中国GMP对QA的要求

第二节质量保证
第八条质量保证是质量管理体系的一部分。企业必须建立质量保证系统，同时建立完整的文件体系，以保证系统有效运行。

第九条质量保证系统应当确保：

(一) 药品的设计与研发体现本规范的要求；

(二) 生产管理和质量控制活动符合本规范的要求；

(三)管理职责明确；

(四)采购和使用的原辅料和包装材料正确无误；

(五)中间产品得到有效控制；

(六)确认、验证的实施；

(七)严格按照规程进行生产、检查、检验和复核；

(八)每批产品经质量受权人批准后方可放行；

(九)在贮存、发运和随后的各种操作过程中有保证药品质量的适当措施；

(十)按照自检操作规程，定期检查评估质量保证系统的有效性和适用性。



第十条药品生产质量管理的基本要求：

(一)制定生产工艺，系统地回顾并证明其可持续稳定地生产出符合要求的产品；

(二)生产工艺及其重大变更均经过验证；

(三)配备所需的资源，至少包括：

1.具有适当的资质并经培训合格的人员；

2.足够的厂房和空间；

3.适用的设备和维修保障；

4.正确的原辅料、包装材料和标签；

5.经批准的工艺规程和操作规程；

6.适当的贮运条件。

(四)应当使用准确、易懂的语言制定操作规程；

(五)操作人员经过培训，能够按照操作规程正确操作；

(六)生产全过程应当有记录，偏差均经过调查并记录；

(七)批记录和发运记录应当能够追溯批产品的完整历史，并妥善保存、便于查阅；

(八)降低药品发运过程中的质量风险；

(九)建立药品召回系统，确保能够召回任何一批已发运销售的产品；

(十)调查导致药品投诉和质量缺陷的原因，并采取措施，防止类似质量缺陷再次发生。

ICH Q7中对质量管理的描述

QUALITY MANAGEMENT 质量管理

2.1 Principles 原则

2.10 Quality should be the responsibility of all persons involved in manufacturing.

质量应该是所有参与生产的人员的职责。

2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

每个生产企业应该建立、文件化并执行一个有管理层和适当的生产人员参与的有效的管理质量的体系。

2.12 The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented.

管理质量的体系应该包含组织架构、程序、流程和资源，以及确保原料药有信心符合预期的质量和纯度标准的必要的活动。所有质量相关的活动都应该规定并使其文件化。

2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the orgnization.

应该有一个独立于生产并且要履行质量保证（QA）和质量控制(QC）职责的质量单元（或质量部门）。根据组织的大小和架构，这个质量单元可以由单独的QA和QC单元或一个人或团队组成。

2.14 The persons authorised to release intermediates and APIs should be specified.

应当指定被授权放行中间体和原料药的人员。

2.15 All quality related activities should be recorded at the time they are performed.

所有质量相关的活动都应该在其执行的时候就记录。

2.16 Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.

任何与已经建立的程序的偏离都应该记录（或登记在案并解释。

2.17 No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation).

在质量单元（部门）圆满完成评价前物料不应该放行或使用，除非在合适的位置有合适的系统允许这样的使用(比如在第10.20章节中描述的待验状态下的放行或等待完成评价时的原料或中间体的使用）。

2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related complaints, recalls, regulatory actions, etc.).

应该存在以一种及时的方式通知负责的管理层相关监管检查、严重的GMP缺陷、产品缺陷和相关措施的程序（比如质量相关的投诉、召回、监管行动等）。

2.2 Responsibilities of the Quality Unit(s)

质量单元的职责

2.20 The quality unit(s) should be involved in all quality-related matters.

质量单元应该参与所有质量相关的事项。

2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

质量单元应该审核和批准所有质量相关的文件。

2.22 The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include but not necessarily be limited to:

独立的质量单元的主要职责不应该被委托（给他人）。这些职责应该书面描述并应该包括但不必限于以下内容：

1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use
outside the control of the manufacturing company;

放行或拒收所有原料药。放行或拒收在生产企业控制范围之外使用的中间体；

2. Establishing a system to release or reject raw materials, intermediates,
packaging and labelling materials;

建立一个放行或拒收原料、中间体、包材和标签的系统；


3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution;

放行销售的原料药前审核关键工艺步骤的已完成的批生产记录和实验控制记录；

4. Making sure that critical deviations are investigated and resolved;

确保关键偏差得到调查和解决；

5. Approving all specifications and master production instructions;
批准所有标准和生产工艺规程；

6. Approving all procedures impacting the quality of intermediates or APIs;
批准所有影响中间体或原料药质量的规程；

7. Making sure that internal audits (self-inspections) are performed;
确保进行内部审计（自检）；

8. Approving intermediate and API contract manufacturers;
批准中间体和原料药的合同生产商；

9. Approving changes that potentially impact intermediate or API quality;
批准潜在影响中间体或原料药质量的变更；

10. Reviewing and approving validation protocols and reports;
审核和批准验证方案和报告；

11. Making sure that quality related complaints are investigated and resolved;
确保质量相关的投诉得到调查和解决；

12. Making sure that effective systems are used for maintaining and calibrating
critical equipment;
确保有有效的系统用于维护和校验关键设备；

13. Making sure that materials are appropriately tested and the results are reported;
确保物料都得到适宜的检测并报告其结果；

14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where appropriate;

确保在适当的情况下，有稳定性数据支持中间体或原料药的复验期或有效期和储存条件。

15. Performing product quality reviews

(as defined in Section 2.5).

进行产品质量回顾（在2.5章节中定义）

WHO GMP中对质量管理的描述

Quality management in the drug industry

医药行业的质量管理

In the drug industry at large, quality management is usually defined as the aspect of management function that determines and implements the “quality policy”,i.e. the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are:

在大的医药行业中，质量管理常常被定义为管理职能中规定并执行“质量政策”的那方面职能。比如组织质量相关的总体意图和方向，由最高管理层正式表达和授权。

质量管理的基本要素有：

— an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources;

一个适当的基础架构或“质量体系”，包含组织架构、程序、流程和资源；

— systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “quality assurance”.

确保一个产品（或服务）有足够信心会满足质量要求的不要的系统化的行动。全部这些行动被称之为“质量保证”。

Within an organization, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier. The concepts of quality assurance, GMP and quality control are interrelated aspects of quality management. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.

在一个组织内，质量保证是一种管理工具。在委托情况下，质量保证也用于产生对供应商的信心。质量保证、GMP和质量控制的概念是质量管理的相关要素。它们在这里描述是为了强调它们的关系和它们对于药品生产和控制的根本的重要性。

1. Quality assurance 质量保证

1.1 Principle. 原则

“Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates GMP and other factors, including those outside the scope of this guide such as product design and development.

“质量保证”是一个涵盖所有个体或集体影响产品质量的因素很宽泛的概念。它是做出的确保药品质量符合其预定用途的目标的所有安排的总和。所以质量保证整合了GMP和其他因素，包括那些不在本指南范围比如产品设计和开发内的那些因素。

1.2 The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that:

适用于药品生产的质量保证体系应该确保：
(a) pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) 1 and good clinical practice (GCP);

药品在一定程度上考虑GMP和其他相关法规比如GLP和GCP的要求进行设计和开发；

(b) production and control operations are clearly specified in a written form and GMP requirements are adopted;

用书面的形式明确规定生产和控制操作并采用GMP要求；

(c) managerial responsibilities are clearly specified in job descriptions;

在岗位描述中明确规定管理职责；

(d) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

为正确的起始物料和包装材料的生产、供应和使用做出一些安排；

(e) all necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out;

实施所有对起始物料、中间产品和最终产品的必要的控制和其他中间过程控制、校验和验证；

(f) the finished product is correctly processed and checked, according to the defined procedures;

按照规定的程序正确地加工和检查最终产品；


(g) pharmaceutical products are not sold or supplied before the authorized persons (see also sections 9.11 and 9.12) have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products;

在被授权的人员确认每批产品已经按照上市许可和其他与药品的生产、控制和放行相关的法规生产和控制前药品不能销售或供应；

(h) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf-life;

存在尽可能确保药品由生产企业储存、销售和后续处理的满意的安排以确保质量在它们整个货架期都得到保持；
(i) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system;

有一个定期评价质量保证体系的质量和适用性的自检和/或质量审计程序；

(j) deviations are reported, investigated and recorded;

偏差被报告、调查和记录；

(k) there is a system for approving changes that may have an impact on product quality;

有批准可能对产品质量有影响的变更；

(l) regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.

应该执行对药品质量的定期评价，目标是确认工艺的一致性并确保其持续改进。

1.3 The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the company’s suppliers, and the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control. It should be fully documented and its effectiveness monitored. All parts of the quality assurance system should be adequately staffed with competent personnel, and should have suitable and sufficient premises, equipment, and facilities.

生产企业必须承担药品质量的职责以确保它们适用于其既定的用途，符合上市许可的要求并且没有因为安全性、质量和功效不足对患者产生风险。达到这个质量目标是高层管理者的职责需要公司内不同部门和所有层级的员工、公司的供应商和经销商的参与和承诺。为了可靠地达到质量目标必须有一个全面设计和正确实施的质量保证结合GMP和质量控制的体系。这个体系应该完全文件化并监控其有效性。质量保证体系的所有部分都要配备足够的有资质的人员并且应该合适和足够的厂房、设备和设施。

2. Good manufacturing practices for pharmaceutical products (GMP)

药品的GMP

2.1 Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers. Under GMP:

GMP是质量保证的一部分，确保产品可以被持续地生产和控制以符合适用其预期用途和满足上市许可的质量标准。GMP的主要目标是减少药品生产的固有风险。这些风险基本有两个类型：交叉污染（特别是非预期的污染）和混乱（混淆）例如由贴在容器上的错误标签引起的。在GMP下：

(a) all manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

所有生产工艺都要明确规定、根据经验系统审核并证明其能够有能力持续一致地生产要求符合它们标准的质量的药品；

(b) qualification and validation are performed;

进行确认和验证；

(c) all necessary resources are provided, including:

提供所有必须的资源，包括：
(i) appropriately qualified and trained personnel;
合适的有资质并经过培训的人员；
(ii) adequate premises and space;

足够的厂房和空间；
(iii) suitable equipment and services;

合适的设备和服务；
(iv) appropriate materials, containers and labels;

合适的物料、容器和标签；
(v) approved procedures and instructions;
批准的程序和工艺规程；
(vi) suitable storage and transport;

合适的储存和运输；
(vii) adequate personnel, laboratories and equipment for in-process
controls;

足够的人员、实验室和设备用于中间过程控制；

(d) instructions and procedures are written in clear and unambiguous
language, specifically applicable to the facilities provided;
用清晰并没有歧义的语言编写的说明书和程序

(e) operators are trained to carry out procedures correctly;
培训操作人员正确地执行程序；

(f) records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated;
在生产中做记录（手工和/或通过记录仪）以显示所有由规定的程序和规程要求的所有步骤都已经在事实上被执行，产品的数量和质量跟期望的一样；任何重大偏差都被完整记录并调查；

(g) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;
以可理解和可以获取的形式保存涵盖生产和销售的可以帮助追踪到一批产品的完整的历史的记录；

(h) the proper storage and distribution of the products minimizes any risk to their quality;
正确地储存和分发产品减少对其质量的风险；

(i) a system is available to recall any batch of product from sale or supply;
可用的从销售或供应端召回任意批产品的系统；

(j) complaints about marketed products areexamined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.

对已销售产品的投诉进行检查、调查质量缺陷的原因并采取适当措施避免缺陷产品再次出现。