巴西卫生监管局ANVISA验厂GMP标准中文版(转载)

巴西卫生监管局ANVISA验厂GMP标准中文版(转载1/3)  

2014-11-06 09:35:35|  分类： GMP通论及跨国

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作者：巴西医药食品网   发布：2014-08-11   分类：医药和器械, 进出口政策  

http://www.medfoodbr.com/archives/473

巴西 GMP巴西缩写为BPF (Boas Práticas de Fabrica??o)

1、巴西GMP是在Q7A的基础上建立起来的。

Q7A是ICH对原料药生产的指导性文件。ICH（人用药品注册技术要求国际协调会议）由三个地区的代表组成，即欧盟、美国和日本。ICH指导文件是三方公认的国际标准，同时ICH指导文件也日益成为国际上公认的药品注册技术标准。巴西GMP沿用了Q7A的基本原则与框架，大致内容也与其相同，但是，巴西GMP也融入了巴西卫生部对GMP的理解与要求，使之比Q7A更具体、更严格。

2、巴西GMP与中国GMP的比较

中国没有单独针对原料药生产的GMP要求，现行98年修订版 GMP，内容过于简单，版本过于陈旧，两者差距非常大，不可同日而语。

3、巴西GMP基本框架

第一部分：说明GMP是质量管理体系的一种；指明质量管理的基本原则与职责。

（第一章至第二章）。

第二部分：对影响产品质量的6要素（5M1E）提出具体要求；对贯穿于所有方面的文件管理提出具体要求。（第三章至第八章）

第三部分：对药品生产质量管理的其它几个重要方面提出具体要求。（第九章至第十七章）

站内下载 链接如下

巴西卫生监管局ANVISA验厂GMP标准中文版

(转自网络)

巴西卫生部

原料药与中间品 GMP

第一章 一般考虑

1.1 企业资质文件齐全，经常受到药监部门的检查。

（要准备：药监部门的检查记录与报告）

1.2 原料药生产应遵循该法规。

1.3 生产企业应保证产品符合既定质量。

1.4 质量保证、质量控制、GMP是密切相关的三个概念。

1.5 生产企业对产品质量负责。

1.6 要有齐全的证据标明：企业在影响产品质量的各个方面实行了GMP管理。

1.7 生物制品应从工作种子库的维护工序就开始要求GMP管理。

2.                  质量管理

QUALITY MANAGEMENT

质量管理决定和执行公司的质量方针,即与质量有关的总体方向和目标,其管理职能由公司的高级管理层正式宣布并授权。

quality Management is the aspect of management function that determines and implements the “Quality Policy”, i.e., the overall intentions and directions related to quality, formally expressed and authorized by the firm high management.

2.1       原则

Principles

2.1.1   公司的所有人员对质量负有责任。

The quality should be responsibility of all the company's collaborators.

2.1.2   生产厂家应该建立执行和保持有效的文件化的质量管理体系，并使管理层和所有与生产有关的人员积极参与。

Each manufacturer should establish, document, implement and keep an effective system of quality management, which involves active participation of the management and all personnel involved in manufacturing.

2.1.3   质量管理体系包括公司的组织结构、程序、过程、资源和必要的活动,确保中间品和药物活性成分符合规定的质量和纯度要求。所有相关的活动都应该在文件中规定。

The system for quality management should comprise the organizational structure, procedures, processes, resources and necessary activities to assure that the intermediate and the pharmaceutical input are in conformity with the intended specifications of quality and purity. All related activities should be defined and documented.

2.1.4   必须有一个质量部门负责保证中间品和药物活性成分满足规定的质量标准，并达到使用要求。

There must be a quality unit responsible for assuring that intermediates and active pharmaceutical inputs are within the demanded quality standards and that can be used for the proposed purposes.

2.1.5   质量部门必须独立于生产部门，其职能包括质量保证和质量控制。质量部门可以有一个人或一个小组和部门组成，这取决于公司的大小和结构。

There must be an independent Quality Unit of production, which comprises responsibilities of both Quality Assurance (QA) and Quality Control (QC), that completes the production responsibilities. The Quality Unit can be represented by a single person or by a group or department, depending on the size and structure of the organization.

2.1.6   授权放行中间品和药物活性成分的人员应该确定好。

The employees authorized to release intermediates and active pharmaceutical inputs should be defined.

2.1.7   所有与质量相关的活动在完成后应予记录。

All activities related to quality should be recorded after their performance.

2.1.8   所有的偏差应该由文件证明和说明。对关键偏差应进行调查，调查过程和调查结论应该形成文件。

All deviations should be documented and explained. Critical deviations should be investigated, and this investigation and its conclusions should be documented

2.1.9   在质量部门对于物料质量作出满意的结论之前，不得放行和使用这些物料。除非有一套合理的系统允许这样操作。但中间品和药物活性成分没有例外。

No material should be released or used before a satisfactory conclusion of the evaluation by the Quality Unit, except when There must be implemented appropriate systems allowing such a practice, with the exception of intermediates for selling and active pharmaceutical inputs.

2.1.10 对于发生的质量偏差，必须有通知质量部门的程序，包括采取相关的行动。

There must be procedures to notify the Quality Unit whenever quality deviations occur, including related actions.

2.2       职责

Responsibilities

2.2.1   介绍

Introduction

2.2.1.1生产和质量部门的主要岗位应该有全职人员担任。必要时可以代理行使某些职能,但责任不能代理。

The main posts of Production and Quality Unit should be occupied by personnel working full time at the firm. There may be necessary to delegate some functions, however, responsibility can't be delegated.

2.2.1.2根据有关的规定为中间品和药物活性成分的生产和质量控制负责人授予称号，并在教育、经验和培训方面有任职资格。

The responsible persons for Production, quality control and quality unit of intermediates and active pharmaceutical inputs should be entitled according to the actual legislation of the respective representative class board and qualified with proper education, experience and/or training.

2.2.1.3生产和质量部门的负责人应联合进行下列质量活动：

The responsible persons for Production and quality unit should exert together certain activities related to quality, such as:

a)   程序和文件的制定和复核包括对其进行更新。

elaboration and review of procedures and documents, including its updating;

b)   监督和控制生产环境  

monitoring and control of manufacturing environment;

c)   卫生  hygiene;

d)  工艺验证  validation of the process;

e)   包括GMP原则应用方面的培训

training, including application of GMP principles;

f)   供应商资格确认  supplier qualification;

g)   合同供应商的批准和监督 approval and monitoring of contract suppliers;

h)  规定物料和产品的存储条件

specifications of storage conditions of materials and products;

i)   对文件和记录归档document files and records;

j)   监督是否符合然GMP  monitoring of compliance with the GMP;

k)  检查和调查可能影响中间品和药物活性成分质量的因素。

inspection and investigation of factors that may affect the quality of intermediate and pharmaceutical input.

2.2.2   质量部门的责任

Responsibilities of the Quality Unit

2.2.2.1质量部门应该对所有与质量有关的活动进行管理。

The Quality Unit should manage all activities related to quality

2.2.2.2质量部门的主要责任不能代理。这些责任应该在文件中规定，至少涉及下列活动：

The main responsibilities of the Quality Unit should not be delegated. These responsibilities should be defined and documents contemplating at least the following activities:

a)   放行和否决所有的中间品和药物活性成分

release or reject all intermediates or active pharmaceutical inputs;

b)  建立和监督对生产过程中使用的原材料、中间品、包装和标签材料放行或否决的制度。

establish and monitor a system for releasing or rejecting raw materials, intermediates, packaging and labeling materials used during manufacturing;

c)   在产品发货前，对生产记录和质量控制记录文件进行复核。

review documentation of production record and Quality Control of the manufactured lot, before its release for expedition;

d)  证明质量偏差已得到调查，并采取了纠正措施。

certify that quality deviations are investigated and corrective actions are implemented;

e)   对于留样的包管、储存和记录活动进行管理manage activities of custody, storage, and documentation of retention samples.

f)   批准对中间品和药物活性成分的质量有影响的所有程序、标准和指令。

approve all procedures, specifications and instructions that cause impact on the quality of the intermediate or pharmaceutical input;

g)   批准自检计划，并证明已经实行。

approve the Self-inspection Program and certify that it is executed;

h)  批准与中间品和药物活性成分的生产和质量控制有关的技术标准和第三方服务合同。

approve technical specifications, third party service contracting related to manufacturing and Quality Control of intermediates and active pharmaceutical input;

i)   批准对中间品和药物成分的质量有影响和潜在影响的变更。

approve changes affecting and that potentially may affect the quality of intermediate and pharmaceutical input;

(j)    批准验证主计划、方案和报告，确保进行必要的验证活动。

approve master plan, protocol and reports of validation and assure that necessary validations are carried out;

(k) 证明记录和调查了与质量有关的投诉和产品退回，必要时采取了纠正措施。

certify that complaints and returns related to the quality should be recorded, investigated and, when necessary, corrective actions are implemented;  

(l)  证明有一套有效的设备维护和校验体系。

certify that there is an effective maintenance and calibration system of equipments;

m) 证明进行了稳定性研究，保证获得的数据能够证明中间品和药物活性成分的有效期和规定的储存装运条件。

certify that stability studies are conducted; in such a way to guarantee that obtained data supports the expiration date and the storage and shipping conditions defined for intermediates and active pharmaceutical inputs;

(n) 进行产品质量评审

perform reviews of product quality;

(o) 对生产区的环境监测进行评估

evaluate the environmental monitoring program of productive areas.

(p) 批准培训计划并证明对员工进行了最初和连续的培训。

approve Training Program and certify that initial and continuous trainings of personnel are performed and

q)  评估召回中间品和药物成分的必要性

evaluate the necessity of intermediate or pharmaceutical input recall

r)   批准校验和预防性维修计划，并证明已经正确地执行

approve the calibration and preventive maintenance program and certify its correct execution.

2.2.3     质量控制的责任

Responsibilities of the Quality Control

2.2.3.1质量控制的主要责任不能代理。这些责任应该在文件中清楚地确定下来，至少包括下列活动：

The main responsibilities of Quality Control can not be delegated. These responsibilities should be defined and documented clearly describing at least these activities:

a)   制定、更新和评估  elaborate, update and review:

I.   原材料、中间品、药物活性成分、过程控制和包装材料的标准和检验方法

specifications and analytical methods for raw materials, intermediates, active pharmaceutical inputs, in-process controls and packaging materials;

II.  取样程序   sampling procedures;

III.             生产区环境监测程序  

environmental monitoring procedures of productive areas;

IV.    评估和存放参考标准品的程序

procedures to evaluate and store reference standards;

b)  批准或否决原材料、中间品、药物活性成分和包装材料

approve or reprove raw materials, intermediates, active pharmaceutical inputs and packaging materials;

c)   签发每批物料的检验报告

issue analytical report of each lot of analyzed material;

d)  对中间品和药物活性成分进行稳定性研究

perform stability study analyses of intermediates and active pharmaceutical inputs;

e)   对中间品和药物活性成分的投诉和产品退回参予调查

take part on investigation of complaints and returns of intermediates and active pharmaceutical inputs;

f)   确保准确标识试剂、物料、仪器和实验室设备

assure the correct identification of reagents, materials, instruments and lab equipments;

g)   验证检验方法  validate analytical methodologies;

h)  按照程序调查不合格结果

investigate results out of specification, according to procedures;

i)   进行所有要求的检验

perform all the required assays;

j)   确认设施和设备的维护

  verify the maintenance of facilities and equipments;

k)  证明实验室设备的校验

certify the performance of calibration in lab equipments;

l)   推动对质量控制区员工进行最初和连续的培训

promote initial and continuous trainings of personnel from the Quality Control area;

m)  进行环境监控分析

perform analyses of environmental monitoring

2.2.4          生产责任

Production Responsibilities

2.2.4.1      生产责任应在文件中明确规定，并至少涉及下列活动：

The production responsibilities should be defined and documented contemplating at least the following activities:

a)            按照书面的程序参与中间品和药物活性成分生产所使用的标准／主配方的确定和复核工作。

take part of elaboration and review of standard/master formula for production of intermediates or

active pharmaceutical inputs according to written procedures;

b)      按照书面程序分发中间品和药物活性成分的生产通知单。

distribute production orders of intermediates or active pharmaceutical inputs according to written

procedures;

c)      根据已批准的要求生产药物活性成分和相关的中间品。

produce active pharmaceutical inputs and, when appropriate, intermediates according to previous

approved instructions;

d)      复核所有的批记录，保证记录完整性并签字。

review all the lot records and assure that they are completed and signed;

e)            证明所有的生产偏差得到记录和评估，并且对关键偏差进行了调查，作出了书面结论。

certify that all production deviations are recorded, evaluated and that critical deviations are

investigated and conclusions recorded;

f)      证明设备和设施已清洁,并在必要时进行卫生处理，及时标识。

certify that facilities and equipments are found clean, when necessary, sanitized, and duly

identified;

g)      证明必须的校验已完成，并保存了记录。

certify that the necessary calibrations are executed and records are kept;

h)      证明验证方案和验证报告得到评审和批准。

certify that protocols and validation reports are reviewed and approved;

i)       提出工艺或者设备的改造建议。

propose alterations in the process or equipment;

j)       对提出的产品、工艺或设备的改造建议进行评估。

evaluate proposed alterations for product, process or equipments;

k)      证明新的或改进的设备和设施合格。

certify that facilities and equipments (when new or modified) are qualified, when necessary and;

l)       证明设备和设施的维护已完成，并且保存了记录。

certify that maintenance of facilities and equipments are performed and records kept.

2.3    产品质量评审

Product Quality Review

2.3.1       为核实工艺的一致性，应该定期对中间品和药物活性成分的质量进行评审。评审应采用书面形式，每年进行一次，并至少包括下列方面

Regular reviews of intermediates and active pharmaceutical inputs should be conducted aiming to verify consistency of the process. Such reviews should be conducted and documented annually and include at least:

a)    对中间品和药物活性成分的关键工艺控制和关键测试结果进行评审

review of controls in critical processes and critical test results of intermediate and pharmaceutical input;

b)     评审所有不符合规定要求的批次。

review of all the lots not showing as established in the specification;  

c)       评审所有的关键偏差和相关的调查

review of all the critical deviations and related investigations;

d)      评审工艺变更或已验证的检验方法的变更。

review of alterations performed in the processes or validated analytical methods;

e)     评审稳定性监控结果。

review of results from stability monitoring program;

f)      评审所有与质量有关的产品退回，投诉和产品召回。

review of all the returns, complaints and recalls related to quality;

g)      评审纠正措施。

review of corrective actions.

2.3.2          对结果进行分析，必要时,采取纠正措施并记录、跟踪和作出结论。

Results should be analyzed and, if necessary, corrective actions should be taken, recorded, followed and concluded.

2.4       质量自检

Quality Self-inspections

2.4.1   质量自检活动的目标是确认中间品和药物活性成分的生产厂家从物料的采购到中间品和药物成分发货的过程符合GMP的要求，自检活动应该至少每年进行一次

Its goal is to verify the conformity of the manufacturer of intermediates and active pharmaceutical inputs with the main GMP, from material acquisition to expedition of intermediates or pharmaceutical input. The self-inspections should be performed, at least, annually.

2.4.2   应该对自检活动制定书面程序。自检应该包括：

It should be elaborated a written procedure on self-inspections. The self-inspection should comprise:

a)   人员   personnel;

b)  设施  facilities;

c)   厂房和设备维护  building and equipment maintenance;

d)  原材料、包装材料和成品的储存

storage of raw material, packaging material and finished product;

e)   设备生产  equipments;

f)   生产和过程控制   production and in-process control;

g)   质量控制   Quality Control;

h)  文件  documentation;

i)   卫生   sanitation and hygiene;

j)   验证和在验证计划   programs of validation and revalidation;

k)  仪器和测量系统的校验

calibration of instruments and measure systems;

l)   中间品和药物活性成分从市场召回

recall of intermediate and pharmaceutical input from the market;

m) 顾客投诉  complaints;

n)  标签控制  label control;

o)  废物处理  waste management:

p)  先前自检的结果和采取的纠正措施

results from early self-inspections and adopted corrective actions.

2.4.3   自检小组应该由合格的专业人员组成，对实际的操作区和GMP有很好的了解。小组成员可以是公司的专业人员或者外部的专家

The self-inspection team should be constituted by qualified professionals, experts in its actuation area and familiarized with GMP. Team members can be professionals of the company or outer experts.

2.4.4   对自检活动应进行记录，至少包括下列方面

Self-inspection should be documented and contain at least:

a)   自检结果  self-inspection result;

b)  评估和结论  evaluations and conclusions;

c)   发现的不合格项 detected non-conformities;

d)  建议的纠正措施和期限，在规定的期限内对自检报告中的不合格项采取和完成纠正措施。

recommended corrective actions and established term for attending.

Corrective actions for non-conformities observed in the self-inspection report should be implemented and concluded within the informed term.

3       人员

PERSONNEL

3.1          概述

General

3.1.1    建立和维护中间品和药物活性成分的质量和生产活动依靠从事这些活动的员工。

必须有足够数量的合格人员，通过接收指导培训和积累的经验来完成、监督和管理中间品和药物活性成分的生产活动。每个人的责任和权力应通过书面形式确定，并由所有的相关人员执行。

Establishment and maintenance of quality and manufacturing of intermediate and active

pharmaceutical input depend on employees that perform them. There must be a adequate number of

qualified personnel by instruction, training, and/or experience, to execute, supervise and manage

manufacturing activities of intermediates and active Pharmaceutical Inputs by which the

manufacturer is responsible. The individual responsibilities and authorities should be established in

written procedures, comprised and applied by all the involved ones.

3.1.2    公司应该有组织结构图。员工的责任不能重叠，这样可避免影响中间品和药物活性成分的质量。员工的工作可以由别人代理完成，条件是代理的人员达到满意的质量水平。人员的GMP执行责任不能缺位或重叠。

The company should have an organization chart. Employees shouldn’t accumulate responsibilities in

order to avoid that the quality of the intermediates and active pharmaceutical inputs is put in danger.  

Their attributions may be delegated to assigned substitutes as long as those present satisfactory

qualification level. It can not be absence or accumulation of personnel responsibilities referring to

GMP application.

3.1.3       所有的人员应该了解GMP的原则并接收最初和连续的培训。培训应该由合格的专业人员定期进行，其内容至少应包括员工所从事的工作，与员工的工作职责和卫生要求相关的GMP知识。对培训记录要进行保存。应该定期对培训进行评估。所有的员工应该热情支持公司维护质量标准。

All personnel should know GMP principles and receive initial and continuous training. Training should be regularly conducted by qualified professionals and should cover, at least, operations performed by the employee, the GMP related to the collaborator’s functions and hygiene instructions as required. Training records should be kept. Training should be evaluated periodically. All employees should be motivated to support the company in maintaining quality standards.

3.2       培训

Training

3.2.1    生产厂家应该通过书面的明确的计划对工作影响到中间品和药物活性成分质量的所有员工进行培训。

The manufacturer should, through a written and defined program, promote trainings of all personnel whose activities may interfere with the quality of the intermediate and active pharmaceutical input.

3.2.2    除了 GMP理论和实践方面的基本培训外，新聘用的人员应该参加公司的整合活动，接受岗位责任方面的培训，并持续进行，接受评估。

            Additionally to the basic training on GMP theory and practice, the newly hired personnel should take part in the integration program and receive proper training for attributions and be continuously trained and evaluated.

3.2.3    培训计划应该考虑到所有的人员，并且经过生产和质量管理部门负责人的批准，保存好培训记录。

The training programs should contemplate all personnel, as well as be approved by responsible persons of production, quality unit and Quality Control, and records should be kept.

3.2.4    在洁净区和具有危险污染源的区域工作的人员应得到相关的培训。

            Personnel working in clean areas and areas where there is contamination hazard, where highly active, toxic, infectious or sensitizing materials are handled, should receive specific

            Training.

3.4       健康、卫生、着装和行为

Health, Hygiene, Clothing and Conduct

3.4.1    所有的人员应该在录用时进行体检，并在以后根据相关的法律法规，针对所从事的工作，接受定期体检

All personnel should undertake health exams for admission and, later, to periodic exams, required for performed activities, according to the specific legislation into force.

3.4.2.   所有的人员应该受到个人健康和安全操作方面的培训。遵守卫生和安全规定。培训应该包括如何应付传染病和外露伤口的情况。

All personnel should be trained in personal health and security practices. All personnel should respect hygiene and security rules. Training should include conduct situations in case of contagious diseases or exposed wound.

3.4.3.  患有可疑的和确认的传染病或者有外露伤口的人员不得从事可能对中间品和药物活性成分的质量造成损害的活动，直到他们的健康状况对中间品和药物

活性成分的质量和安全不会构成风险。   

           All personnel with suspected or confirmed infectious disease or exposed wound can't

            perform activities that may compromise the quality of intermediates and active pharmaceutical inputs. They should be excluded from these activities until the health status does not represent risk to the quality and security of the intermediate and active pharmaceutical input.

3.4.4. 教育和鼓励所有的人员对于影响中间品和药物活性成分的异常情况向直接领导汇报。

All employees should be instructed and encouraged to relate to their immediate supervisor any conditions out of the established procedures that can interfere with the manufacturing of intermediates or active pharmaceutical inputs.

3.4.5. 人员应该避免与中间品和药物活性成分直接接触。

Personnel should avoid direct contact with intermediates or active pharmaceutical inputs.

3.4.6. 为了保证产品不受污染，员工应该穿干净的工作服。工作服应该适合每个生产区域，可以重新使用的工作服应该存放在合理封闭的环境中，直到经过清洗和必要的消毒处理。工作服的报废应该按照操作程序进行。

In order to assure product protection against contamination, employees should wear clean uniforms proper to each production area. Uniforms, when reused, should be kept in adequate and close environments, until they are washed and, when necessary, disinfected or sterilized. Uniform discards should follow operational procedures.

3.4.7.      工作服应该由公司提供和清洗。

Uniforms should be supplied by the company. Its washing is a company's responsibility.

3.4.8. 为了保护员工，生产厂家应该按照从事的操作活动，考虑使用有效的集体保护设备和个人保护设备。

In order to assure protection to the employees, the manufacturer should turn available Collective Protection Equipment (CPE) and Individual Protection Equipment (IPE) according to the developed activities.

3.4.9.  吸烟、吃喝、咀嚼口香糖或者栽种植物，食品、饮料、香烟和个人药品应限制在特定的地区，与生产区域分开。  

            Smoke, eat, drink, chew gums or keep plants, food, beverages, tobacco and personal medications should be restrict to certain assigned areas, separated from manufacturing areas.

3.4.10. 参观者和未经培训的人员不得进入生产区。如果不可避免，这些人员应该在指定专业人员的指导和引导下进入。  

Visitors and non-trained persons should be prohibited from entering the production areas. If it's inevitable, these persons should be directed and followed by an assigned professional.

3.4.11. 采取措施，避免未经许可的人员进入生产区、仓库和质量控制区。不在这些地区工作的人员不得穿行这些地方。

            Arrangements should be taken in order to avoid the entrance of non-authorized persons into the production area, storage and Quality Control. Persons not working in these areas shouldn't use them as passageway.

4.        厂房和设施

BUILDINGS AND FACILITIES

4.1.     概述

General

4.1.1. 厂房和设施的位置、设计、建造、使用和保养应该有利于进行生产活动。其设计应该最大程度减少错误，保证能够进行充分的清洁和维护，避免交叉污染，尘土的积累或者有可能影响中间品和药物活性成分的质量、环境保护和员工安全的其他有害作用。

Buildings and facilities should be located, designed, built, adapted and kept in a way that they are adequate to the operations to be performed. Its design should minimize the risk of mistakes and enable adequate cleaning and maintenance in such a way that it avoids cross-contamination, dust and dirt accumulation or any adverse effect that may affect the quality of intermediates and active pharmaceutical inputs, the environmental preservation and the employees' security.

4.1.2. 设施的环境在需要采取措施保护生产操作和生产流程的情况下，最大限度减少对物料和产品的污染。

Facilities should have environments that, when considered in conjunction with measures consigned to protect manufacturing operations and production flow, present minimum risk of contamination of the materials or products handled there.

4.1.3.   厂房和设施应该有足够的空间安排设备和物料的布局，避免污染，便于清洁。

            Buildings and facilities should have adequate space for arranged placing of equipments and materials to avoid contamination and to make the cleaning easy.

4.1.4. 设施应该保持良好的保养、卫生和清洁状态。设施的维修和保养不得对中间品和药物活性成分的质量带来风险。

Facilities should be kept in good conservation, hygiene and cleaning status. It should be assured that maintenance and repair operations don't represent any risk to the quality of intermediates and active pharmaceutical inputs.

4.1.5.   电力供应、照明、空调（温度和湿度）和通风系统应该合理，对中间品和药物活性成分的生产和设备的充分运行没有直接和间接的影响。

Electric energy supply, lightning, air conditioned (temperature and moisture) and ventilation should be proper in such a way that they don't affect direct or indirectly the manufacturing of intermediates and active pharmaceutical inputs and the adequate functioning of the equipments

4.1.6.   实验室应该与生产区域分开。过程控制的区域可以设在生产区，但条件是生产活动不影响实验室的测试准确性，实验室和实验活动对中间品和药物活性成分的生产过程没有负面影响。

            The laboratory should be separate from the production areas. Areas used for in-process controls can be located in production areas, only if the production process operations don't affect adversely the accuracy of laboratory measures and, the laboratory and its operations, don't affect adversely the production process of the intermediates and active pharmaceutical inputs.

4.1.7. 设施的设计和配置应该最大限度防止昆虫和其他动物的进入。

            Facilities should be designed and equipped in a way to allow maximum protection against accessing of insects and other animals.

4.2.     仓库

Storage Areas

4.2.1. 仓库应该有足够的能力存放各类物料和产品：原材料、包装材料；中间品和药物活性成分，存贮状态分为待检、合格、不合格、退回和召回。

Storage areas should have enough capacity to enable the arranged stock of a number of material and product categories: raw materials; packaging materials; intermediates and active pharmaceutical inputs, in the quarantine, approved, rejected, returned and recall status.

4.2.2. 仓库的设计应该能够保证理想的存储条件。仓库应干燥、整洁，温度和湿度与存放的物料相适应，不允许存在交叉和环境污染的情况。对这些存储条件在必要的情况下应该进行核实、监控和记录。Storage areas should be designed in a way to assure ideal storage conditions. They should be clean, dry and kept in compatible temperature and moisture with the stored materials, not allowing cross and environmental contamination. These conditions, when required, should be verified, monitored and recorded

4.2.3. 在收货区和发货区，应该保护物料不受天气和环境变化的影响。收货区的设计和装备应该允许物料的容器在存放前得到清洁。

In the receipt and shipping areas, materials should be protected from climatic and environmental variations, when required. Receipt areas should be designed and equipped in such a way to allow received material containers are cleaned before they are stored.

4.2.4.  待检区的产品应该放在限定的隔离区域。对这一区域要标识清楚，只有经过授权的人员才能进入。代替实际待检区的其他系统应该具有同样的安全性。产品的状态应分别标识好，避免意外的更改。

Products in quarantine should be put in restrict and separate area of the storage area. This area should be clearly marked and only authorized personnel are allowed to access it. Any other system that replaces the physical quarantine should offer the same security, assuring the non-release for use or commercialization. Products should be identified, individually for its status in order to prevent accidental changes.

4.2.5.   应该有原材料取样区，如果取样在仓库进行，应该使用对样品的质量或被取样的产品的质量没有危害的取样设备在特定的环境中进行。如果取样在仓库以外的地区进行，应该避免可能的微生物污染和交叉污染。

            There should be areas for sample collection of raw materials, when applicable. If sampling is to be made in the storage area, it should be performed in specific environment for this finality with sample collection equipments that don't compromise the sample quality or the sampled product (e.g.: sampling of tank truck, solvent tank). When it's away from the storage area, sampling should be performed in such a way that it can't be possible microbiological contamination and/or cross-contamination

4.2.6.   退回的、拒收的或召回的物料或产品应该存放在单独的标识好的区域。Storage of returned, rejected or recalled materials or products should be performed in a segregated and identified area.

4.2.7. 危险性很高的物品应该存放在安全受保护的区域，并按照相关的规定及时隔离和标识。

Highly active materials, substances that present risks of dependency, fire or explosion and other hazardous substances should be stored in secured and protected areas, duly segregated and identified according to the actual specific legislation.

4.2.8. 与GMP相关的印刷品的存储应该安全操作，限制外人进入，避免混淆和错误；应该由指定的人员按照明确的书面程序搬运。Storage of printed materials related to GMP should be securely performed, with restrict access, avoiding mixings and deviations; it should be handled for assigned personnel, following defined and written procedures.

4.3.     称重房间

Weighting Room

4.3.1. 原材料称重房间或区域应该位于仓库或生产区。房间的设计应该专门针对此用途，具有独立的和充分的排风系统，防止交叉污染的产生。

Rooms or areas destined to weight raw materials can be located either in the storeroom or production area. The rooms should be designed exclusively for this purpose, having independent and adequate exhaustion system, when applicable, that avoids occurrence of cross-contamination.

4.4.     生产区

Production Area

4.4.1. 为最大限度减少交叉污染，应该有单独的设施生产某些中间品和药物活性成分，如生物制剂等。应该有单独专门的区域生产高敏感性的物质。

To minimize the likelihood of cross-contamination occurrence, there should be separate facilities for production of certain intermediates and active pharmaceutical inputs, such as biological preparations (live microorganisms), hormones, cytotoxic substances, immunosupressors. There should be separate and exclusive areas for the production of highly sensitizing substances (penicillin, cephalosporin and its respective derivates). Facilities should have airflow systems entirely independent, designed specifically for this purpose.

4.4.2.   物质设施的布局应该符合生产流程，使生产与生产操作的顺序和要求的洁净级别相适应。

            Physical facilities should be arranged, according to the operational flow, in such a way to allow that the production corresponds to the sequence of production operations and to the required cleaning levels.

4.4.3.   生产区应该使设备和物料的布局最大程度减少不同的中间品和药物活性成分混合的风险，避免交叉污染的产生，减少因为遗漏、疏忽或错误的生产和控制操作引起的风险。

Production areas should allow logical and arranged positioning of equipments and materials, in such a way to minimize the mixing risk between different intermediates and active pharmaceutical inputs or its compounds, and to avoid the occurrence of cross-contamination and decrease the risk of omission, negligence or erroneous application of any step of manufacturing or control.

4.4.4.   对管道、照明、通风点和其他装置的设计和安装应该便于清洁。

Piping, luminaries, ventilation points and other installations should be designed and installed in such a way to make the cleaning easy

4.4.5. 管道应该尺寸得当，设计能够避免液体和气体的回流，在不影响安全的情况下保持关闭。

Graters and gutters should have adequate size and should be designed in such a way to avoid liquid or gas reflux, and should be kept closed when not interfering in the security.

4.4.6. 生产区应该有有效的通风系统，并且配备空气控制装置，必要时应该由合理的湿度和过滤系统。这些区域应该在生产期间和空闲时间定期监控，确保满足规定的区域要求。

production areas, when applicable, should have effective ventilation system, with air control units, including temperature control and, when necessary, proper moisture and filtration system for the handled products. These areas should be regularly monitored during the production period and at rest, in order to assure the fulfillment of specifications for the area.

4.4.7. 中间品和药物活性成分的包装设备在设计上要避免产生混合或交叉污染的情况。

the physical facilities for packaging intermediates and active pharmaceutical inputs should be designed to avoid the occurrence of mixings or cross-contaminations.

4.4.8. 根据每种操作的需要对生产区照明，特别是对于使用肉眼在线控制的区域。The production areas should be illuminated, according to the necessity of each operation, especially in locations where visual control in the production line is conducted.

4.5.     质量控制区

Quality Control Area

4.5.1. 质量控制试验室的设计应该便于实验活动。有足够的空间避免产生混合或交叉污染。

Quality Control laboratories should be designed to facilitate operations performed there. They should have sufficient space in order to avoid the occurrence of mixings and cross-contamination.

4.5.2. 实验室的设计应考虑使用合适的建筑材料，并有一套设备保证检验的环境条件和人员的健康。

The laboratory should be designed considering the utilization of adequate construction materials and should have a set of devices that assure environmental conditions for the performance of analyses and the protection of personnel health.

4.5.3.   必要时应备有单独的房间保护某些仪器免受电子干扰、震动，防止与湿气和其他外部因素过分接触。

            If necessary, there should be separate rooms for protecting certain instruments from electrical interferences, vibrations, excessive contact with moisture and other external factors.

4.6.     辅助区

Ancillary Areas

4.6.1. 休息室和餐厅应跟其他区分开。

Resting rooms and refectory should be separated from other areas.

4.6.2.   衣服存放间、衣帽间和厕所应便于进入，供使用的人数合理。厕所设施不得与生产和仓库直接连通。并且一直保持清洁和消毒。  

Clothing rooms, cloakrooms and toilet facilities should be easily accessed and proper for the number of users. The toilet facilities should not have direct communication with the production and storage areas. They should always be clean and sanitized.

4.6.3. 维修区应该设在生产区、质量控制区和其他地区以外的地方。需要在生产区存放和更换的零部件应放在指定的地方并且标识好。

The maintenance areas should be situated in separate locations of the production areas, Quality Control and other areas. If tools and replacement pieces are kept in production areas, they should be in reserved locations and perfectly identified for this purpose.

4.8.     公共设施

Utilities

4.8.1. 影响产品质量的所有公共设施（蒸汽、压缩空气、热空气、通风和空调）应该进行标识、确认和合理监控。在超出规定范围的情况下采取纠正措施。All utilities that interfere with the product quality (steam, gases, compressed and heated air, ventilation and air conditioned) should be identified qualified, and properly monitored, and it should be adopted corrective actions when they are out of specified limits.

4.8.2. 公共设施的图纸在需要时应能够提供，并提供最新的。

Utility blueprints should be updated and available when solicited.

4.8.3. 应该有合理的通风、空气过滤器、排风系统和设备，这些系统的设计和制造应该能够最大程度减少污染和交叉污染，特别是在中间品和药物活性成分暴露在外的区域里。

There should be ventilation, air filter and exhaustion systems and equipments, when appropriate. These systems should be designed and built in order to minimize risk of contaminations and cross-contamination, specially, in the areas where intermediates and active pharmaceutical inputs are exposed to the environment.

4.8.4.   生产区的空气如果存在再循环，应该采取得当措施最大程度减少污染和交叉污染。

            When air is recirculated in production areas, it should be taken adequate measures for minimizing risk of contamination and cross-contamination.

4.8.5. 对于永久性安装的管道应正确标识。可以通过标明专用管道线、文件、电脑控制系统和其他方法满足上述要求。管道的位置应避免中间品和药物活性成分的污染。Piping permanently installed should be correctly identified. This can be accomplished for identification of individual lines, documentation, computerized control systems or alternative means. Piping should be located to avoid risk of contaminations of intermediates and active pharmaceutical inputs.

4.9.     水

Water

4.9.1. 对于生产中间品和药物活性成分的用水质量的最低要求是饮用水。

The minimum acceptable quality of water used for manufacturing of intermediates and active pharmaceutical inputs should be drinkable.

4.9.2. 根据相关的法规对生产中间品和药物活性成分的用水进行监控，满足使用要求。

The water used in the manufacturing of intermediates and active pharmaceutical inputs should be monitored and adequate to its intended use, according to the actual legislation.

4.9.3. 工艺用水如果由生产厂家处理，处理系统应该得到验证和监控。

When the water used in the process is treated by the manufacturer, the treatment system should be validated and monitored.

4.9.4. When the manufacturer of a non-sterile active pharmaceutical input intends to commercialize it for manufacturing of sterile drugs, the water employed in the final steps of isolation and purification should be monitored and controlled for total microbial counting and endotoxins.

4.9.5.   用水的检验结果如果超出相关法律规定的限度，应对原因进行调查，并采取预防和纠正措施，做好记录。

            When analytical test results of the potable water are over the limits established by the actual legislation, the causes should be examined and preventive and corrective actions identified and recorded..

4.10.   卫生处理

Sanitation

4.10.1. 生产中间品和药物活性成分使用的厂房应该保持清洁，并进行合理的卫生处理。

Buildings used for manufacturing of intermediates and active pharmaceutical inputs should be kept in conditions of cleaning and adequate sanitation.

4.10.2. 应该建立书面的程序，包括清洁厂房和设施的责任、清洁和卫生处理计划、方法和使用的设备和材料。

Written procedures should be established, containing responsibilities, cleaning and sanitation schedules, methods, equipments and materials to be used for cleaning of buildings and facilities.

4.10.3. 为防止设备、原材料、包装和标签、中间品和药物活性成分遭到污染而使用的清洁剂和消毒剂应有书面的使用程序。

Written procedures should be established for use of rodenticide, insecticide, fungicide, fumigants, sanitizing and cleaning agents used to prevent contamination of equipments, raw materials, packaging and labeling material, intermediates and active pharmaceutical inputs.

4.11.   废物处理

Waste Management

4.11.1. 应根据治理环境污染的相关法律和法规建立书面程序，规定固体、液体或气体废物的处理。并使所有的操作人员了解。

There should be written procedures for destination of solid, liquid or gaseous effluents, according to rules and legislations that regulate environmental pollution, to which should be previous knowledge of all the personnel working with effluents.

4.11.2. 生产、厂房和周围地区产生的固体、液体或气体废物应采用安全和卫生的方式处理。废弃物料使用的容器和管道应该标识好。

Solid, liquid or gaseous effluents resulting from manufacturing, buildings and surrounded areas should be disposed in a safe and sanitary way until its destination. Containers and piping for discard material should be identified.

4.11.3. 废水和废物应按照其特征进行标识和分类，确定废物和废水的排放地点、实施的处理。对于处理的情况和频率进行记录。

Effluents and wastes should be identified and classified according to its nature. There should established destination, performed controls and release location of waste according to its nature. There should established destination, performed controls and release location of waste and treated effluents. It should be recorded the performed controls and its frequency.

5.         设备

EQUIPMENTS

5.1.     概述

General

5.1.1. 生产中间品和药物活性成分所使用的设备应该设计为合理的尺寸和布局，方便使用、清洁、卫生处理和维护。

Equipments used for manufacturing of intermediates and active pharmaceutical inputs should be designed, have adequate dimensions and location that facilitate the use, cleaning, sanitation and maintenance.

5.1.2. 设备的制造应该使表面在与中间品和原材料接触时不改变药物活性成分的质量。

Equipments should be built in a way that surfaces contact with raw materials and intermediates do not alter the quality of active pharmaceutical inputs.

5.1.3.   应建立设备确认。There should be established equipment qualification

5.1.4. 应该对生产设备进行标识Equipments from the production unit should be identified.

5.1.5. 与设备操作有关的物质如果能改变中间品和药物活性成分的质量不得与中间品和药物活性成分接触。对此操作出现的任何偏差进行调查，保证不会损害中间品和药物活性成分的生产和质量。  Substances involved with equipment operation and that can alter the quality of intermediates and active pharmaceutical inputs should not contact these ones. Any deviation away from this practice should be evaluated and assured to not damage manufacturing and quality of intermediates and active pharmaceutical inputs.

5.1.6. 设备和容器应该尽可能在封闭的状态下使用，如果需要打开，应该采取措施避免污染的风险。

Whenever it is possible, equipments and containers should be used closed. When they are open, it should be adopted procedures in order to avoid risk of contamination.

5.1.7.  不使用的和／或有缺陷的设备应立刻标识好，并从生产和质量控制区搬走。Equipments not being used and/or defective should be immediately identified, and they should be removed from Production and Quality Control areas as soon as its inutility is proved.

5.2.     设备维护和清洁

Equipment Maintenance and Cleaning

5.2.1. 应该建立计划和程序对设备进行预防性和纠正性维护，包括维护的责任，并对维护进行记录。

There should be established schedules and procedures for preventive and corrective maintenance of equipments, including responsibilities for maintenance. Maintenance should be recorded.

5.2.2. 应建立书面的设备清洁、卫生处理和投放使用的程序。程序应包括进行有效清洁的要求，至少涉及下列方面：

There should be established written procedures of equipment cleaning and sanitation and its release subsequent for its use in production. Procedures should contain instructions for allowing cleaning in a reproductive and efficacious way. It should be included in the procedures, at least:

(a)  设备清洁和卫生处理的责任划分

attribution of responsibility for equipment cleaning and sanitation;

(b)  清洁计划，包括卫生处理

cleaning schedules, including, when appropriate, sanitation;

(c)  对清洁方法和材料的完整描述，包括清洁剂的稀释。

complete description of methods and materials, including dilution of cleaning agents used;

(d) 为保证设备清洁和卫生处理的效果对其拆卸和重装的合理要求。

when appropriate instructions for disassemble and reassemble each equipment part in order to assure cleaning and sanitation;

(e)  批生产结束后设备的投放要求i

nstructions for release of equipment release after production of a lot;

(f)  清洁后设备的保护要求

instructions for equipment protection after cleaning;

(g)  设备使用后的检查和投放

checking and release of equipments after use;

(h)   确定过程结束和设备清洁之间的最长时间，这对清洁程序很重要

establish maximum time between process conclusion and equipment cleaning since it is significant for the cleaning procedure;

(i)  确定设备清洁和下次使用之间的最长时间，以及要重新评估的参数。

      establish maximum time between equipment cleaning and next use as well as which parameters should be reevaluated.

5.2.3.      对器具进行清洁、存储和合理的消毒以防止污染

utensils should be cleaned, stored and, when appropriate, sanitized or sterilized for preventing contamination.

5.2.4. 在连续生产不同批次的同种产品时，设备的清洁应有合理的间隔时间

It should be performed equipment cleaning in proper intervals, when it occurs to continuous production of the same product of different lots.

5.2.5. 在生产不同产品的过程中，应该清洁非专用的设备，防止交叉污染。Non-dedicated equipment should be cleaned between the manufacturing of different products for prevent cross-contamination

5.2.6.   应确定废物控制范围和清洁剂的选用标准。

            There should be established acceptance criteria for waste limits and selection of cleaning agents.

5.2.7. 应按照清洁状态对设备进行标识

Equipment should be identified according to its cleaning condition.

5.3.     校验

Calibration

5.3.1. 质量控制、称重、测量和监控所使用的设备应该按照书面程序和确定的计划进行校验。

Equipments used in Quality Control, weighting, measurement and monitoring should be calibrated according to written procedures and established schedule.

5.3.2. 设备的校验应使用的检定的标准或来源于检定标准的标准进行。

Equipment calibrations should be performed using certified patterns or traceable patterns to the certified patterns.

5.3.3. 校验记录应该保存

Calibration records should be kept.

5.3.4. 应了解实际的校验状态，并进行检查。

The actual calibration status should be known and susceptible of checking.

5.3.5. 称重和测量仪器只有在校验后才能使用

Weighting and measuring instruments should only be used when they are calibrated.

5.3.6. 设备如果与检定标准出现偏差应进行调查，确定偏差是否对中间品和药物活性成分的质量产生了影响。

Deviations originated from patterns of approved instruments should be investigated, for determining if these can have effect on quality of intermediate and pharmaceutical input.

5.4.     计算机化系统

Computerized Systems

5.4.1. 与良好生产实践相关的计算机化系统应该进行验证，并考虑各种参数，信息化应用的复杂性和关键条件。Computerized systems related to the Good Manufacturing Practices should be validated, considering parameters of diversity, complexity and critical condition of the informatized application.

5.4.2.   根据使用电脑的软件和硬件，保持合理的运行设施和运行确认。It should be kept proper operational facilities and qualifications according to the hardware and software of used computer.

5.4.3.  对计算机化系统进行充分的控制防止对数据的随意改动。并且避免每次改变的疏漏，记录每次改变，包括数据输入。

Computerized systems should have sufficient controls to prevent access or non-authorized changes to the database. Controls should prevent omissions and process record of each change performed including data input, responsible and when it was made.

5.4.4. 电脑系统的操作和维护人员应该有书面的程序供使用

Written procedures should be available to the responsible persons of operation and maintenance of computerized systems.

5.4.5. 人工记录的数据应有第二个负责人进行核实

Manually recorded data should be verified by a second responsible person.

5.4.6. 对与计算机化系统有关的影响中间品和药物活性成分的质量、记录和实验结果可靠性的事件，应该调查和记录。

Incidents related to computerized systems that can affect the quality of intermediates and active pharmaceutical inputs and reliability of records or from test results should be recorded and investigated.

5.4.7.   应该按照更改程序对电脑系统进行更改，更改需要得到正式的批准，并记录和测试。每次更改的记录应该保存，包括对系统进行改造和提高。这些记录应该表明系统经过验证。

            Change in the computerized systems should be made according to the procedure for changing and should be formally authorized, documented and tested. Records of every change should be kept, including modifications and improvements performed in the system. These records should show that the system is validated.

5.4.8        若发生系统故障造成记录结果丢失的情况，应使用备用的系统，保证数据安全的方法应在所有的电脑系统中确定下来。

When system failures occur and these result in record loss, an alternative system should be supplied. Means to assure the data protection should be established for all computerized systems.

6.    文件和记录

DOCUMENTATION AND RECORDS

6.1.      概述  General

6.1.1.  文件是质量体系的基本构成部分，应涉及到GMP的各方面。其目标是为生产和质量控制使用的所有物料和方法确定标准，以保证所有生产人员了解其责任，并能获得相关的信息。另外，它除了能对任何可疑批次的质量偏差进行追诉和调查外，还能最终保证授权人员获得所有必要的信息，确定销售的中间品或者药物活性成分是否已经放行或者没有作出决定。每一个文件可以放在在同一个大文件中，或者分别存放，但要便于查找，成为生产批记录的组成部分。

Documentation constitutes essential part of the Quality system and it should be related to every GMP aspects. It has as a goal define specifications of all materials and methods of manufacturing and control, in order to assure that all personnel involved in the manufacturing know its attributions and it has access to the involved information. Additionally, it has the finality to guarantee that the authorized person has all necessary information to decide if it's released or non-determined lot of intermediate or pharmaceutical input to selling, in addition to enable tracing and investigation of any suspected lot of quality deviation. Every document may be joined in the same file, or remain separate, easily available, constituting the record of the manufacturing lot

6.1.2.     数据的记录应采用可靠的方法，如人工、电子处理系统和其他方法。应该建立与质量体系有关的标准／主配方和程序。如果数据记录通过电子处理的方式进行，只由指定的人员才能修改电脑中的数据。对数据的更改应进行记录。使用密码和其他方法限制电脑的使用。关键数据的输入

应指定记录人以外的人员操作，使用磁盘、胶卷、打印纸张和其他介

质上的备份来保护批数据的电子记录。

Data should be recorded in a reliable way, manually, electronic processing system or other means. Standard/master formulas and procedures related to the system in use should be available, as well as the data precision recorder conferred. If the data record is made by means of electronic processing, only assigned persons can modify filed date into the computers. There should be recording of performed alterations. The access to computers should be restricted by passwords or other means. The data input considered critical should be conferred by an assigned person, different from that one that made the records. Electronic records of lot data should be protected by copy transference of copies in magnetic tape, microfilm, paper printing or other mean.

6.2.      文件体系和标准  Documentation System and Specifications

6.2.1.  与中间品和药物活性成分相关的所有文件应按照书面的程序起草、复核、更新和分发。正本文件可以采用书面、电子介质和其他适当的方式存档。

Every documentation related to manufacturing of intermediates and/or active pharmaceutical inputs should be prepared, reviewed, approved, updated and distributed according to written procedures. Original documents can be in paper formulary, electronic media or other adequate forms of document filing.

6.2.2.  对文件不得涂改。文件应该由具体的负责人签字。更改的记录应该能看清楚上次的数据，并由负责人签字和注明日期。

Documents should not be blotted out. They should be available signed by the respective responsible persons. Altered records should enable the identification of the last data, should be signed and dated by the responsible.

6.2.3.  数据记录应在完成工作后立刻填写，并注明操作负责人。记录的修改应注明日期并签字。原来的记录应保持清晰可读。

Record data should be filled in the respective blanks, immediately after executed the activities and should identify the responsible person by the performance. Corrections should be dated, signed and the original records should remain legible.

6.2.4.  控制文件的起草、复核、更换、撤回和分发。对正本文件应定期评估和更新，保留评估记录。应有防止错误使用旧版本文件的体系。Emission, review, replacement, withdrawal and distribution of documents should be controlled. Original documents should be regularly reviewed and updated, keeping review history. There should be a system preventing inadvertent use of the last version.

6.2.5.  文件和记录应该保留，保留期限在程序中规定

Documents and records should be retained and the retention period should be established in procedures.

6.2.6.  各种生产、质量控制和发货记录应在该批产品有效期满后保留至少一年Every production, control and distribution records should be retained for at least 1(one) year after the lot expiration date.

6.2.7.  在保留期内，文件和记录可以采用原件的形式或者复印间的形势保存。During the retention period, documents and records should be retained as originals or as copies in case of third party's documents.

6.2.8.  建立生产过程中使用的原材料、中间品、药物活性成分、包装和标签材料以及其他材料的规格、检验方法和验收标准，并形成文件。Specifications, analytical methodologies and acceptance criteria should be established and documented for raw materials, intermediates, active pharmaceutical inputs, packaging and labeling materials and other materials used during the manufacturing of intermediates and active pharmaceutical inputs.

6.2.9.  对于文件中使用的电子签名应进行确认。

When electronic signatures are used in documents, these should be authenticated and safe.

6.3.      设备清洁、卫生、消毒、维护和使用记录

Records of Cleaning, Sanitation, Sterilization, Maintenance and Equipment Use.

6.3.1.  设备的使用、清洁、卫生、消毒和维护记录应标明时间、上次操作的产品、产品批号以及清洁和维护人员的身份。记录应该能够追溯，便于查找。

Record of use, cleaning, sanitation an/or sterilization and maintenance of equipments should present date, time, last product, actual product (when applicable) and lot number of each processed intermediate or pharmaceutical input, as well as the identification of the individual that executed the cleaning and the maintenance. Records should be traceable and be promptly available.

6.3.2.  应该有设备的清洁、卫生、消毒和维护记录，记录以附件的形式和或者附在生产指令上面。

Records of cleaning, sanitation and/or sterilization and maintenance should be available in the equipment and transcript and/or annexed to the production order, when it's utilized.

6.4.      原材料、中间品、活性药物成分、包装和标签的规格

Raw Material, Intermediates, active Pharmaceutical Inputs, Packaging and Labeling Materials Specifications

6.4.1.  说明主要包装材料和印刷材料的规格，至少包括：

Specification of primary packaging materials and printed materials should have a description, including, at least:

(a) 名称和内部参考代码  name and in-house reference code;

(b) 质量和数量方面的验收标准  quantitative and qualitative requisites with respective acceptance limits;

(c) 印刷材料的样本  printed material model and

(d) 存储条件  storage conditions;

6.4.2.  说明原材料、中间品和药物活性成分的标准，包括：

Specification of raw materials, intermediates and active pharmaceutical inputs should have a description of:

(a) 原材料和药物成分的名称以及各自的识别码

name of raw material or pharmaceutical input according to DCB, DCI or CAS (compulsorily in this order), when applicable and its respective identification code;

(b) 药典中的专论，如果没有正式的参考文献，应提供研发的验证的标准和方法。

pharmacopeial monograph reference. Case there is no official compendium references, present developed and validated specifications and methodologies;  

(c) 质量和数量方面的验收标准

quantitative and qualitative requisites with respective acceptance limits;

(d) 存储条件   storage conditions;

(e) 化学结构和分子式

chemical structure and molecular formula, when applicable;

(f)  中间品名称  intermediate name, when applicable;

(g) 物理形式  physical form.

6.4.3.  包装材料应该满足标准，与里面的中间品和药物成分相容。

Packaging materials should satisfy specifications emphasizing the compatibility of these materials with intermediate and pharmaceutical input contained in them

6.4.4.  检验程序应注明在每种原材料有效期内进行检验的频率。

Procedures of control assay should indicate the frequency with which new assays should be performed of each raw material within its expiration date.

6.4.5.  在购买中间品或发货时或需要使用相关的数据评估成品时，应该有可用的标准。

pecifications for intermediates should be available whenever these materials are acquired or shipped, or if, when data on intermediates have to be used to evaluate the final product.

6.5.      合成路线   Route of Synthesis

6.5.1.  有必要确定合成路线

It's necessary to define the route of synthesis.

6.5.2.  有必要了解合成路线中分子的立体化学行为。

Its necessary to know the sterochemical behavior of the molecules of the route of synthesis, when applicable.

6.5.3.  It's necessary to identify the chiral centers of the molecule and the pharmacological differences between isomers, when applicable.

6.5.4.  In case of chiral molecules, having an isomer with adverse pharmacological effect, should be presented a validated methodology of analysis, able to detect that this isomer is within the specified limits.

6.5.5.  需要规定过程控制   It's required to define in-process controls.

6.5.6.  应该由中间品和药物活性成分的技术信息

There should be technical information referring to intermediates and active pharmaceutical inputs:

(a) 合成路线  route of synthesis;

(b) 中间品分子和纯化的描述

description of intermediate molecules and purification;

(c) 使用的催化剂  catalisers utilized;

(d) 主要污染物的数量和限度

quantification and limit of the main contaminants;

(e) 与使用的有机和无机溶剂的关系

relation to organic and inorganic solvents utilized;

(f)  药物成分中溶剂废物的限度

limit of solvent wastes in the pharmaceutical input;

(g) 关键步骤的描述  description of critical steps;

(h) 合成控制参数   parameter of synthesis control;

(i)  使用的检验方法   analytical methods utilized;

(j)  异构体含量数据  data on isomer contents;

(k) 异构体检测形式   forms of detection utilized for isomers;

(l)  可能的多形体和检测方法  probable polymorphs and methods of detection utilized;

(m)   收率   yield;

(n) 原材料控制参数  parameters of control of raw material;

(o) 用水的类型  type of utilized water;

(p) 成品的物理状况  physical status of the finished product;

(q) 是否符合有关疯牛病的法律法规

  fulfillment to the actual sanitary legislation concerning bovine spongiform encephalopathy, when applicable;  

(r)  是否符合有关其他污染物的法律法规。

fulfillment to the actual sanitary legislation concerning other contaminants whose risks or malefic effects were proved, when applicable;

6.6       标准／主配方  Standard/Master Formula

6.6.1.  每个生产批次应该有批准的标准／主配方

There should be an authorized standard/master formula for each lot size to be manufactured.

6.6.2.  中间品和药物活性成分的标准／主配方应该有一个负责人确定、签字和注明日期，并由质量部门批准，注明日期。

The standard/master formula of each intermediate or active pharmaceutical input should be elaborated, dated, signed by a responsible person and be approved and dated by the Quality Unit.

6.6.3.  标准／主配方应包括   Standard/master formula should include:

(a) 中间品或药物成分的名称以及内部参考代码

name of the intermediate or pharmaceutical input what is manufactured and an in-house reference code;

(b) 批量  lot size;

(c) 按照名称和具体代码确定原材料、中间品和包装材料的完整清单

complete list of raw materials, intermediates and packaging materials assigned by names or specific codes;

(d) 准确注明使用的原材料或中间品的数量或关系，包括计量单位。数量的差异应该证明。

exact indication of the amount or relation of each raw material or intermediate to be used, including measuring unit. Variations in the included amounts should be justified;

(e) 使用的生产设备  location and production equipments to be utilized and

(f)  详细生产要求，包括  detailed instructions of production, including;

- 遵循的的生产次序  sequences to be followed;

- 运行参数  operational parameters;

- 取样说明和过程控制以及各自的验收标准

sampling instructions and in-process controls with its respective acceptance criteria;

- 各道工序和整个工艺完成的时间限制

time limits for conclusion of individual steps of individual process and/or total process;

- 工艺的预期收率  expected yield in proper phases of the process;

- 说明和需要特别注意的地方或者相关的参考

remarks and special precautions to be followed, or respective references related to them and;

-  中间品或药物成分的存储要求，包括包装和标签材料，特殊的存储条件，并规定操作的极限时间。

instructions for storage of the intermediate or pharmaceutical input for assuring its proper use, including packaging and labeling materials, and special storage conditions with definition of limit time for operation.

6.6.4.  过期的标准／主配方应从实际文件中去掉，但应根据确定的标准归档参考。

Obsolete standard/master formulas should be removed from use as actual document, however they should be filed as reference according to established criteria.

6.7.      生产批记录  Production Lot Records

6.7.1.  每批中间品和药物成分应该具有生产记录。产品在发货前应对生产指令进行确认，以保证使用了正确的标准／主配方。药物成分的批记录应具有可追溯性。

Each lot of intermediate or pharmaceutical input should  have its production record. The production order of the lot should be verified before shipping, in order to assure that it is the correct version of the standard/master formula. The lot record of pharmaceutical input should enable its traceability

6.7.2.  批生产记录应采用单一的批号或识别号编码、注明日期，并签字。在连续生产中，可使用产品代码以及时间和日期来标识产品直到获得最终的编码为止。

Production records of the lot should be coded with a single lot number or identification, dated and to be signed when issued. In the continuous production, the product code along with the date and time can be used as identifier until the final number is allocated

6.7.3.     生产批记录中各工序文件应包括：

Documentation of each step in the records of lot production should include:

每道工序开始和结束的时间

dates and times of beginning and end of each step, when applicable.

标明使用的设备 identification of equipments utilized;

生产中重新加工的原材料、中间品或其它材料数量、检验和批号amount, analytical control and lot numbers of raw material, intermediates or any utilized material reprocessed during production;

关键工序的参数记录  recorded results for parameters of critical processes;   

取样    any performed sampling;

再循环的物料和使用的程序any recovered material and applied procedures;

执行每道工序的人员签字，评估确认人员的签字。

ignatures of personnel executing each step and, in the critical steps, also signatures of personnel supervising and verifying;

过程控制和实验室检验的结果

results from in-process control and lab tests;

在合理的期限内预期和实际的收益

expected and actual yield in proper phases or periods;

根据批生产指令进行的包装记录

record of packaging performed in accordance to the instruction of the lot manufacturing;

药物成分和中间品销售使用的标签

epresentative label of pharmaceutical input or intermediate when done for

commercialization;

对生产和质量控制记录进行复核，分析和调查任何偏差。对关键偏差认真调查。调查应扩大到与偏差有关的同一种产品的其他批次或其他产品，必要时应记录调查结果。记录应包括结论和采取的措施。

records of manufacturing and control should be reviewed, and any deviation should be analyzed and investigated. Critical deviations should be judiciously investigated. The investigation should be extended to other lots of the same product and other products that may be associated to the deviation, when necessary, should be done a record about the investigation result, and such record should include conclusions and provisions taken;

放行检验的结果

results from release tests;

申请领取但没有使用的物料批号和数量

lot number and amount of any material required and not utilized;

生产中发现的其他相关事件

any relevant occurrence observed in the production.

6.7.4.  应建立书面程序调查中间品或药物成分的偏差，调查应扩大到可能受偏差影响的其他批次。

Written procedures should be established and followed in order to investigate deviations of a lot of intermediate or pharmaceutical input out of specifications. The investigation should be extended to other lots that may be affected with the deviation.

6.8.      质量控制记录   Quality Control Records

6.8.1.  质量控制记录应该包括从每次实验中取得的完整数据：

Quality Control records should include complete data obtained from every test, containing

描述实验使用的样品，包括名称、批号或其它明显的代码、取样日期、

数量、检验日期、生产厂家和来源。

description of samples received for test, including name, lot number or other distinct code, collect date, amount, test date, manufacturer and origin, supplier and provenience (if there is);

说明使用的每种检验方法

indication or reference of each method of test utilized

每次实验中获得的完整数据记录，包括、图示、打印的摘要和仪器图

谱，并标明检验的物料和批次。

complete record of every data generated during each test, including

calculation, graphics, printed extracts and instrumentation spectra, with

identification of material and lot analyzed.

检验结果和确定的验收标准 test results and established acceptance limits;

标明检验人员和检验日期

identification of the individual who executed each analysis and date when the

analysis was performed;

记录复核人员和日期

date and identification of the responsible for review of records

6.8.2     对记录进行保存以便 It should be kept for:

改进建立的检验方法

modification of an established analytical method;

定期校验仪器和设备

periodic calibration of instruments and equipments;

中间品和药物活性成分的稳定性试验

stability tests of intermediates and active pharmaceutical products;

调查不合格结果

investigation of results out of specification

6.9. 批记录评审  Lot Record Review

6.9.1.  中间品和药物活性成分的批记录评审应包括所有相关的因素，如生产条件、过程控制结果、生产文件、满足的标准和最终包装的检验。

The evaluation of intermediates and active pharmaceutical inputs should include all relevant factors, including production conditions, results from in-process control, manufacturing documents, fulfillment of specifications and test of the final packaging.

6.9.2.  关键工序和实验室控制的记录应经质量部门复核和批准，然后放行或发货。

            Records of critical steps of the process and lab control should be reviewed and approved by the Quality Unit before a lot of pharmaceutical input is released or shipped.

6.9.3.  对不合格结果和质量偏差的调查报告进行评估，作为复核生产批记录的组成部分。

Investigation report of results out of specification and deviation away from the quality should be evaluated as part of review of lot production records.

6.9.4.  生产批记录的复核应包括对质量偏差的调查。Review of lot record should contemplate investigation of quality deviations.

No record review by production!!!

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7.         物料控制   MATERIAL CONTROL

7.1.      一般控制   General Controls

7.1.1.  根据书面程序接收、标识、存储、取样和检验原材料。

Raw materials should be received, identified, stored, put in quarantine sampled, analyzed as established specifications and identified concerning its status (approved or rejected), according to written procedures.

7.1.2.  原材料只能从合格供应商采购，并具有规格标准。

Raw materials should only be acquired from qualified suppliers and they should be in the list of specifications

7.1.3.  应有书面程序规定物料的接收、标识、待检、存储、取样、搬运、检验和批准或拒绝。

There should be written procedures for receipt, identification, quarantine, storage, sampling, handling, tests and approval or rejection of materials.

7.1.4.  中间品和／或药物活性成分的生产厂家应该对所有材料供应商的资格进行确认。

Manufacturers of intermediates and/or active pharmaceutical inputs should have a program to qualify material suppliers.  (ALL MATERIALS)

7.1.5.  物料根据标准从经质量部门确认合格的的供应商采购

Materials should be acquired according to a specification and from qualified supplier(s) by the Quality Unit.

7.1.6.  采购材料的标识至少应包括

Identification of acquired materials should have, at least:

a)   生产厂家名称、地址和电话

manufacturer's name, C.N.P.J. [National Directory of Legal Entities] (when applicable), address and telephone;

b)  供应商名称、地址和电话

supplier's name, C.N.P.J. [National Directory of Legal Entities] (when applicable), address and telephone (if any);

c)   物料名称

material name (DCB, DCI or CAS), compulsorily in this order, when possible;

d)  生产厂家的批号。manufacturer's lot number;

e)   供应商的批号   supplier's lot number, when applicable;

f)   生产日期   manufacturing date;

g)   有效期   expiration date;

h)  数量和各自的计量单位  amount and its respective measure unit;

i)   存储条件   storage conditions;

j)   安全警告   security warnings, when applicable

7.2.      接收和待检   Receipt and Quarantine

7.2.1.  对收到的材料进行确认，保证发货与订单相符合。确认后入库前，对物料的容器进行目测，检查标识是否正确，内部使用的名称和生产厂家名称是否一致，容器的状况、密封是否破损，是否有其他污染的情况。Every material received should be verified in a way to assure that delivery is in conformity with the order. After verifying and before entering the stockroom, every container or group of containers of materials should be visually inspected for correct identification and correlation between the name employed in-house and by the manufacturer (or supplier, if any), container condition, broken seals and other evidences of adulteration or contamination.

7.2.2.  所有的物料在入库后应立即放在待检区域，直到被质量控制部门批准。Every material should be kept in quarantine, immediately after its receipt, until they are approved by the Quality Control.

7.2.3. 若发来的原材料由生产厂家的不同批次构成，应对每一个批次取样，分别检验和放行。

            When a delivery of raw material is composed by different lots from a same manufacturer (or supplier, if any), each lot should be considered separately for sampling, analysis and release.

7.2.4.  对容器的破损或其它可能影响物料质量的问题应进行记录和调查Damages in containers or any other problems occurring that may affect the material quality should be recorded and investigated.

7.2.5.  对于需要跟现有库存进行混合的物料，应进行标识、取样和检验。只有在批准后才能将物料加入库存。

Materials to be mixed to preexistent stock should be identified, sampled, analyzed and only can be incorporated into the stock after approval.

7.2.6.  如果发货使用非专用的容器，应采用下列方式，保证不会有交叉污染：When deliveries are transported in non-dedicated containers, there should be a guarantee that there will not be cross-contamination, by means of:

(a) 清洁和卫生处理证明 cleaning and/or sanitation certificate;

(b) 杂质检测 test of impurities.

7.2.7.  大的容器存放和卸载地点应合理标识

Big containers of storage and discharge location should be properly identified.

7.2.8.  对物料的容器分别标识，确保可追溯性。至少应使用下列信息

Material containers should be identified, individually, or according to other adopted system by the company in order to guarantee traceability. At least, the following information should be available:

(a) 物料名称和内部参考代码。

name of the material and respective in-house reference code, if the company has established the system;

(b) 生产厂家提供的批号和公司接收货物时提供的批号

lot number attributed by the manufacturer/supplier when existing and the number given by the company when receiving;

(c) 每批的状态（待检、批准或拒收）

status, condition of each lot (in quarantine, approved or rejected).

7.3.      生产前对物料取样和检测

Material Sampling and Analysis before Production

7.3.1.  对收到的每批物料进行检验确认其质量。原材料由于具有危险的特征而不能检测的应获得生产厂家的检验报告，在质量控制记录中存档。

A test for verifying the identity of each lot of the received material should be performed. Raw materials that can't be analyzed due to its hazardous nature should have the manufacturer's Certificate of Analysis, which will be filed in the records of the Quality Control.

7.3.2.  物料的样品应具有代表性

Samples should be representative of a lot of the material received.

7.3.3.  取样容器的数量和取样数量应根据取样计划确定。

The number of sampled containers and the sample size should be based on a sampling plan.

7.3.4.  只有经质量部门放行的原材料才能用于生产中间品或药物成分

Only released raw materials by the Quality Unit may be used for manufacturing an intermediate or pharmaceutical input.

7.3.5.  取样应该在规定的地方按照适当的环境条件遵循批准的程序进行，防止交叉污染。

Sampling should be conducted in defined locations to prevent cross-contamination under adequate environmental conditions and obeying approved procedures

7.3.6.  取样过程中使用的设备如果与物料接触应进行清洁，必要时进行卫生处理和消毒，放在合适的地方。

Every equipment used in the sampling process that has contact with the materials should be cleaned, and, if necessary, sanitized and sterilized and kept in proper locations.

7.3.7.  每一个盛有样品的的容器应进行标识，包含下列信息：

Each container containing sample should be identified and should have the following information:

(a) 取样物料的名称  name of the sampled material;

(b) 批号   lot number;

(c) 取样容器的数量   number of the sampled container;

(d) 取样人员的签字   signature of the person who collected the sample;

(e) 取样日期   date in which the sample was collected.

7.3.8.  取样的容器应作标识  The container sampled should be identified.

7.4.      储存

Storage

7.4.1.  中间品和药物活性成分应按照生产厂家在稳定性研究基础上确定的条件存储。

Intermediates and active pharmaceutical inputs should be stored in established conditions for the manufacturer, based on stability studies.

7.4.2.  物料的搬运和储存需要防止物料变质和污染。

Materials should be handled and stored to prevent degradation and contamination.

7.4.3.  物料应离开地面和墙面存放，并有合理的清洁和检查空间。

Materials should be stored away from the floor (ALL!!!) and walls, with proper space for allowing cleaning and inspection

7.4.4.  物料的存放条件和期限须保证其质量。库存管理应按照先到期先出库的原则。

Materials should be stored under conditions and adequate periods in a way to preserve its integrity and identity. The stock should be controlled in a way that the turnover obeys the rule: first-to-expire, first-out (FEFO).

7.4.5.  危险性物料应存放在安全的地方，根据相关规定及时隔离和标识。Highly active materials, substances that present risks of dependency, fire or explosion and other hazardous substances should be stored in safe and protected areas, duly segregated and identified, according to actual specific legislation.

7.4.6.  对拒收的材料进行标识、隔离和控制，防止被使用。

Rejected materials should be identified, segregated and controlled to prevent its use.

8.                  生产和过程控制

PRODUCTION AND IN-PROCESS CONTROLS

            生产操作应按照明确规定的程序进行。在生产前应确认和记录设备和现场是否有上次生产的产品，工序所使用的文件和物料是否准备好，设备是否清洁和适合使用。

Production operations should follow clearly defined procedures. Before the production is initiated, it should be verified and recorded if equipments and worksite are free of products manufactured before, and if documents and needed materials for the planned process are available. Additionally, it should be verified if equipments are clean and adequate for use.

8.1.      生产程序  Procedures for Production

8.1.1.  生产应按照标准／主配方进行

Production should be conducted according to the Standard/Master Formula.

8.1.2.  应规定和验证中间品和药物成分的关键生产工序。

Critical steps for the quality of the intermediate and pharmaceutical input should be defined and validated.

8.1.3.  生产由合格的受过训练的人员完成

Production should be conducted for qualified and trained personnel.

8.1.4.  在整个生产中，使用产品名称、批号和生产步骤对容器、物料、设备和区域进行标识

            During the whole production, containers, materials, equipments and area (when applicable) should be identified, with the name of the product, the lot number and the step of production.

8.1.5.  所有物料和产品的搬运应按照书面程序进行，并记录。

All handling of material and product should be executed according to written procedures and be recorded.

8.1.6.  对于发生的任何影响物料质量的问题应进行记录并通知生产负责人采取措施。

The occurrence of any problem that can put in risk the quality of materials, it should be recorded and informed to the responsible for production for pertinent measures.

8.1.7.  需要进行物料一致性检查并记录。对任何偏差进行调查和记录。Material reconciliations should be performed and recorded. Any deviation should be investigated and recorded

8.1.8.  未经授权的人员不得进入生产区

Access to production areas should be restricted to authorized persons.

8.1.9.  相关生产工序的实际收率应该与预期收益率作比较。根据产品研发、试生产、工艺验证和生产历史确定预期收率和验收标准。

Actual yields should be compared to the expected yields in the defined steps of the production process. Expected yields and acceptance limits should be established based on product development, pilot scale, validation of the process and production history.

8.1.10.对所有的偏差进行记录和调查。对关键偏差进行调查，采取纠正措施并记录

Every deviation should be documented and investigated. Every critical deviation should be investigated and corrective actions should be implemented and recorded.

8.1.11.采用文件或者电脑系统标明各种设备的相关工序

Process steps should be indicated in the individual equipments, by documentation and/or computerized systems.

8.1.12.对重新加工和返工的物料进行合理标识，注明产品名称、数量、情况、要完成的操作、操作人员和日期，并放在指定的地方。应有一套系统和程序防止未经许可使用物料。

Materials to be reprocessed or reworked should be adequately identified for product name, amount, situation, operation to be executed, operator's identification, date and stored in defined location. There should be a system or procedure of security that prevents its non-authorized use.

8.2.      原材料  Raw Materials

8.2.1.  原材料应按照程序和规定的条件称重或测量。天平和测量装置应适合使用

Raw materials should be weighted or measures under defined conditions in procedure. Balances and measuring devices should be adequate for the intended use.

8.2.2.  对于在以后生产中使用的物料，应使用相容的容器包装，并使用下列信息标识：

When a material is subdivided for later use in production, it should be packed in a compatible container and be identified with the following information:

(a) 物料的名称或识别码 name of the material and/or identification code;

(b) 控制或接收编号 control or receipt number, when applicable;

(c) 物料的数量 amount of the material in the container;

(d) 最长使用时间 maximum time for use;

(e) 容器的总数量 number of container/total number of containers;

(f)  来源批次的情况 identification of the origin lot;

(g) 存储条件和注意事项 conditions and precautions of storage.

8.2.3.  对关键物料的称重、测量或操作进行确认，使用前，生产人员应核对生产通知单中规定的物料。

Weightings, measures or operations of critical subdivisions should be confirmed or submitted to an equivalent control. Before use, production personnel should confer specified materials in the order of manufacturing for intermediates or active pharmaceutical inputs.

8.2.4.  应有书面程序对生产中的溶剂进行混合操作。在混合前应事先对溶剂进行检验和放行。对混合的物料按照先前确定的时间间隔进行复查。There should be written procedure for practice of mixture of solvents during the production. They should be previously analyzed and released before mixing. The mixed material should be reevaluated in time intervals previously established.

8.3.      中间品和药物活性成分  Intermediates and active Pharmaceutical Inputs

8.3.1.  应按照确定好的标准对中间品进行检验、标识和储存。

Intermediates should be analyzed, identified and stored according to established specifications.

8.3.2.  每批中间品和药物活性成分应满足确定的质量、纯度、含量和效价标准，包括溶剂废物和杂质的检验标准

Each lot of intermediate and active pharmaceutical input should fulfill with the established specifications for quality, purity, identity, contents or potency, including specifications for tests and limits for solvent wastes and impurities.

8.3.3.  药物活性成分应满足巴西卫生部所认可的官方标准。如果没有官方标准参考，可以使用经过验证的检验方法。

Active pharmaceutical inputs should satisfy established specifications in official compendia accepted for Brazilian federal sanitary body. If there is no reference in official compendia, analytical methodology employed can be used, once it is validated.

8.3.4.  处于待检状态的中间品和药物活性成分在最终放行前应按照生产厂家规定的条件储存。药物活性成分的生产应按照相关的法规进行。Intermediates and active pharmaceutical inputs kept in quarantine should remain under defined conditions by the manufacturer, until its final release. Active pharmaceutical inputs should be manufactured according to the actual legislation.

8.4.      极限时间  Limit Time

8.4.1.  生产工序的极限时间应该在标准／主配方中规定，并进行控制，确保中间品和药物活性成分的质量。

Limit times for manufacturing steps should be specified in the standard/master formula, and should be controlled in order to assure the quality of intermediates and active pharmaceutical inputs. 对偏差进行记录和分析。Deviations should be documented and analyzed.

            Not applicable when the conclusion of process reactions or steps are determined with sampling and in-house controls.

8.4.2.  在以后生产中使用的中间品应按照保证质量的条件储存。

Intermediates to be used in future processing should be stored in conditions that assure its integrity.

8.5.      取样和过程控制   Sampling and In-Process Control

8.5.1.  对于引起中间品和药物活性成分质量变化的工序进行监控，并根据研发期间获得的信息和从历史记录中得到的情况规定过程控制和验收标准。It should be performed monitoring and control of performance of process steps that cause variability in the characteristics of the quality of intermediates and active pharmaceutical inputs. In-process controls and its limits of acceptance should be defined, based on information acquired during development stage or those originated from historic data.

8.5.2.  过程控制的检验项目和检验取决于中间品或药物成分的特征，正在进行的工序特征和它对产品质量的影响

Acceptance items and analyses performed in in-process controls depend on the nature of the intermediate or pharmaceutical input, of reaction or process step that is being conducted and its impact on the quality of the product.

8.5.3.  关键的过程控制和对关键点的控制，包括控制点和控制方法应在质量部门批准的书面程序中说明

Critical in-process controls and monitoring of critical points, including control points and methods, should be indicated by written procedures approved for the Quality Unit.

8.5.4.  过程控制由合格的生产和质量控制人员完成。工艺调整要在预先设定的范围内进行，并经质量部门批准。所有的检验和结果应完全文件化作为记录的一部分。

In-process controls should be performed by qualified production or Quality Control personnel. In-process adjustments may be performed within pre-established limits and approved by the Quality Unit. All analysis and results should be entirely documented as part of record of the manufacturing lot.

8.5.5.  过程控制的取样计划和程序应参考科学的方法采用书面形式制定Sampling plans and procedures for in-process controls should be written and referred in scientific methodologies.

8.5.6.  过程取样应防止和避免污染被取样的物料，保证取样后样品的质量

In-process sampling should be performed to prevent and avoid contamination of the sampled material and assure the integrity of samples after collection.

8.5.7.  对于以监控和调整生产工艺为目的的过程检验出现的不合格参数可以不进行调查。

Investigations on out of specification parameters are not necessary for in-process analyses that are performed with the finality of monitoring and/or adjusting the production process.

8.6.      批共同加工  Lot Joint Processing.

            将一批产品的几部分进行混合或将具有同样标准的几批产品合并起来供以后加工，称为批共同加工。

It's considered lot joint processing, the mixing process of fractions from a single lot or combination of various lots with the same specification, for later processing.

8.6.1.  每次进行批共同加工需要有质量部门预先判断和批准

Every operation of lot joint processing should be predicted and approved by the Quality Unit.

8.6.2.  使用确定的生产工艺生产并入共同加工的批次，并对各批分别检验，确认在规定的标准内，然后进行共同加工。

Each lot incorporated in the joint processing should be manufactured using an established production process and should be tested individually for verifying if it's within the adequate specifications before the joint processing.

8.6.3.  批共同加工应经过一到和多道工序，作为一批由质量部门检验

The joint processing of lots should compulsorily undertake for one or more process steps, characterizing as a lot and, then, analyzed by the Quality Control.

8.6.4.  对加工程序应进行控制和记录，并对最终的批次进行检验，以符合规定的标准。

Joint procedures should be controlled, documented and the final lot should be analyzed in order to confirm established specifications.

8.6.5.  共同加工的生产指令应允许对各个进行批次进行追溯。

The manufacturing order of the joint processing should allow the traceability of individual lots.

8.6.6.  应该对批加工进行验证

Joint processing operations should be validated.

8.7.      批混合   Lot Mixture

8.7.1.  具有相同标准的几批中间品和药物活性成分混合成一批称为批混合，混合好的批次应该经质量控制部门检验，并保存混合记录。

It's considered mixture the homogenization of lots of intermediates and active pharmaceutical inputs distinct with the same specifications, characterizing as a lot. The lot should be analyzed by the Quality Control and records of mixture should be kept.

8.7.2.  每一次批混合需要经过质量部门预先判断和批准

Every mixing operation of lots should be predicted and approved by the Quality Unit.

8.7.3.  若中间品和药物活性成分具有关键的物理属性，应对批混合操作进行验证，以达到混合均匀的状态，验证应包括对可能影响混合过程的关键属性进行检验

Where physical attributes of intermediates and active pharmaceutical inputs are critical, mixing operations should be validated in order to demonstrate homogeneity. The validation should include test of critical attributes that may be affected by the mixing process.

8.7.4.  不合格批次不得与其它批次混合

Out of specification lots should not be mixed with other lots with the finality to reach adequate specifications.

8.7.5.  使用确定的生产工艺生产需要混合的批次，并对各批分别检验确认在规定的标准内，再进行混合。

Each lot incorporated in the mixture should be manufactured using an established production process and should be analyzed individually for verifying if it's within adequate specifications before mixing.

8.7.6.  混合后批次的有效期应按照最早生产批次的生产日期确定

Expiration date of the lot resulting from the mixing should be base on manufacturing date of the oldest lot.

8.8.      污染控制  Contamination Control

8.8.1.  对同种产品的不同批次连续生产时，应建立控制标准，确定设备清洁的频率，使残余的物料不影响产品的质量。对此过程需要验证

When lots from a same product are manufactured in a continuous system or campaign, it should be established control criteria for determining the periodicity of equipment cleaning in a way that passive residual materials carried for successive lots do not alter the product quality. This process should be validated.  

8.8.2.     生产操作应避免污染中间品和药物活性成分

Production operations should be conducted in a way that it prevents contamination of intermediates or pharmaceutical input.

9.         中间品和药物活性成分的包装和标签

PACKAGING AND LABELING OF INTERMEDIATES AND ACTIVE PHARMACEUTICAL INPUTS

9.1.      概述   General

9.1.1.  应有书面程序规定包装和标签材料的接收、标识、储存、待检、取样、检验、放行和搬运，防止意外使用拒收的材料。

There should be written procedures describing receipt, identification, storage, quarantine, sampling, tests, release and handling of packaging and labeling materials, and that prevent the accidental use of rejected materials.

9.1.2.  包装和标签应符合规定的标准

Packaging and labeling materials should be in conformity of established specifications.

9.1.3.  对于每批包装和标签材料应保留记录，证明材料的接收、检验、批准和放行活动

Records should be kept for each lot of packaging and labeling material that prove the receipt, inspection, analyzes and approval or rejection.

9.2.      包装和标签材料  Packaging and Labeling Material

9.2.1.  包装材料不得影响中间品和药物活性成分的质量，并提供充分的保护防止物料受外界的影响和可能的污染。要有书面的标准可用。

Packaging materials should not interfere with the quality of the intermediate or the pharmaceutical input and should assure adequate protection against outer influences and occasional contaminations. It should be available written specifications.

9.2.2.  为避免混淆和更改，应该建立一套控制办法，并检查标签。如果通过电子手段进行控制，应确认系统工作正常。

There should be a control system and label checking, in order to avoid mix-up/change. When the conference is performed by electronic means, it should be performed verifications for conferring perfect functioning of electronic code readers, label counters and other instruments.

9.2.3.  标签内容应包括下列方面：

Labels should be clearly identified with the following information:

(a) 物料名称  

material name (DCB, DCI or CAS), compulsorily in this order, when possible;

(b) 含量和／或效价，如适用  contents and/or potency, if applicable;

(c) 批号 lot number;

(d) 有效期和生产日期  expiration date and manufacturing date;

(e) 数量和相应的计量单位 amount and its respective measure unit;

(f)  警告 warnings if necessary;

(g) 存储条件 storage conditions;

(h) 生产厂家名称、标识和地址 manufacturer's name, identification and address;

(i)  供应商名称  supplier's name, if applicable;

(j)  技术负责人的姓名

technical responsible one's name and registry in representative class board;

(k) 根据实际规定和产品分类必需的其他项目

other requisites according to product category according to actual legislation.

9.2.4.  容器应整洁，必要时进行卫生处理来满足使用要求

Containers should be clean and, if necessary, sanitized to assure the intended use.

9.2.5.  对于需要重新使用的容器，应根据书面程序清洁，并移走和销毁所有以前的标签，销毁过程需要记录

When containers are subject to reutilization, they should be cleaned according to documented procedures and all precedent labels should be removed and destroyed. The destruction process should be recorded.

9.2.6.  不用的包装材料要进行标识，从仓库移走，并记录处理过程

Primary or secondary packaging material out of use should be identified, removed from stock and recorded to its destination.   

9.3.      标签散发和控制  Label Emission and Control

9.3.1.  只有经过授权的人员才能进入标签存放区

Access to storage areas of labels should be allowed only for authorized personnel.

9.3.2.  印刷材料应安全存放，防止未经授权的人员进入

Printing materials should be stored in safe conditions and non-authorized access should be prevented.

9.3.3.  过期的标签应销毁  Obsolete labels should be destroyed.

9.3.4.  对包装使用的标签打印设备进行控制，保证每次打印的标签符合该批生产记录中规定的标签样本

Devices used for printing labels in packaging operations should be controlled for assuring that every printing is in conformity with the specified copy in the lot production record.

9.3.5.  对一批产品的标签应核对真实性和符合性，并记录

labels issued for a lot should be conferred for identity and conformity. Conference should be recorder.

9.4.      包装和标签操作  Packaging and Labeling Operations

9.4.1.  应有书面程序使包装和标签材料的使用不出问题

There should be written procedures in order to promote the correct use of packaging and labeling materials.

9.4.2.  对产品贴标签应防止混淆，包装不同的产品应在分开的区域进行

Labeling operations should be performed to prevent mixings. There should be a physical spatial separation of operations that involve different production packaging.

9.4.3.  应建立程序核对标签散发的数量、使用的数量和退回的数量。对偏差进行记录、调查，由质量部门采取纠正和预防措施

There should be reconciliation procedures between amounts of issued, used, and returned labels. Deviations should be recorded, investigated and the corrective and preventive actions implemented by the Quality Unit.

9.4.4.  包装和贴标签的地点在使用前应进行检查，确保移走所有不使用的包装和标签材料，并对这一检查进行记录

Packaging and labeling location should be inspected before use in order to assure that all packaging and labeling materials not necessary for this operation are to be removed. This inspection should be recorded.

9.4.5.  核对已包装和贴标签的中间品和药物活性成分，保证容器和批包装正确，并记录结果。

Intermediates or active pharmaceutical inputs packaged and labeled should be conferred in order to assure that containers and lot packages are correct. Results should be recorded.

9.4.6.  在包装中发现有异常情况的产品应提交指定人员检验、调查和批准后，才能退回生产工序，并保留记录

Products involved in unusual occurrences during packaging operation, should only be returned to the process, after they are submitted to inspection, investigation and approval by appointed person. Records should be kept.

9.4.7.  印有未使用批号的包装材料和多余的标签应销毁，并记录销毁过程。应按照书面程序将没有编码的印刷材料移交仓库。

Packaging materials and exceeding labels coded with lot numbers not employed should be destroyed, the destruction process should be recorded. For devolution of non-coded printed materials to the stock, it should be followed written procedures.

9.4.8.  中间品或药物活性成分的包装在发运前应由生产厂家进行密封

Packages of intermediates or active pharmaceutical inputs should be sealed by the manufacturer before its shipping.

9.4.9.  在批生产记录中应包括印刷标签的样本

A model printed label should be included in the lot production record.

10.       发货 SHIPPING

10.1.   发货区的材料应按照标签中规定的条件储存

In shipping areas, materials should be kept under the same storage conditions specified in the label.

10.2.   中间品和药物活性成分只有经过质量部门放行才能发货

Intermediates and active pharmaceutical inputs should be shipped only after release by Quality Unit.

10.3.   中间品和药物活性成分的运输应使其质量不受影响

Active pharmaceutical inputs and intermediates should be transported in such a way that its quality isn't affected.

10.4.   在按照合同运输的情况下，应采用书面形式确定中间品和药物活性成分的运输条件

In case of transport performed by contracts, document should be firmed, establishing transport conditions of active pharmaceutical inputs and intermediates.

10.5.   应有程序比较和评估车辆的状况是否能满足中间品和药物活性成分的运输要求，并保存记录

There should be procedure for conferring and evaluating if vehicle conditions satisfy established specifications for the transport of intermediates and active pharmaceutical inputs. Records should be kept.

10.6.   从事运输中间品和药物活性成分的公司应有从事这种活动的资格

Companies performing transport of active pharmaceutical inputs and intermediates should have functioning authorization for this activity.

10.7.   应建立一套可追溯体系迅速识别和确定正在运输的中间品和药物活性成分的方位，保证能够迅速召回产品

There should be an installed traceability system that allows prompt identification and location of each lot of shipped intermediate and pharmaceutical input, in a way to assure its prompt recall.

10.8.   对要发货的中间品和药物活性成分应有一个程序提供发货信息。

There should be procedure for conferring shipping data with identification of intermediates and active pharmaceutical inputs to be shipped.         

11.       质量控制实验室  QUALITY CONTROL LABORATORY

11.1.   概述   General

11.1.1.检验程序有质量部门批准，并发到负责检验的部门

Assay procedures should be approved by the Quality Unit and should be available in the responsible units for the execution of the assay.

11.1.2.对标准应该进行定期检查以便更新

It should performed periodic reviews of specifications as reference literature updating.

11.1.3.质量控制实验室应具有药典、文献资料、设备手册、参考标准品和其他需要的材料

Pharmacopeias, literatures, equipment manuals, reference standards and other required materials should be available for the Quality Control laboratory.

11.1.4.公司应该有自己的质量控制实验室，与生产独立，作为质量部门的一部分The company should have its own Quality Control laboratory independent from production that is integrating part of the Quality Unit.

11.1.5.对质量控制的最低要求如下

Minimum requisites for the Quality Control are the following:

(a) 按照书面程序和验证的方法进行检测

tests should be performed according to written procedures and validated methodologies;

(b) 仪器应按照规定的期限校验

instruments should be calibrated in defined intervals;

(c) 拥有要求的检验设备 have required equipments for assay performance;

(d) 合格的经过培训的人员 qualified and trained personnel;

(e) 在操作区的活动有可使用的程序

available procedures in the area for performance of developed activities;

(f)  对实际执行的每一步程序应有记录，对偏差进行彻底调查和记录

There should be records in such a way that every procedure have had really performed and that any deviation has entirely investigated and documented.

11.1.6.    供以后参考的留样应  Retention samples for future reference should

(a) 贴上标签，注明包含的物品、批号、取样日期和分析编号

present a label containing identification of its contents, lot number and sampling date and analysis number;

(b) 有满足二次完整检验的足够数量

have sufficient amount to allow, at least, two complete analyses;

(c) 中间品和药物活性成分的样品应使用与销售产品一样的包装，在规定的条件下存放。

samples of intermediates and active pharmaceutical inputs should be kept in a package equivalent to commercialization material and stored in specified conditions.

11.1.7.     留样的储存时间

Storage time of retention samples for future reference:

(a) 原材料样品：保留到库存失效期和／或该批中间品和药物活性成分确认合格的日期（溶剂、气体、不稳定的原材料和水除外）

raw material samples: up to the end of the stock and/or up to verification of conformity of the lot of intermediates or pharmaceutical input (except solvents, gases, instable raw materials and water);

(b) 中间品和药物活性成分样品：应在有效期满后保存一年

samples of intermediates and active pharmaceutical inputs: should be retained for 1 (one) year after its expiration date

11.1.8.  对下列方面应便于进行质量控制

Quality Control should be easily available in the sector:

a)   标准  specifications;

b)  取样程序  sampling procedures;

c)   检验方法和记录（包括分析单和／或记录）

analysis methods and records (including analytical sheets and/or notebooks);

d)  报告和／或检验证书  bulletins and/or analytical certificates;

e)   环境监测记录  records of environmental monitoring, where specified;

f)   方法验证记录  records of validation of methods;

g)   仪器校验和设备维护的程序和记录

procedures and records of calibration of instruments and maintenance of equipments.

11.1.9.根据验收标准和生产工艺对中间品和药物活性成分确定适当的标准。标准应包括对杂质的控制。如果中间品或药物活性成分有微生物纯度方面的标准，应对微生物总数和不允许的微生物数量设定一个采取纠正措施的限度。若中间品或药物活性成分有内毒素方面的要求，应规定采取措施的限度

Adequate specifications should be established for intermediates and active pharmaceutical inputs according to acceptance standards and consistent to the manufacturing process. Specifications should include control of impurities. If the intermediate or active pharmaceutical input has a specification for microbiologic purity, action limits for total microorganism counting and undesired microorganisms (subject to rejection) should be established. When intermediate or active pharmaceutical input has specifications for endotoxins, action limits should be specified.

11.1.10.应按照书面程序制备和识别试剂和标准溶液，并确定使用有效期

Reagents and standard solutions should be prepared and identified according to written procedures and the validity of use determined.

11.1.11.中间品和药物活性成分的参考标准品应适合检验操作，并有文件证明来源，按照生产厂家要求的条件储存

            Primary reference standards should be proper to analysis performance of intermediates and active pharmaceutical inputs, with documented origin and kept in storage conditions recommended by the manufacturer.

11.1.12.如果没有公认的参考标准品，应建立内部标准品。并对其同一性和纯度进行检验。检验记录应保存

When a primary reference standard of an officially recognized source is not available, an in-house standard should be established. Tests of identity and purity of the in-house standard should be performed. Documentation of tests should be kept.

11.1.13.辅助参考标准品应正确制备、标识、检验、批准和储存。对于每批辅助参考标准品, 应对照主要参考标准品确定是否适合。对每批辅助参考标准品应按照书面程序对照主要标准品定期重新分析。

Secondary reference standards should be correctly prepared, identified, analyzed, approved and stored. Suitability of each lot of secondary reference standard should be determined comparing to primary reference standard. Each lot of secondary reference standard should be periodically reanalyzed against the primary standard according to a written procedure.

11.2.   中间品和药物活性成分的检验

Analyses of Intermediates and Active pharmaceutical inputs.

11.2.1.对每批中间品和药物活性成分应进行质量控制检验，确定符合要求

Quality Control Analyses should be conducted for determining the conformity with the specifications of each lot of intermediate and active pharmaceutical input.

11.2.2.对于通过受控的特定工艺获得的中间品和药物活性成分, 应说明杂质情况，识别的和未识别的杂质, 杂质情况应包括同一性 、对一些物质的定量分析、发现的每种杂质的含量范围和每种识别出的杂质的分类

For each intermediate and pharmaceutical input obtained by a controlled specified process should be established a profile of impurities, describing he identified ones and the non-identified ones. The profile of impurities should include the identity and some qualitative analytical designation, range of each impurity observed and classification of each identified impurity.

11.2.3.对于中间品和药物活性成分的杂质情况应跟以前出现的杂质情况定期做比较，以发现由于原材料、设备运行参数或者生产工艺的变更产生的变化。Data on the profile of impurities for intermediate or pharmaceutical input should be compared in defined intervals in relation to the history of profile of impurities, in order to detect changes resulting from modifications in raw material, operation parameters of equipments or in the production process.

11.2.4.如有规定，应对每一批中间品和药物活性成分进行微生物检测

Microbiologic tests should be conducted in each lot of intermediate and pharmaceutical input, when specified.

11.3.   检验报告  Certificate of Analysis

11.3.1.对每一批发货的中间品或药物活性成分应出具检验报告

Certificates of analysis should be issued for each shipped lot of intermediate or pharmaceutical input.

11.3.2.检验报告应至少包括：In the certificate of analysis, it should have at least:

a)   中间品或药物活性成分的名称

intermediate or pharmaceutical input's name (DCB, DCI or CAS, compulsorily in this order, when possible),

b)  批号  lot number;

c)   生产日期  manufacturing date;

d)  有效期  expiration date;

e)   所有的实验项目，包括验收标准和取得的结果，检验方法依据的标准

each performed test, including acceptance limits and obtained results, and references of analytical methodology used;

f)   检验报告的签发日期、质量部门授权人员的签字

date of certificate emission, identification and signature by an authorized person from the Quality Unit, and;

g)   生产厂家  manufacturer's identification.

12.       验证  VALIDATION

12.1    概述   General

            满足GMP要求需要对生产工艺进行验证，对各种支持活动进行验证，这些活动包括公共设施、检验方法、电脑系统和清洁操作。验证是采用文件证明生产工艺通过使用确定的参数，预先确定的标准和质量属性，能够有效而稳定地生产中间品和药物活性成分。验证的类型有三种：前验证、同步验证和回顾验证。前验证在产品研发阶段进行，对生产过程的风险进行分析。同步验证在日常生产中进行，回顾验证依据对历史记录的评审和分析Fulfillment of GMP requires validation of production processes, as well as the validation of support activities (utilities, analytical methods, computerized systems and cleaning operations).

            Validation is a documented evidence that the process, operated through established parameters may effectively and reproductively produce an intermediate or pharmaceutical input gathering pre-established specifications and attributions of quality.

            There are three types of validation: prospective, concurrent or simultaneous and retrospective validation. Prospective validation should be performed during the stage of product development, through analysis of risks in the manufacturing process. The concurrent/simultaneous validation should be performed during the routine production. The retrospective validation should be based on review and analysis of history records of the functional specifications.

12.2.   验证方针  Validation Policy

12.2.1.验证方针规定验证的范围，包括生产工艺、检验方法、公共设施、清洁操作和电脑系统。公司的验证方针应包括负责验证计划、复核、批准和记录的人员

The validation policy should define the scope of validation contemplating the steps of production processes, analytical methodologies, utilities, cleaning operations and computerized systems. The company's validation policy should include responsible persons by planning, review, approval and documentation.

12.2.2.关键的参数应该在研发过程中或从工业化生产的历史数据中确定，包括关键工序的识别和控制范围的确定

The critical parameters should be identified during the development stage or from historic data of industrial scales, the required limits for an operation should be defined. Parameters should include the identification of critical steps of the process and establish its limits.

12.2.3.对中间品和药物活性成分的质量和纯度其关键作用的操作应进行验证Operations that are critical for quality and purity of the intermediate and pharmaceutical input should be validated.

12.3.   文件化   Documentation

12.3.1.  验证主计划   Validation Master Plan

12.3.1.1.      验证主计划应建立，至少包括下列方面

There should be a validation master plan containing, at least, the following topics:

a)   目标  objective (and the previous requisites);

b)  使用流程图、柱状图或突出关键工序的示意图对工艺的说明

presentation of processes by means of flowchart, block or descriptive diagrams highlighting critical steps;

c)   验证活动的组织结构，突出责任

organizational structure of the validation activities, highlighting the responsibilities;

d)  对指定的活动进行验证或者不验证的原因

reason for inclusion or exclusion of given validation;

e)   用于参考和评估的可追溯系统

traceability system for references and reviews;

f)   验证计划需要的培训

indication of Trainings required for the validation program;

g)   验证活动的计划和时间表

planning and schedule of activities to be performed;

(h) 对其他文件的交叉参考 cross reference to other documents;

(i)  在验证的期限和标准 periodicity and criteria for Revalidation;

(j)  需要确认的设备清单

presents list of equipments and facilities that should be qualified;

(k) 验证报告的设计 prevision of elaboration of validation reports.

12.3.1.2.验证主计划应随附下列文件  Validation Master Plan should enclose:

(a) 检验方法 Analytical methods

(b) 清洁 Cleaning

(c) 生产工艺 Production processes

(d) 公共设施 Utilities

(e) 电脑系统 Computerized Systems   

12.3.2.验证方案  Validation Protocol

12.3.2.1.应建立验证方案，规定验证方法。方案应该由质量部门批准

It should be established a validation protocol specifying how a validation process would be conducted. The protocol should be approved by the Quality Unit.

12.3.2.2.验证方案应规定 The validation protocol should specify

a)   工艺说明 description of the process;

b)  设备和设施说明 description of the equipments and facilities;

c)   需要监控的变量v ariable to be monitored;

d)  提取的样品（取样地点、频率、数量和取样程序）

samples to be collected (location, frequency, amount and procedure of sampling);

e)   监控的产品特性／属性和性能，说明检方法

characteristics/attributes and performance to be monitored, specifying analytical methods;

f)   验收标准 acceptable limits:

g)   责任的确定 definition of responsibilities;

h)  记录和结果评估所使用方法的描述，包括统计分析

description of the methods used for recording and evaluating results, including statistic analysis;

i)   关键工序 process critical steps;

j)   验收步骤 acceptance steps;

k)  执行的验证类型 type of validation to be conducted;

l)   验证计划需要的培训  required trainings for the validation program.

12.3.2.3.应确定关键点，可能性、范围、来源、优先程度和最终评估

It should be identified critical points, establishing probability, extension, origin, priorities and final evaluation.

12.3.2.4.在中间品或药物成分的研发阶段进行前验证。根据以前决定关键情况的经验详细确定每一步

Validation should be prospective when performed in the development stage of intermediate or pharmaceutical input. Each process step should be detailed, based on past experiences for determining critical situations.

12.3.2.5.      同步验证应包括对产品有效期内趋势和稳定性研究的分析，至少要对生产的三批产品进行分析Concurrent validation should include analysis of tendency and stability studies throughout the product life, at least in three lots of industrial production.

12.3.2.6.回顾验证应证明生产工艺、系统、程序和设备保持不变，至少在以前生产的10批产品中没有改变；对过程控制和最终控制的结果进行评估，确定工艺参数的范围。应进行趋势分析确定可接收范围。

In he retrospective validation, it should be proved that production processes, systems, procedures and equipments remain unchangeable, at least in the last ten manufactured lots; results of in-process and final control tests should be evaluated. Difficulties and deviations recorded in the production should be analyzed for determining limits of the parameters for the process. It should be performed a trend analysis for determining the extension of acceptable range.

12.3.2.7.回顾验证选择的产品批次应在评审期间生产的产品中具有代表性，包括不符合要求的批次，批次的数量应足够说明工艺的一致性。对留样进行检测确认回顾验证的数据。

Selection of lots for retrospective validation should be representative of all manufactured lots during period of review, including lots that don't met specifications, and the number should be sufficient for demonstrating the consistency of the process. Retained samples may be testes for data confirmation for retrospective validation of process.

12.3.3.  验证报告  Validation Report

12.3.3.1.验证报告应参考验证方案，包括获得的结果、偏差、结论、变更和建议

The validation report should refer to the protocol and be elaborated contemplating obtained results, deviations, conclusions, changes and recommendations.

12.3.3.2. 与验证方案的任何偏差都应记录、调查和说明

Any deviation away from the validation protocol should be documented, investigated and justified.

12.3.3.3.      在验证结果合格的情况下验证过程才能满足要求，否则应分析偏差的来源，确定需要的变更，即使偏差的结果可以接收

The validation process is satisfactory when the results are acceptable. Otherwise, it should analyze the origin of noted deviations and determine required alterations, even if it presents acceptable results.

12.4.   确认  Qualification

12.4.1.  在开始验证活动前，应对关键设备、系统和公共设施完成确认，并形成文件。确认包括：

Before beginning the activities of the validation process, the qualification of critical equipments, systems and utilities should be finalized and documented. The qualification should be performed conducting the activities of:

·        项目确认：根据最终用途对设施、设备或系统的设计方案进行评估Project Qualification (PQ): evaluation of the proposal of the facility design, equipments or systems according to the intended finality.

·        设施确认：对安装的和改造的设备、系统和公共设施是否符合批准的设计要求、建议或者生产厂家的要求进行评估

Facility Qualification (FQ): evaluation of conformity of equipments, systems and utilities, installed and modified, with the approved design, with the recommendations and/or with manufacturer's requirements.

·        运行确认：确定设备、系统和公共设施在整个运行过程中能否实现预期的性能。在检验活动中使用的所有设备应在使用前进行标识和校验Operation Qualification (OQ): set of operations that establish which equipments, systems and utilities present the expected performance in all operational ranges considered. Every equipments utilized in the test execution should be identified and calibrated before they are employed.  

·        性能确认：按照方案中规定的方法和标准确认设备、系统和公共设施在联合使用的情况下能够有效运行

Performance/Acting Qualification (PQ): verify that equipments, systems and utilities, when operating in conjunction are able to perform efficaciously the reproducibility, methods and specifications defined in the protocol.

12.5.         检验方法的验证 Validation of Analytical Methods

12.5.1.  与巴西卫生部认可的检验方法不同的检方法只有在经过验证后才能使用

Analytical methods, different from those existing in the recognized official compendia by the Brazilian federal sanitary entity, can only be utilized if they are duly validated.

12.5.2.  在认可的法定标准中没有涉及的检验方法应进行验证。所有使用的方法应在实际使用的环境下验证并记录。检验方法的验证应按照相关的规定

Analytical methods that aren't included in recognized official compendia should be validated. All methods employed should be proper and validated under actual circumstances of use and documented. The validation of analytical methods should follow guidelines of actual legislation.

12.5.3.  检验方法验证应包括生产中间品和药物成分所使用的所有方法

The analytical validation should include all the analyses of manufacturing steps of intermediate or pharmaceutical input.

12.5.4.  在检验方法的验证开始前应考虑对设备和仪器进行确认

The qualification of equipments and instruments should be considered before beginning validation of analytical methods.

12.5.5.  已经验证的检验方法如有任何改变应及时记录、说明和评估以便证明这种改变不会影响结果的准确性和可靠性

Any alteration performed in an analytical methodology already validated should be duly recorded, justified and evaluated in order to prove that such alteration wouldn't affect accuracy and reliability of results.

12.6.   清洁和卫生验证  Cleaning and Sanitation Validation

12.6.1.  清洁的过程应进行验证，清洁验证应针存在污染或物料外露情况对中间品和药物成分造成质量风险的情况或工序

Cleaning processes should be validated. The cleaning validation should be directed for situations or steps of the process where contamination or exposition to materials puts in risk the quality of the intermediate or pharmaceutical input.

12.6.2.  对中间品或药物活性成分的选择应依据可溶性、清洁难度和根据效价、毒性和稳定性计算的废物控制标准

the selection of pharmaceutical input or intermediate, defined as worth case, should be based on solubility, cleaning difficult and calculation of waste limits base on potency, toxicity and stability

12.6.3.  变更产品的清洁过程应进行验证

Cleaning processes for changing products should be validated.

12.6.4.  使用专用设备生产同一种产品时，应在验证过程中规定标准，确定清洁间隔时间和方法。

In case of lot production of a same product in a dedicated equipment or production by campaign, criteria should be defined during validation for establishing cleaning intervals and methods.

12.6.5.  清洁验证方案应至少包括

The protocol for cleaning validation should describe, at least:

a)   待清洁的设备   equipments to be cleaned;

b)  清洁使用的程序、物料和试剂

procedures, materials and agents used by cleaning;

c)   选择清洁剂的标准和可接收残留物的限度

criteria of choice and acceptable residual limit of cleaning agents, when applicable,;

d)  验收标准  criteria of acceptance;

e)   监控参数   monitored and controlled parameters;

f)   检验方法包括检测和定量范围

analytical methods, including limits of detection and quantification;

g)   取样程序，包括样品的类型、取样的方法和标识的方法

sampling procedures, including types of samples to be obtained and how they should be collected and identified;

h)  研究数据的恢复  recovery study data, when applicable;

i)   连续进行三轮清洁的最少次数

minimum number of three cycles of cleaning to be performed consecutively;

j)   微生物标准   microbiologic criteria when applicable;

k)  确定从生产结束到清洁开始的时间间隔

definition of interval between the end of production and the beginning of the cleaning procedure;

l)   清洁有效性的确定 definition of the cleaning validity.

12.6.6.  应规定检测可溶和不可溶残留物所使用的取样方法。取样方法应足以在清洁以后从设备表面获得有代表性的残留物样品

it should be defined the sampling method for detecting insoluble and soluble residuals. The sampling method should be adequate for obtaining representative sample of residuals found on equipment surfaces after cleaning.

12.6.7.  验证后的检验方法应具有检测残留物和污染物的灵敏度，对每种检验方法的量化标准应足够灵敏，使发现的残留物和污染物的含量达到标准。应确立恢复方法所达到的水平。残留物的验收标准应实际可行。验收标准可根据药物成分的药理、毒理和生理活动确定

Validated analytical methods to be employed should have sensibility to detect residuals or contaminants. The limit of quantification for each analytical method should be sufficiently sensitive to detect the acceptable level established by the residual or contaminant. The reached level of recovery of the methods should be established. The limits of residuals should be practical, acceptable, verifiable, and based on the most pernicious residual. The limits may be established based on pharmacological, toxicological or physiological activity known of the pharmaceutical input or of its most pernicious compound.

12.6.8.  对设备的清洁和卫生处理过程的验证应包括根据确定的验收标准在微生物或内毒素污染可能影响中间品或药物活性成分质量的工序中减少这些污染。应考虑存在对微生物的再生有利的条件和存储时间

The validation of the cleaning and sanitation process of the equipment should include reduction of microbiologic contamination or endotoxins according to the established limits, in the processes where such contamination may affect the specification of the intermediate or active pharmaceutical input. The existence of conditions favorable to reproduction of microorganisms and the storage time should be considered.              

12.6.9.  在清洁操作完成后，不允许形成回水进入设备

There should not be allowed formation of  the backwater into the equipment, after cleaning / sanitation operations have been performed.

12.6.10.              验证结束后，应对清洁过程定期监控确保其有效性。对 设备的清洁进行监控并进行检测

The cleaning processes should be monitored in proper intervals after the validation for assuring its effectiveness. The equipment cleaning should be monitored for analytical tests.

(NO VISUAL ???)

12.7.   工艺验证   Process Validation

12.7.1.  对前验证和同步验证应使用连续三批合格的产品作参考，但有可能需要其他的工序证明工艺的一致性。对回顾验证需要使用至少连续10个批次的产品来评估工艺的一致性

For prospective and concurrent/simultaneous validation, three successful consecutive lots of the production should be utilized as reference, but there may be situations where lots of additional processes are required for proving the consistency of the process. For retrospective validation, it should be utilized at least 10 consecutive lots for evaluating the consistency of the process.

12.7.2.  在验证过程中应监控工序的关键参数

Critical parameters of the process should be controlled and monitored during the studies of the validation process.

12.7.3.  工艺的验证应确认中间品或活性药物成分的杂质情况满足规定的范围The validation of the process should confirm that the profile of the impurity for each intermediate and active pharmaceutical input is within the specified limits.

12.8.   计算机系统的验证  Validation of Computerized Systems

12.8.1.  在生产中间品和药物活性成分的过程中，包括仓储、发货和质量控制过程，计算机系统的引进仍然需要满足规定的要求。计算机系统取代人工操作不应该降低中间品和药物活性成分的质量。

The introduction of computerized systems in manufacturing processes of intermediates and active pharmaceutical inputs, including storage, distribution and quality control do not alter the necessity of satisfying the principles cited in the regulation. When the computerized replaces a manual operation, there should not be reduction in the quality of intermediates and active pharmaceutical inputs;

12.8.2.  计算机系统主要使用人员和技术人员应进行合作。有关人员应接收系统管理和使用的相应培训

There should be cooperation among key personnel (users) and those involved with the computerized systems (technical area). The responsible persons should receive proper training for the management and use of systems.

12.8.3 计算机系统的验证取决于各种因素包括规定的用途和增添新的部件。验证应成为计算机系统整个使用期的一部分，这个时期包括计划、检测、验收、记录、操作、监督和更改阶段。

The validation of computerized systems depends on various factors including the use for which it's destined and the incorporation of new elements. The validation should be considered as a part of the entire cycle of life of a computerized system. This cycle includes stages of planning, specification, schedule, test, acceptance, documentation, operation, monitoring and modifications.

12.8.4.  设备的安装条件应得当，使外部的因素不影响系统

Equipments should be installed in adequate conditions, where external factors do not interfere with the system.

12.8.5.  验证方案应对计算机系统进行详细的最新的说明，包括原则、目标、安全措施、系统范围和和系统的主要使用特点以及与其他的系统和程序相互作用的方式。

The validation protocol should have a detailed and updated description of the system (including diagrams, if necessary). The document should describe principles, objectives, safety measures, and system scope, as well as the main characteristics in which the system will be used and how it should interact with other systems and procedures.

12.8.6.  使用的软件应应遵循质量部门规定的所有步骤。

The software employed should follow all steps described by the Quality Unit.

12.8.7.  系统在适当的时候应能自动确认数据输入和加工的准确性

The system should include, when appropriate, a inner and automatic form to verify the correct input of data and its processing.

12.8.8.  在使用计算机系统之前，应对其进行大量的测试，确认能达到预期的效果。在使用计算机系统取代人工系统时，需要两套系统平行运行一段时间。

Before a computerized system is put in use, it should be extensively tested to be confirmed that it's able to reach the expected results. If a manual system is being replaced, takes part of the tests and the validation that the two systems function in parallel during a period of time.

12.8.9.  只有经过授权的人员才能进行数据的输入和编辑。防止未经授权处理数据的方法有：使用密码、个人代码和对电脑终端进行使用限制。关于数据输入或编辑权力的授予、取消和更改应有规定的程序。未经授权人员试图接近记录应视为使用系统。

Data should be inserted or edited only for authorized personnel. Adequate methods that prevent the authorized handling of data include: use of keys, passwords, personal codes and restrict access to computer terminals. There should be defined procedures for this issue, for the cancellation and for alterations of the authorization for inserting or editing of data, including the alteration of personal passwords. It should be considered the utilization of systems that record access attempts by non-authorized individuals.

12.8.10.       若采用人工方式输入关键数据，应加强检查，证明记录的准确性。应通过另一个人或经过验证的电子手段执行这种检查

When critical data are inserted manually, there should be an additional checking proving the accuracy of he record. This checking should be performed for a second person or by validated electronic means.

12.8.11.       输入或确认关键数据的操作人员身份应在系统中记录下来。只有经过授权的人员才能编辑数据。对数据的任何更改需要经过授权，并有记录，注明更改原因。对所有输入和编辑的数据进行完整的记录应视为系统的一部分。The system should record the identity of the operators that introduce or confirm critical data. The authority for editing data should be restricted to authorized individuals. Any alteration in data should be authorized and recorded, specifying the reason for changing. It should be considered the inclusion in the system of a component that generates a complete record of all the inputs and data editions.

12.8.12.       为满足质量审核的需要，应能够提供保存的电子数据的清晰打印版本

For matters of quality audit, it should be possible to obtain physical and clear copies of the electronically stored data.

12.8.13.       应通过实际或电子手段保护数据不受故意或无意造成的损坏

The security of data against intentional or accidental damages should be guaranteed for physical or electronic means.

12.8.14       对保存数据方法的利用度、稳定性和安全性进行评估

the mean utilized for the data storage should be evaluated for its accessibility, durability and security.

12.8.15.       数据应通过正常的安全程序得到保护。数据的备用副本应保存在安全的地方，保存期应事先确定。

Data should be protected by regular procedures of security. The security copies should be kept for a previously determined period and in a safe place.

12.8.16.       在系统出现故障的情况下应有合理的备选方案，备用系统投入运行的时间应根据使用的紧急程度进行确定

There should be adequate alternatives for the systems requiring to be operating in cases of failure (contingency). The required time to put in work the alternative system should be in accordance to the possibility of urgency for use.

12.8.17 在系统出现故障或停电的情况下，应有明确的程序处理，并对程序进行验证。系统出现的任何故障以及采取的任何纠正措施都应记录Procedures to be followed in cases of system failures or power drop should be defined and validated. Any failure, as well as any attitude taken in order to correct the failure, should be recorded.

12.8.18.       应建立程序对出现的系统错误进行记录和分析，并采取纠正措施Procedure should be established for registering, analyzing errors and for allowing the corrective measures may be taken.

12.8.19.       若聘用外部咨询人员提供计算机系统，应签订合同，清楚地规定责任

When external consultants are hired for supplying a computerized system, There should be a contract, defining clearly the responsibilities

12.8.20.       When the release of a lot for the market is done through a computerized system, this should allow that only qualified and authorized personnel perform it; the system should yet identify clearly and record the responsible person by the action.

12.9.   再验证  Revalidation

12.9.1.概述   General

12.9.1.1.      进行再验证是为了确保对生产工艺、系统和设备的有意或无意改动不会改变工艺特性和产品质量

Revalidation is required in order to assure that intentional or non intentional alterations in the process of production, systems and equipments do not alter adversely the process characteristics and the quality of the product.

12.9.1.2.      再验证的范围取决于改动的特征和对生产不同方面的影响程度。对于按照计划进行的工艺改动可以不对工艺进行再验证

The extension of the revalidation depends on the nature of  the changes and on how they affect different aspects of production, previously validated. It may not be necessary to revalidate the process simply due to a punctual alteration.

12.9.1.3.      对于出现的影响生产或标准程序的变动，包括在自检中发现的和对产品的性能有影响的，应进行再验证

Revalidation should be performed for occasion of input of any changes that affect the manufacturing and/or the standard procedure, including those detected in self-inspection, with influence on the performance characteristics established for the product.

12.9.1.4.      原材料、包装材料、生产工艺、设备、系统、检验方法和公共设施的任何变动应由公司的验证小组进行评估，决定是否需要进行再验证和验证的范围

Each change of raw material, packaging material, manufacturing process, equipment, systems, analytical methods and utilities (water, steam, etc.), should be evaluated by the company's validation group, which decides whether it is sufficiently significant for justifying revalidation and its scope.

12.9.1.5.      变更后的再验证可以依据原来验证期间进行的检测和活动，包括过程检验和有关设备的检验。

Revalidation after changes may be based on performance of the same tests and activities performed during the original validation, including in-process tests and those referring to the equipments.

12.9.2.  定期再验证   Periodic Revalidation

12.9.2.1.      由于机器的磨损和人员可能出现的错误，在没有发生变动的情况下，应按照计划的期限进行再验证

Revalidation in scheduled intervals should be performed in case where changes have not been performed, considering the wearing of equipments and possible human mistakes.

12.9.2.2.      定期再验证的主要依据是历史数据、过程检验和成品检验所产生的数据，客观确认在上次验证以后工艺是否与以前保持一致，在对历史数据进行评估的过程中，应评估对收集数据的趋势分析。

Periodic revalidation should be based mainly on review of historical data, generated during in-process tests and finished product, after the last validation, having as objective verify whether the process is met consistent with the last validation or not. During the review of the referred historical data, it should be evaluated the trend analyses of collected data.

12.9.2.3.      定期再验证的时间间隔应在文件中规定

The interval of period revalidation should be defined and documented.

12.9.2.4.      定期再验证应确认生产工艺的下列方面

In the production processes, the following points should be verified for occasion of periodic revalidation:

a)   按照规定的计划完成校验

realization of calibrations according to the established schedule;

b)  按照规定的计划完成预防性维护

realization of preventive maintenance according to the established schedule;

c)   更新和执行POP ，updating and implementation of POP and

d)  完成清洁和卫生计划 realization of the cleaning and hygiene programs.

13.       变更控制  CHANGE CONTROL

13.1    应建立变更控制体系，评估影响中间品或药物活性成分生产和质量控制的任何变化

A system of change control should be established for evaluating every changes that could affect production and control of intermediates or active pharmaceutical inputs.

13.2.   应有书面程序规定变更的确定、记录、合理的评审和批准，涉及下列方面：原材料、标准、检验方法、设施、公共设施、设备（包括电脑）、工艺步骤、包装和标签材料和电脑软件

Written procedures should supply the identification, documentation, proper review and the approval of the changes in raw materials, specifications, analytical methods, facilities, utilities, equipments (including computers), processing steps, packaging and labeling materials and computer software.

13.3.   对于原材料、标准、检验方法、公共设施、过程设备、生产工艺的变动和其它可能影响产品质量的变动应建立书面程序规定需要采取的行动Written procedures should contemplate actions to be adopted if is proposed a change of raw materials, specifications, analytical methods, utilities, process equipments, production processor yet ant other change that may affect the quality of the product.

13.4.   任何提出的变更应经质量部门批准

Any proposition of change should be approved by the Quality Unit.

13.5.   变更控制体系应保证所有的变更正式提出，其对产品质量的影响得到评估，对变更进行了说明、记录和批准。

The system of change control should assure that all changes are formally proposed and evaluated for impact on the quality of the product, justified, documented and approved/authorized.   

13.6.   变更可按照关键程度分类，这取决于它的特征、范围和对工艺的影响。质量部门应该评估计划的变更是否需要再验证

Changes may be classified in degree of criticality, depending on the nature and extension and effects that may cause in the process. The Quality Unit should evaluate if the intended change requires revalidation.

13.7.   对变更的批准需要确保审查和取代所有原来的程序

To perform approved changes should be assured that all the original procedures are reviewed and replaced.

13.8.   未经质量部门评估，变更后生产的首批产品不得放行

The first manufactured lots after the change should not be released for commercialization without judicious evaluation of the Quality Unit.

13.9.   根据变更的关键程度，应进行新的稳定性研究，评估变更对产品质量的影响

Depending on the degree of criticality of the change, it should be performed a new study of stability for evaluating the impact of the changing in the quality of the product.

13.10. 生产工艺上的重要变更引起产品标准发生改变的，应通知客户Significant changes in the production process that cause modifications in the specification of the product should be notified to the clients;

13.11. 系统或电脑系统变更应按照规定程序进行，包括变更验证、检测、批准和执行的规定。只有经过受变更影响的系统负责人批准，才能进行变更。变更应进行记录，并对任何重要的变动进行验证。

Alterations in a system or in a computer program should be done according to a procedure defined that includes provisions for validation, tests, approvals and implementation of the change. The alteration should be only implemented with the approval of the responsible person by the part of the affected system for the change. The alteration should be recorded and any significant modification should be validated.   

14.       物料的拒收和再利用

REJECTION AND REUTILIZATION OF MATERIALS

14.1.   拒收   Rejection

14.1.1.  不符合规定标准的物料应有不合格标识，在等待销毁、再加工或移交给供应商期间，其保存必须防止被使用。

Materials that are not in conformity with the established specifications should be identified as in non-conformity and must be stored in a way to avoid its utilization while waiting destruction, reprocessing or devolution to the suppliers.

14.1.2.  应建立书面程序规定拒收材料的搬运，包括原材料、中间品、包装材料或活性药物成分

It should be kept written procedures related to handling of rejected materials, either are they raw materials, intermediates, packaging materials or active pharmaceutical inputs.

14.2.   再利用  Reutilization

14.2.1.  再加工   Reprocessing

14.2.1.1.      中间品或药物成分不符合规定标准的，可以通过重复一个或多个生产工序进行再加工

When an intermediate or pharmaceutical input is not in conformity with the defined specifications, it may be reprocessed by means of repetition of one or more steps of the production process.

14.2.1.2.      中间品或药物成分的再加工事先应经过质量部门的评估和授权，保证产品质量不受产生的副产品和部分拒收物料的负面影响Reprocessing of intermediate or pharmaceutical input should be preceded by evaluation and authorization of the Quality Unit for assuring that the quality of the product is not adversely affected by the formation of by-products or partially reacted materials.     

14.2.2.  返工  Rework

14.2.2.1.      在返工前，应进行认真调查，确认不符合标准的原因

Before beginning the process of rework, it should be performed a careful investigation to identify the reason of the non-conformity to the standards or established specifications.

14.2.2.2.      对不符合标准的批次，应制定返工方案，说明责任、返工步骤、检验和预期的结果。对返工的批次进行评估，保证达到规定要求

It should be established a protocol for rework of a lot which does not satisfy established specifications, describing responsibilities, steps to be reworked, tests and anticipated results. The reworked lot should be evaluated in order to assure that it has satisfied the established specifications.

14.2.2.3.      返工批次的杂质情况应包括使用的反应方法

The profile of impurities of the reworked lot should take in con sideration the reaction mean utilized.

14.2.2.4.      若使用的检验方法不得当，无法确定返工批次的特性，应使用其他的检验方法，但在使用前要进行验证

When the analytical methods in use are inadequate for characterizing he reworked lot, additional analytical methods should be validated before its utilization.

14.2.2.5.      返工的批次只有完成稳定性研究或类似研究才能发货

The reworked lot can only be commercialized after execution of stability study and identified like this.

14.2.3.  物料和溶剂回收 Material and Solvent Recovery

14.2.3.1.      对于溶剂、原材料、中间品和药物活性成分的回收建立程序。    回收的物料应满足使用标准，其质量应通过过程控制保证

There should be procedures for recovering solvents, bittern, raw materials, intermediates and active pharmaceutical inputs. The recovered material should satisfy the specifications established for its use. In the continuous processes, the quality of these recovered materials may be guaranteed for in-process control.   

14.2.3.2.      溶剂、原材料、中间品和药物活性成分的回收可以使用同样的工艺或不同的工艺，只要对回收程序进行监控确保符合相应的的质量标准

Solvents, bitterns, raw materials, intermediates and active pharmaceutical inputs may be recovered and reutilized in the same processes or in different processes, as long as the recovery procedures are controlled and monitored in order to assure that they comply with proper quality standards.

14.2.3.3.      新回收的溶剂或原材料达到规定的要求方可混合

New and recovered solvents or raw materials may be mixed if they are within the defined specifications.

巴西卫生监管局ANVISA验厂GMP标准中文版(转载3/3)  

2014-11-06 09:40:35|  分类： GMP通论及跨国

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15.       稳定性   STABILITY

15.1    中间品和药物活性成分的稳定性研究

Stability Study of Intermediates and Active Pharmaceutical Inputs

15.1.1.  应建立书面计划，监控中间品和药物活性成分的稳定性，注明使用的检验方法。研究结果用来确认合理的储存条件和产品有效期

It should be implemented a documented program to monitor the characteristics of stability of intermediates and active pharmaceutical inputs, with indication of the analytical methods to be employed. Results should be utilized for confirming the adequate storage conditions and the proposed expiration date.

15.1.2.  对稳定性研究使用的检验方法应进行验证

Analytical methods utilized in the stability study should be validated, as the actual legislation.

15.1.3.  中间品和药物活性成分稳定性研究所使用的样品应在同样包装条件下包装，其包装尺寸、化学成分和物理特性与销售产品的包装相同Samples destined to the stability study of intermediates and active pharmaceutical inputs should be packed in the same packaging conditions, with proportional dimensions, with the same chemical composition and physical characteristics of the packaging of commercialization conserving proportions of dead volume.

15.1.4.  稳定性研究应采用三批中间品和药物活性成分确定有效期Stability study should be conducted with three lots of intermediates and active pharmaceutical inputs manufactured for determining the expiration date.

15.1.5.  具有不稳定分子的中间品和药物活性成分实验应每隔三个月进行一次

For the intermediates and active pharmaceutical inputs with instable molecules, it should be anticipated the realization of tests in three-month intervals.

15.1.6.  加速稳定性研究应对最长为24个月的临时有效期提供支持，有效期按照长期稳定性研究结果确定。

Accelerated stability studies should take part of a program that allows projecting a provisory self-life period of, at most, 24 months. Expired the defined period as provisory, the expiration date should be confirmed against the presentation of a long-term stability study;

15.1.7.  对于库存的中间品，稳定性研究应保证产品在储存条件下保持质量不变。因此应建立这些产品的有效期和储存条件

In the case of stored intermediates, it should be presented studies that guarantee the maintenance of proposed specifications for the product in this condition. Thus, expiration and storage conditions of these products up the primary packaging step, among other required parameters, should be established.

15.1.8.  稳定性研究的方案应包括物理、化学和理化评估以及微生物评估。应采用合理的验证方法评估副产品和／或降级产品的存在或其定质和定量形成

The protocol of the stability study should contemplate physical, chemical, physical-chemical evaluations, as well as microbiological ones, when it's the case. It should be evaluated, also, the presence or qualitative and quantitative formation of by-products and/or degradation products, utilizing adequate and validated methodology.

15.1.9.  对于加速稳定性研究出现的不合格结果应视为无效

When occurring out of specification results during the accelerated stability study, this would be considered invalid.

15.1.10.       对于加速稳定性研究，检验样品的保存期应至少为0, 1, 2, 3和6个月，稳定性研究应完成方案中规定的所有检验项目

for accelerated studies, samples should be analyzed at least with 0, 1, 2, 3 and 6 months of storage. It should be performed all the specific tests for evaluation of the stability described in the stability protocol.

15.1.11.       对于长期稳定性研究，检验样品的保存期应至少为0, 3, 6, 9, 12, 18 和24个月，从第二年以后到产品的失效期每年进行。稳定性研究应完成方案中规定的所有检验

For long-term studies, samples should be analyzed at least with 0, 3, 6, 9, 12, 18 and 24 months, and annually after the second year up to the claimed expiration date. It should be performed all the specific tests for evaluation of stability described in the approved stability protocol by the Quality Unit.                  

15.1.12.       稳定性报告应提供在研究期间获得的结果和结论。可以采用表格和图示的形式说明结果

The stability report should present results obtained during the study and its conclusion. It may be utilized tables and graphics for result presentation.

15.1.13.       稳定性报告应包括  In the stability report, there should be:

a)   中间品或药物成分的名称

name of the intermediate or pharmaceutical input;

b)  批号 lot number(s)

c)   批量 lot size(s);

d)  批生产日期 date of manufacturing of the lot(s)

e)   包装材料的规格 specification of the packing material;

f)   按批测试样品数量 number of tested samples by lot;

g)   按期限测试样品的数量 number of analyzed samples by period;

h)  储存条件 storage conditions;

i)   检验项目 tests to be performed;

j)   检验频率和标准范围 frequency of tests and limits of specifications;

k)  检验结果 test results;

l)   结论 conclusion.

15.1.14.       稳定性研究完成后，应提出中间品和药物成分保存要求，在包装中体现。After the stability study of the product is concluded, recommendations on storage should be included in the packaging of the intermediate and pharmaceutical input.

15.1.15.       在必要时应包括其它的信息：避免阳光照射、放在干燥的地方和其他条件

Additional information such as: protect from light, keep in a dry place and others should be included when necessary;

15.1.16.       稳定性研究中应考虑巴西的气候条件

Brazilian climatic conditions should be considered in the stability study.

15.2.   有效期  Expiration

15.2.1.  中间品和药物成分的有效期根据稳定性研究中对数据的评估确定

The expiration date for the intermediate and pharmaceutical input may be based on the data evaluation  obtained from stability studies.

15.2.2.  中间品和药物活性成分的有效期可以根据对试生产的批次进行的稳定性研究，条件是试生产使用的方法和程序模拟批量生产所使用的工艺

The expiration date for the intermediate and pharmaceutical input may be based on the stability study of the lots of pilot scale, when it employs a method and a procedure of manufacturing that simulate the final process used in industrial manufacturing scale.

16.       投诉、产品召回和退货  COMPLAINTS, RECALL AND RETURNS

16.1.   对于以口头形式或书面形式收到的与质量有关的所有客户投诉应按照书面程序进行记录、评估，并调查产生质量偏差的原因，形成文件

All complaints related to the quality, received verbally or written referring to intermediates and active pharmaceutical inputs, should be recorded, evaluated and the cause for possible quality deviations investigated and documented, according with written procedures.

16.2.   投诉记录应至少包括  Records of complaint should include, at least:

投诉人姓名和地址  complainer's name and address;

起始物料或批号start material or lot number;

投诉提交人的姓名和电话号码

name and telephone number of the person submitting the complaint;

投诉的特点 nature of complaint;

收到投诉时的数据data when the complaint was received;

首先采取的调查行动，包括行动的日期和执行人的身份

initial action for investigation, including date and identity of the person who

started the action;

对投诉者的最初答复（包括答复日期）

initial answer supplied to the complainer (including date of the issued

answer);

完整的调查，调查行动的报告，签字和注明日期

complete investigation, with report of actions taken, signed or dated;

中间品或药物成分处理的最终决定

final decision for the destiny of the intermediate or lot of pharmaceutical

input;

对投诉人的最终答复  final answer to the complainer.

16.3.   对投诉记录进行保存，以便评估趋势，采取纠正措施的频率。

Records of complaints should be retained in order to avoid trends, frequencies of reports for product and critical analysis for taking the corrective action.

16.4.   应有书面程序规定在何种情况下需要召回中间品和药物成分

There should be a written procedure that defines situations in which the pharmaceutical input and intermediate should be recalled.

16.5.   应指定一名负责人采取措施协调产品召回

It should be assigned a responsible person for measures to be adopted and by coordination of market recall.

16.6.   应有一套系统能够快速而有效地将怀疑有质量偏差的产品从市场召回

It should be available a system capable of recalling, prompt and efficiently, of the market, if necessary, products suspected of having quality deviations.  

16.7.   召回的中间品和药物活性成分在等待作出决定期间应进行标识，单独存放在安全的地方

Intermediates and/or active pharmaceutical inputs recalled should be identified and stored in separate and safe areas, while waiting for decision on its destiny.

16.8.   对于可疑的质量偏差或召回产品的任何想法，应立即通知所有相关卫生部门（地方、国家和国际部门）

All competent sanitary authorities (local, national and/or international) should be immediately informed of the suspect of quality deviation or on any intention to recall the products.

16.9.   对由于投诉引起的质量偏差所采取的决定和措施应进行记录、签字并附在相应的批记录中

All taken decisions and measures resulting from a quality deviation originated from a complaint should be recorded, signed, dated and annexed in the corresponding lot records.

16.10. 有质量偏差或怀疑有质量偏差的产品发货记录应迅速提交给负责召回产品的人员。记录应提供直接收到产品的分销商和买方的足够信息，包括在出口情况下收到样品进行检测的买方信息，从而使产品从市场上完全撤出

Records on lot distribution that presents or is under suspect of quality deviation should be promptly put on disposition to the responsible person for the recall. Records should have sufficient information on the distributors and buyers to whom the product has been directly supplied, including in case of exported products, information on buyers who have received samples to perform assays, so the product in question is effectively removed from the market.

16.11. 对于药物活性成分的移交，应有标准的操作程序规定其接收、储存和原因调查

There should be Standard Operational Procedures for receipt, storage and investigation of the causes for devolution of the active pharmaceutical inputs.

16.12. 退回的中间品或药物活性成分应在仓库特定的区域进行及时标识，并指定人员收货

Intermediates or active pharmaceutical inputs returned should be duly identified in delimited or restricted area for storage and an assigned person for the their receipt.

16.13. 从市场退回的中间品和药物活性成分只有经过质量部门的检验和放行后才能再次销售

Intermediates and active pharmaceutical inputs returned by the market can only be considered to reselling after they have been analyzed and released by the Quality Unit, according to written procedures.

16.14. 对于退回产品质量的任何怀疑不能成为重新使用产品的合理理由

When there is any suspect of quality of the returned product, this should not be considered adequate to be incorporated or reutilized.

16.15. 应保留中间品和药物活性成分的退回记录

Records of returned intermediates or active pharmaceutical inputs should be kept.

16.16. 对于移交产生的质量偏差的所有决定和采取的措施应进行记录、签字并附在相应的批记录中

All decisions and measures taken resulting from a quality deviation originated from devolution, should be recorded, signed, dated and annexed to the corresponding lot records.

16.17.  每次有关移交的文件应包括

For each devolution, documentation should include:

被委托人的名称和地址  trustee's name and address;

中间品或药物成分、批号和退回的数量

intermediate or pharmaceutical input, lot number and amount returned;

移交的原因  reason for devolution;

新签发的检验报告   new analysis report dated and signed and

退回的中间品或药物成分的目的地

destiny of returned intermediate or pharmaceutical input.

17.       生产合同和／或质量控制

MANUFACTURING CONTRACT AND/OR QUALITY CONTROL

17.1.   生产和或检验合同应经双方协商订立，避免出现造成不合格程序、产品或检验错误。合同应由双方采用书面形式详细确定GMP/GLP方面的责任，各个部分的明确特点包括质量措施,和与产品放行和检验报告签发相关的方面      The manufacturing and/or analysis contract should be mutually agreed between the parts, in a way to avoid mistakes that can result in a process, product or analysis of unsatisfactory quality. It should be firmed a written contract between the contractor and the contracted defining in details the GMP/GLP responsibilities and establish clearly the attributions of each part, including the quality measures, about the release of each product lot for selling or about emission of certificate of analysis.     

17.2.   合同的所有内容应符合GMP/GLP。应特别考虑防止交叉污染,并具有可追溯性

All involved in the contract should comply with the GMP/GLP. It should be given special consideration to prevention of cross-contamination and traceability.

17.3.   除非经双方同意，不得变更工艺、设备、检验方法、标准和其它合同要求

Changes in the process, equipment, analysis method, specifications, or other contractual demands should not be made, except if both parts are informed and changes approved.

17.4.   书面合同应规定中间品和／或药物成分的生产程序和/或检验方法

The firmed written contract should establish manufacturing procedures and/or analysis of intermediate or pharmaceutical input with all technical activities to both related.

17.5.   合同应规定发包人可审核承包人设施，以便确认是否符合

GMP/GLPThe contract should establish that the contractor can audit the contract's facilities, in order to verify the conformity with GMP/GLP.  

17.6.   对于检验合同，应有经过授权的人员最终批准中间品和药物成分的放行In case of analysis contract, foreseen in the actual legislation, the final approval for release of intermediate and pharmaceutical input for commercialization should be performed by contractor's authorized person.  

17.7.   发包人向承包人提供所有必要的信息，使承包人按照中间品和药物成分的标准进行操作。发包人应保证承包人了解有关中间品、药物成分、服务或检验的所有问题，这些问题可能损害其设备、设施、人员、其它物料和中间品或药物活性成分

The contractor should supply to the contracted all necessary information so the latter can perform contracted operations according to the specifications of the intermediate or pharmaceutical input as well as any other legal requirements. The contractor should assure that the contracted be informed of any problems concerned the intermediate or the pharmaceutical input, service or assays, that put in hazardous its facilities, its equipments, its personnel, other materials and other intermediates or active pharmaceutical inputs.

17.8.   发包人应保证承包人所发出的所有的中间品或药物活性成分符合标准，并经过授权人员放行

The contractor should guarantee that all intermediate or active pharmaceutical inputs delivered by the contracted, fulfills with its specifications and that the product are to be released by the authorized person.

17.9.   除了具有经验和合格人员外，承包人应具有圆满完成发包人所要求服务的设施、设备和充分知识。The contracted should have facilities, equipments, and adequate knowledge, besides the experience and qualified personnel, for performing satisfactorily the service solicited by the contractor. The manufacturing contract only can be performed by manufacturers that hold Operating Authorization and Health License for the manufacturing activity of active pharmaceutical inputs and/or intermediates.   

17.10. 未经发包人预先评估和批准，承包人不得向第三方转让合同规定的服务。承包人和第三方签订的合同应采用跟发包人签订的合同同样的方式确定可使用的检验和生产信息  

            The contracted can not transfer to third parties services foreseen in the contract, without the contractor previously evaluate and approve such contract modification. The firmed agreements between the contracted and third parties, should foresee availability of analytical information and information on manufacturing, of the same way that the firmed agreement between the contractor and contracted.  

17.11. 承包人不得从事对其生产和／或检验的产品质量有负面影响的任何活动

The contracted should restrain from performing any activity that can affect adversely the quality of the manufactured product and/or analyzed by the contractor.

17.12. 合同应规定双方在生产和质量控制方面的责任。合同的技术内容由合格的技术人员确定，并经双方同意

The firmed contract between the contractor and the contracted should specify the responsibilities of each part about manufacturing and product control. Technical aspects of the contract should be composed by qualified persons necessarily having knowledge of production technology, analysis of quality control and GMP and should be agreed for both parts.     

17.13. 合同应清楚规定采购、质量检验、物料放行、生产和控制方面的责任The contract should describe clearly the responsibilities for acquisition, control assay and release o materials, for production and for performance of quality controls, including in-process controls, as well as the sampling responsibility and performance of analyses.

17.14. 合同应规定生产记录、检验记录和参考样品应由承包人保存。生产和检验记录的正本或复印件应在生产和检验所在地保存

The contract should establish that manufacturing records, analytical records and reference samples should be kept by the contractor, or be at its disposal. Manufacturing and analytical records, original or copies, should be disposal in the locality where the activity has place.

17.15. 合同应规定中间品和／或药物成分的发货由承包人进行，并保存记录The contract should establish that shipping of intermediate an/or pharmaceutical input are performed by contractor, and records kept.

17.16.  合同应考虑在拒收原材料、中间品和药物活性成分的情况下采取的行动。

The contract should prevent actions to be adopted when there is rejection of raw materials, intermediates and active pharmaceutical inputs.

谢谢分享!怎么全球的都是大同小异啊！感觉全球文章一大抄啊！

谢谢分享、感谢付出的努力！