶子),容器垫,封装,封装垫…….等,包括给药附件和容器标签。一级包装组件是指与制剂直接接触的组件,或者可能会直接接触的组件。二级包装组件是指不会与制剂直接接触的组件。

A container closure system refers to the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional

protection to the drug product. A packaging system is equivalent to a container closure

system. 容器/封装系统是指包装组件的组合,在一起盛装和保护制剂。这包括一级包装组件和二级包装组件,后者的目的是为药品提供额外保护。包装系统就等同于容器/封装系统。

A package or market package refers to the container closure system and labeling, associated components (e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons or shrink wrap). A market package is the article provided to a pharmacist or retail customer upon purchase and does not include packaging used solely for the purpose of shipping such articles. 包装或上市包装是指容器/封装系统,以及标签,相关组件(例如量杯,滴管,药匙等),以及外包装(例如纸箱或收缩包装)。上市包装是指提供给药剂师或零售消费者的包装物件,不包括仅仅用于运输目的的包装物件。

Quality refers to the physical, chemical, microbiological, biological, bioavailability, and stability attributes that a drug product should maintain if it is to be deemed suitable for therapeutic or diagnostic use. In this guidance, the term is also understood to convey the properties of safety, identity, strength, quality, and purity (see 21 CFR 211.94(a)). 7质量是指:一种药品可被看做具有治疗或诊断用途时,它所具有的理化、微生物、生物、生物利用度以及稳定性方面的品质。在本指南中,此术语还被理解为安全性,等效性,规格,质量和纯度等性质(见21 CFR 211.94(a))。

An extraction profile refers to the analysis (usually by chromatographic means) of

extracts obtained from a packaging component. A quantitative extraction profile is one in which the amount of each detected substance is determined. 提取性特征是指对从包装组件中所得提取物的分析(通常用色谱的方法)。定量提取性特征是指所提取的每种成分的测得量。

B. CGMP, CPSC and USP Requirements on Containers and Closures CGMP, CPSC

和USP对容器和密封的要求

Current good manufacturing practice (CGMP) requirements for the control of drug

product containers and closures are included in 21 CFR Parts 210 and 211. A listing of the relevant sections is provided in Attachment A. In addition, a listing of Compliance Policy Guides that deal with packaging issues is provided in Attachment B. References in this guidance to CGMP regulations are provided for completeness. For additional information, refer to the FDA Compliance Program Guidance Manual for Pre-Approval Inspections/Investigations (7346.832) which describes specific responsibilities for

CDER scientists and for field investigators. 现行良好生产规范(CGMP)关于“药品容器/封装的控制”的要求在21 CFR的第210和211部分。相关部分的清单请见附件A。另外,关于包装方面的“Compliance Policy Guides达标政策指南”清单请见附件B。本指南关于CGMP的参考文献对本指南有补充作用。更多的信息,请参考“FDA达标项目指南手册”,以指导“批准前检查/调查(7346.832)”,里面描述了CDER科学家和现场检查的具体职责。

The FDA requirement for tamper-resistant closures is included in 21 CFR 211.132 and the Consumer Product Safety Commission (CPSC) requirements for child-resistant

closures are included in 16 CFR 1700. An outline of these and other applicable

regulatory requirements is provided in Attachment A. FDA关于防篡改封装的要求请见21 CFR 211.132,消费者产品安全委员会(CPSC)对“儿童防护封装”的要求请见16 CFR 1700。附件A提供了这些法规要求和其他相应法规要求的要点。

The United States Pharmacopeial Convention has established requirements for

containers which are described in many of the drug product monographs in The United States Pharmacopeia/National Formulary (USP/NF). For capsules and tablets, these requirements generally relate to the design characteristics of the container (e.g., tight, well-closed or light-resistant). For injectable products, materials of construction are also addressed (e.g., "Preserve in single-dose or in multiple-dose containers, preferably of Type I glass, protected from light"). These requirements are defined in the "General Notices and Requirements" (Preservation, Packaging, Storage, and Labeling) section of the USP. The requirements for materials of construction are defined in the "General Chapters" of the USP (see Attachment A). 美国药典委员会建立了对容器的要求,这在“美国药典/国家处方集(USP/NF)”的各药品专论中进行了描述。对于胶囊和片剂,这些要求通常与容器的设计特征有关(例如牢固,密闭良好,或者避光)。对于注射剂产品,还有生产材料的要求(例如,“保存在单次给药或多次给药容器中,最好采用I型玻璃,避光”)。这些要求在美国药典的“通则和要求”(保存,包装,贮存和标签)部分。关于生产材料的要求在美国药典的“总章”(请见附件A)。

C. Additional Considerations 其他需要考虑的事项

1. Submissions of INDs

The packaging information in the chemistry, manufacturing, and controls

section of an IND usually includes a brief description of the components, the

assembled packaging system and any precautions needed to ensure the

protection and preservation of the drug substance and drug product during their use in the clinical trials.

For general guidance regarding the container closure system information to be submitted for phase 1 studies, refer to the FDA guidance for industry Content and Format of investigational New Drug Applications(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived

Products (November 1995).

General guidance regarding the container closure system information to be

submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified

Therapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, and Controls Content and Format, when finalized (draft guidance published April 21, 1999).

2. Submissions on Packaging of a Drug Product by Another Firm

a. Contract Packager

FDA网站使用说明
篇三:fda指南

Orange Book : Approved Drug Products with Therapeutic Equivalence Evaluations

橙皮书:被批准的药物的治疗等效性评估

Proprietary Name

按商品名检索

Patent

Display Newly Added Patents

显示新增专利

Display Patent Delistings

显示退市专利

TE Code Therapeutic Equivalence-Related Terms

治疗等效性评估编码

fda指南。

Drug Substance Claim

化合物专利

Drug Product Claim

制剂专利

Patent Use Code

对专利针对的适应症进行分类,不同代码对应不同适应症

RLD :Reference Listed Drug

分为Yes和No

一般为原研制剂,大多数情况这个是NDA,FDA评估仿制药与RLD比较体内生物等效性。也不一定所有的原研都是RLD。做生物等效性应选择RLD中有的是YES的来做比较,不能选NO的。有YES的RLD不止一个,所以就有了TE CODE不同的分级

RLD项下有的是yes,有的no,出现这种情况,一般是由于原研药有多个剂量(像这里的VYTORIN就有3个剂量),FDA根据原研厂家申报时候提供的数据,评估安全、有效、可控等各方面信息后,指定哪个剂量的药品作为以后仿制药厂家仿制做生物等效性试验时的参比制剂(RLD),一般情况下是一个产品的最高剂量作为RLD,但也存在中间剂量为RLD的情况。如果仿制厂家能够证明几个剂量之间处方比例一致,溶出行为一致,其他不是RLD剂量的产品可以豁免生物等效性试验。

Navigate the Drug Section

Drug Approvals and Databases

常用的有

Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Search

Dissolution Methods Database Search

Drugs@FDA Search

Inactive Ingredient Search for Approved Drug Products Search

Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations) Search

Guidance, Compliance, & Regulatory Information

Affordable Care Act (ACA 6004)

可支付医疗法案

Bioequivalence Recommendations for Specific Products

对特殊产品的生物等效性建议

Guidances (Drugs)

Nicotine-Containing Products

尼古丁的产品

Regulatory Guidance Drug Registration and Listing

监管指导药品注册和清单

Warning Letters and Notice of Violation Letters to Pharmaceutical Companies 警告信

Drugs@FDA

Approval History, Letters, Reviews, and Related Documents

Medication Guide

美国FDA指南-中文版
篇四:fda指南

《美国FDA认证与申办指南》

权威资讯系列

《合成原料药DMF起草大纲》

使用说明:

1、 本大纲是为了帮助我公司客户把握DMF的整体内容而准备

的,由于DMF内容繁多,从整体上了解内容框架和组成部分,对于理解FDA对DMF的要求和意图非常有必要;

2、 根据FDA的要求,凡是本大纲提到的内容,原料药制造商均

应该提供。因此,客户务必依照规定提供尽可能详细的内容。

3、 本大纲的内容和相关要求能够确保客户目前的运作达到FDA

的cGMP标准,因此,准备DMF的过程,也使客户按照FDA的要求进行整改和提高的过程,这些都为FDA未来的现场检查打下良好基础;

4、凡是本大纲中提到的非技术性具体内容要求,请参照本公司专有的与此大纲配套的相关DFM指导性文件,包括《FDA药物主文件指南》、《关于在药品递交中递交的有关原料药生产的支持文件的指南》、《药物申办中质量管理方面通用技术文件格式与内容要求》;

5、凡是本大纲中提到的技术性具体内容要求,如杂质、稳定性、验证等具体技术要求,请参照本公司专有的FDA相关技术标准文件,包括《原料药认证指南》、《制剂认证指南》、《化学药物稳定性指南》、《化学药物杂质指南》、《化学药物化验与合格参数指南》、《化学药物验证指南》等;

《合成原料药DMF起草大纲》

一、公司和生产场地的基本描述

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