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FDA医疗器械质量体系手册 第二章 质量体系

(2011-01-18 09:11:21)


2. Quality Systems质量体系


     Design Controls 设计控制
     Component Selection 元件选择
     Labeling Content 标签控制
     Process Quality 工艺流程控制
     Management Responsibility 管理责任
     Formal and Documented Quality System 正式并且成文的质量体系
     Approval of Product 产品批准
     Quality Acceptance Activities 质量验收活动
     Quality System Audits 质量体系审核
     Employee Training 员工培训


The Quality System (QS) regulation requires that each manufacturer shall establish and maintain a quality system that is appropriate for the specific medical device(s) designed or manufactured (820.5 and 820.20). The GMP requirements are harmonized with the International Organization for Standards (ISO) 9001:1994 and ISO DIS 13485. The quality system should be an integrated effort -- a total systems approach, to satisfy the particular safety and performance needs of a specific manufacturer, product, and user-market. The quality assurance (QA) activities do not simply consist of inspection and testing spot solutions or "fire-fighting," no matter what the product is or how small the manufacturer. In all cases, quality should be considered at the earliest stages in every significant area that has an effect on the quality, safety, and effectiveness of the device. These areas include product development, design verification and validation, component and/or supplier selection, documentation, development of labeling, design transfer, process development and validation, pilot production, routine manufacturing, test/inspection, device history record evaluation, distribution, service or repair, and complaints. Complaints and, of course, favorable comments constitute customer feedback that may result in improvements in the device, labeling, packaging or quality system.



Most important of all is management commitment. Management and employees should have the correct attitude if their quality system program is to be effective. Quality consciousness should be developed in every employee. Each person should be made aware of the importance of his or her individual contributions in the overall effort to achieve an acceptable level of quality.



After a quality system is in place and checked, it should not be allowed to stagnate -- it should continue to be dynamic. The system remains dynamic through continuous feedback, "big-picture" monitoring by system audits, management review, and corrective and preventive action. Sufficient personnel with necessary education, background, and experience should be in all departments to ensure that quality system activities are properly and adequately performed.



The result is an organization that is operating in a known state-of-control for the device design, process design, manufacturing processes, and records. A properly functioning quality system results in increased safety and effectiveness of the device, reduced liability exposure, reduced regulatory exposure, increased customer satisfaction, less scrap, lower costs, much less confusion, higher employee morale, and, as a result, higher profits.



There are several QA systems in common use, including quality control, good manufacturing practices, product design assurance, the ISO 9000 series of international QA standards, and total quality assurance. Quality control is a minimal system which emphasizes test and inspection. The QS regulation is a government mandated QA system for medical device manufacturers. It emphasizes device, labeling, packaging and process design and all aspects of production: facilities, equipment, design development, design and production documentation, correct design transfer, production control, production records and feedback. Total quality assurance is a system which emphasizes that: all employees and suppliers are responsible for their activities; design requirements are established and met; process requirements are established and met; all production activities are controlled; finished product specifications are met; and feedback results in appropriate corrections.



Product design assurance is a QA system which assures that customer needs are determined, and that product design requirements are established and met. The ISO 9000 series of QA standards ranges from basic quality control to very significant design and production systems.



ISO 9001 is the most comprehensive because it covers design, production, servicing and corrective/preventive activities. The FDA GMP requirements are slightly more extensive because they include extensive coverage of labeling, and complaint handling.



An ideal system for quality assurance is discussed in order to explain the concept of a system. An ideal QA system is composed of an organization that executes a QA program according to documented policy and specifications in order to achieve stated objectives as shown in Figure 2.1.



FDA医疗器械质量体系手册 <wbr>第二章 <wbr>质量体系

Figure 2.1 Elements of a Quality System
图2.1 质量体系的元素

The written policies and objectives are set by management and are influenced by outside factors such as customer requirements, standards, and regulations. For example, the customer requirements and needs and resulting device specifications should be known to be correct, as these are based on market research, technical and medical considerations, consensus standards, review of existing devices, environmental and compatibility considerations, and design review. The objectives are to produce safe and effective devices at a profit. Ideally, the quality system includes everyone in the company as everyone is fully committed to the quality system program. In addition, however, quality assurance departments such as design QA and production QA are established to help achieve specific objectives. Tasks to be performed to meet these objectives are described in procedures and other documents.


Documentation for a quality system is composed of: product-specific technical documentation such as engineering drawings, component purchase specifications, procedures for manufacturing processes and testing; labels, etc.; and general quality system documentation, such as standard operating procedures (SOP's) for employee training, audits, etc., that are applicable for all products. All activities and product quality are monitored; and any deviations from device and process specifications and company policies are fed back into the system where the deviations are corrected. Likewise, complaint and service information are processed and fed back for appropriate corrections. If the required activities including the feedback are performed, the quality system is self correcting and, thus, the manufacturer is operating in a state-of-control. FDA requires manufacturers of medical devices to operate in a state-of-control.

质量体系文档是由:由诸如工程图纸,元器件采购规格,工艺流程及测试步骤所特定的产品,标志等;和诸如对员工培训及审计的标准操作程序(SOP)以及对所有产品都适合的通用质量体系文件组成。所有活动及产品质量都受监控。所有背离产品或工艺规格指标及公司质量政策的偏差都反馈回体系,并对偏差进行修正。同样地,客户投诉及维修信息受处理并反馈以得到适当的纠正。如果所需的活动包括反馈都在施行,质量体系则是自我修正的并且制造商从而是运作与受控状态。 FDA要求医疗器械制造商是在受控状态下运行。


An adequate and properly implemented quality system such as the one required by the QS regulation or ISO 9001, because of its broad scope, has a high likelihood of preventing the design, manufacture, and shipment of defective products. Basic quality controls such as inspection and testing, are important parts of a quality system because they provide information that should be fed back into the program where action can be taken to correct root causes of quality problems. Identifying and solving quality problems is a core requirement of the QS regulation. This approach is in contrast to merely applying superficial corrections by pass/fail quality-control inspection including rework of finished product or in-process assemblies.


Feedback is necessary to verify the adequacy of the design, manufacturing processes, and the controls used. It also helps trigger corrective action to solve root causes of quality problems rather than just performing rework.


Design Controls设计控制

Each manufacturer is required by regulation to establish and maintain design control procedures for any class III or class II device, and a selected group of class I devices. The class I devices subject to design controls are devices automated with computer software and the following specific devices:


868.6810 Catheter, Tracheobronchial Suction导尿管,支气管吸管
878.4460 Glove, Surgeon's外科手术手套
880.6760 Restraint, Protective保护性限制器
892.5650 System, Applicator, Radionuclide, Manual放射性系统,辅料及手册
892.5740 Source, Radionuclide Teletherapy放射性远距离疗法的放射源

Because the intrinsic quality level of devices and processes is established during the design phase, the quality system program should include this phase if the program is to assure overall quality, meet customer requirements, meet company quality claims, and comply with the intent of the FD&C Act. The terms "product assurance" and "design QA" are often used to identify the quality system activities related to product design. The QS regulation uses the term "design controls." A product assurance system or design QA system combined with a production QA system constitutes a total quality system.


Quality system, production, regulatory, and other appropriate personnel should participate in the review, evaluation, and documentation of the components, device, and process design. It is from data established during this preproduction phase that all other activities derive such as, purchasing, processing, and testing. Development and validation data are also useful in cases of regulatory or product liability actions to show that the design and manufacturing processes were well conceived and properly validated, reviewed, and documented.



Total quality systems extend from customer requirements through development and production to customer use and feedback. Thus total quality systems encompass the medical device law and regulations, particularly the QS regulation. The FD&C Act, and its implementing regulations such as those for Labeling, Premarket Notification, Investigational Device Exemptions (IDE), Premarket Approval (PMA), and GMP requirements impact the quality of devices at various times during the design product life-cycle. The IDE, PMA, 510(k), labeling and QS regulation with their preproduction and production requirements constitute a total quality system. For example, Section 501(c) of the Act states that a product is adulterated if it does not have a quality equal to the quality stated or implied by the product labeling. Analysis of device recall problem data by FDA has shown that such problems are divided almost equally between design and production. Thus, a production quality assurance program is not sufficient to produce safe and effective devices -- design shall also be covered. A design quality assurance system is required by the QS regulation.

Two other reasons for having a total quality system are 21 CFR Part 803, Medical Device Reporting (MDR), and product liability. MDR requires manufacturers of medical devices to report to FDA certain adverse events that they receive from any source. Product liability actions are often the result of poor design, labeling, and manufacturing. Reporting and liability exposure are reduced by using a total quality system.

全面质量体系将范围扩展至客户使用及反馈。因而全面质量包含医疗器械法律法规,特别是QS法规。FD&C法案以其实施的法规,包括标志,市场前通知,调研性器械法规豁免(IDE),市场前批准(PMA),以及GMP在所设计产品生命周期各个时期影响着其质量。IDE,PMA,510(k),标志及QS法规中关于生产前及生产时的要求构成全面质量体系。例如如法案501(c)节所述的如果产品未达到产品标志所述的或提示的质量,则被认为是次品。FDA通过对召回产品的问题数据分析发现,类似的问题由设计和生产所产生的几乎一样多。因而,生产质量的质量保障程序对于医疗器械的安全和有效是不够的,设计也应包括在内。设计质量保障体系是QS体系所要求的。采用全面质量体系的另两个原因是21CFR803部分,医疗器械报告(MDR ),以及产品义务。MDR要求医疗器械制造商向FDA报告其从任何来源收到的某些不利事件。产品(赔偿或召回)义务活动通常是有不良设计,标志和制造所导致的。报告和(赔偿或召回)义务暴露可通过全面质量体系减少。

Intrinsic or desired quality is established by the design specifications for the product, its components, and the manufacturing processes. Complying with the QS regulation assures that the manufacturing processes can consistently achieve desired levels of quality and that the finished device meets its device master record specifications. This result is a significant quality step. However, if the device as designed is of poor quality, the GMP production controls will only assure that a poor quality device is manufactured. Thus, the QS regulation requires an overall quality system program, which embraces evaluation of customer needs; product design; verification and validation; labeling development and control; all manufacturing and control activities; and customer feedback.


Component Selection元器件选择

Component and raw material specifications developed during the design phase should be well conceived and adequate for their intended purpose. New components or components for an unusual application need to be verified (qualified) for the intended use. In some cases, where large quantities of components or raw materials are involved, the specifications should include valid and well understood methods of sampling and acceptance. These specification and sampling/acceptance plans should also be accessible and acceptable to suppliers. The specifications are device master record (DMR) spec document or the specifications appear in a DMR drawing or procedure.



Manufacturers shall establish and maintain procedures to ensure their purchased and otherwise received products and services conform to their specified requirements. The manufacturers shall then assess their suppliers, contractors, and consultants based on their ability to meet the established specifications. When possible, an agreement shall be established to include that the suppliers, contractors, and consultants will notify the manufacturer of any changes in the product or service that may affect the quality of a finished device.


Labeling Content标志内容

The regulations in 21 CFR Part 801, Labeling; Part 809, In Vitro Diagnostic Products for Human Use; and Part 812, Investigational Device Exemptions, are intended to control the content of labeling. Likewise, 21 CFR Part 807, Premarket Notification; and Part 814, Premarket Approval and 820.30, Design Controls, help control the content of labeling by design and premarket submissions. The intent of these regulations and the FD&C Act is for manufacturers to have a labeling control program such that their labeling always complies with the regulations and meets the needs of the users. By a formal process under a total quality system during the design phase, clear and concise printed and/or software labeling are written and reviewed; and the ink substrate and attachment methods for printed labeling are developed. Such labeling is designed to meet customer and regulatory requirements. Thereafter, the procurement, use of the correct label, and the correct attachment of labels is assured under a manufacturer's quality system elements for these activities.


Process Quality工艺质量

Manufacturing methods and processes to be used should be developed, equipment selected, and processes and methods qualified. For all significant processes such as welding, molding, lyophilizing, sterilizing, and packaging/sealing where the output cannot be fully verified, the qualification should include a full validation of the processes. The output may not be fully verified for economic, technical, or practical reasons and thus validation is needed. Production specifications and methods employed in manufacturing should result in standard in-process and finished products without excessive sorting or reprocessing. Inspection and test methods should be developed that will adequately monitor product characteristics to make certain these are within the acceptable specifications. These methods should be developed, evaluated, validated where necessary, and documented during the product and process development phase. The methods should be implemented at the beginning of routine production.



Any adverse effects the manufacturing processes, manufacturing materials, or equipment may have on device safety and performance should be identified. Where necessary, procedures have to be developed, implemented, and monitored to control these characteristics. Quality system personnel should participate in the timely (i.e., early) development of special controls, test or inspection methods, or training programs needed to insure product quality. Acceptance methods should be developed for accurate measurement of outgoing product quality.


Management Responsibility管理者责任

As set forth by the QS regulation (820.20), one of the most important responsibilities of management when developing a quality system is to establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization. This means each manufacturer shall establish the appropriate responsibility, authority, and interrelation of all personnel who manage, perform, and assess work affecting quality, and provide the independence and authority necessary to perform these tasks. The QS regulation also requires that each manufacturer shall establish and maintain an adequate organizational structure to ensure that devices are designed and produced in accordance with the GMP requirements. To meet these regulatory requirements, manufacturers are required to provide adequate resources, including the assignment of trained personnel for management, performance of work, and assessment activities, including internal quality audits.


Management with executive responsibility shall appoint a member of management who will have authority over and responsibility for:



  • Ensuring that quality system requirements are effectively established and effectively maintained; and
  • 确保质量体系按要求有效建立,维护并且
  • Reporting the performance of the quality system to management with executive responsibility for review.
  • 向行政管理职责的管理者报告质量体系绩效以供评价

Thus, the QS regulation requires that management with executive responsibility shall review the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the regulatory requirements and the manufacturer's established quality policy and objectives. The dates and results of quality system reviews shall be documented.



The quality assurance personnel should be able to identify system problems, to recommend and provide solutions, and to verify implementation of the solutions. Other personnel may also identify and solve quality problems. The quality system should support such activities by all personnel. Feedback from quality assessment activities is necessary to verify the adequacy of the manufacturing process and the controls used. It also helps trigger corrective action to solve root causes of quality problems rather than just performing rework.


Typically, a quality system identifies problems with device quality through review of verification and validation data, inspection/test data, analysis of device history and service records, failure analysis, analysis of complaints, and review of other objective data. In this regard, reduction in productivity is often an indicator of quality problems. Low morale and confusion are indicators of inadequate procedures, and/or training and poor management. Also, measurement of scrap and rework is an effective method of detecting quality problems and reducing costs. These are examples of sources that provide feedback to the quality system.



In conclusion, each manufacturer is required to establish a quality plan which defines the quality practices, resources, and activities relevant to the devices that are designed and manufactured. The manufacturer shall establish how the requirements for quality will be met [820.20(d)]. Each manufacturer shall establish quality system procedures and instructions. To facilitate the understanding, use, review, and updating of the quality system, an outline of the structure of the documentation used in the quality system shall be established where appropriate [820.20(e)].


Formal and Documented Quality System正式的质量体系文档

The QS regulation requires that each manufacturer prepare and implement quality system procedures adequate to assure that a formally established and documented quality system is implemented The system should include not only formal documentation, but also an obvious commitment to quality from top management. There should be manifest indications that management recognizes the need for a quality system in order to assure quality products. In many manufacturers, this commitment is accomplished through means such as: a management policy; assignment of responsibilities and authorities; and general statements and actions such as employee training that define goals of the quality system. This policy is supported by a number of more detailed quality system documents such as verification methods, sampling procedures, inspection/test procedures, product audits, and records indicating that measurement and monitoring of quality has occurred. The number of documents needed depends on the size and complexity of the operation and the characteristics of the product. The QS regulation requires the manufacturer to maintain various records such as:


  • design history files,设计历史文件,
  • device master records,器械主记录,
  • device history records,器械历史记录,
  • maintenance schedules and records,维护保养日程及记录,
  • complaint files and failed device/component files,投诉及失效器械/零件的记录
  • audit reports,审计报告
  • distribution records, and分销记录,及
  • personnel training records.人员培训记录

Most of these records are discussed in more detail in later chapters. In each case, the records should be appropriate for the device and the operation involved. Any changes to device master records should be made by a formal procedure and be formally approved.



Among other records, the device master record contains manufacturing procedures and standard operating procedures (SOP's). Some manufacturers tend to write an excessive number of general SOP's. Manufacturers should not generate and use procedures that are not needed. Also, standard operating procedures tend to not match actual operations because the operations gradually change as the company grows or as products are added without amending the procedures. Such procedures may require operations that have no benefit, or require excessive collection of data, or collection of data that is never used. Thus, manufacturers need to occasionally flow chart and analyze their operations to determine, among other things, if the existing procedures are inadequate, correct, or excessive. Flow-charting is a tool that directs a detailed audit of an operation. Flow-charting to analyze operations is an excellent method for improving operations and the associated quality system activities. At the end of Chapter 10, Purchasing and Acceptance Activities, an example of a flow-chart is contained in PA­1004, Procedure for Receiving and Inspection of Material, integral page 4 of 9.


Approval of Product产品批准

The quality system includes procedures for assuring that all products such as components, packaging, labeling, manufacturing materials, and finished devices have been approved for use; and that contracted items and services are suitable [820.50, 820.80]. Likewise, the quality system shall assure that rejected items are identified and properly disposed [820.90]. Additionally, the quality system shall assure that production records are reviewed before the product is distributed [820.80(d)]. These records are part of the device history record. Device history records shall be reviewed to verify that the operations represented have been properly conducted and that the records are complete.

质量体系包括确保所有产品诸如元器件,包装,标志,原材料,以及成品都经过批准使用的步骤。这同样也适用于合同承包项目及服务[820.50, 820.80]。类似地,质量体系要确保拒收的物料被识别和妥善处理[820.90]。此外,质量体系要确保生产记录在销售前得到评审。这些记录是器械历史记录的一部分,而器械历史记录应被回顾以确定所表现的操作是否正确执行,记录是否完整。

Quality Acceptance Activities质量验收活动

The quality system shall determine that all tests and inspections are performed correctly (see 820.80, 820.181, and 820.20). Some of the methods used to accomplish this are adequate test and inspection procedures, training of test personnel, quality system audits, review of quality system records, and product audits. However, simply instituting a quality system and checking that it is conducted correctly is not enough to satisfy the QS regulation. The regulation also requires that the quality system be appropriate and adequate for the purpose. This determination should be done during final product development, pilot production, and, of course, whenever product and/or processes are modified. In cases where conformance to specifications cannot be adequately measured by in-process or finished product testing and inspection, the system should include validation of processes.

质量体系应确定所有的测试和检验是正确执行的(见 820.80, 820.181, 和 820.20)。达成这点的部分方法是正确适当的测试检验步骤,受过培训的测试人员,质量体系审核,评审质量体系记录,以及产品审核。然而,对质量体系及检查的简单的直觉以及正确执行检查并不足以满足QS法规的要求,法规也要求质量体系对于目的是适当的和合适的。这个结论要在产品开发的最后阶段,试生产,并且当然也包括产品或工艺流程的改变时得出。当最终产品的指标符合不能适当地在流程内或终测时检测,体系也要包括工艺过程验证。

Quality System Audits质量体系审核

The QS regulation requires (820.20) that each manufacturer shall prepare and implement quality system procedures adequate to assure that a formally established and documented quality system program is performed. Many activities are required to fulfill this requirement. As management performs their assigned routine duties, they should be aware of the obvious aspects of the quality system. However, to make sure that all aspects, obvious, hidden or subtle, of the required program exist and are operating correctly, the QS regulation requires planned and periodic audits (820.22) of the quality system. Management with executive responsibility reviews audit reports as part of their review of the suitability and effectiveness of the quality system.


Employee Training员工培训

QS regulation requires quality awareness training for manufacturing and quality system personnel [820.25(b)]. Personnel involved in quality system activities shall be properly trained, both by education and experience. No matter how effective quality system and production systems are as concepts, people still play the major role in producing a quality product. Lack of training -- as reflected in instances of negligence, poor operating techniques, or inability of employees to discharge their functions properly -- can lead to defective products and, sometimes, to regulatory or liability problems. Management should be diligent in looking for factors that indicate a need for employee training.


A quality system should include an ongoing formal program for training and motivating all personnel. All employees should be made aware that product quality is not solely the responsibility of management. Quality is the responsibility of every employee -- any employee can potentially generate a quality problem through negligence. It is extremely important to understand the following points with respect to typical quality-related functions.


  • Top management sets the quality attitude for the company.最高管理层建立公司的质量态度
  • Research and development has primary responsibility for designing quality into the device.研发部门对产品的设计质量负有最基本的责任
  • Technical services or an equivalent functional group has primary responsibility for documenting the design.技术服务或相当的职能部门负有设计文档的基本责任。
  • Manufacturing, process or "scale-up" engineering has primary responsibility for designing quality into the manufacturing processes.制造,工艺或量产工程部门负有制造流程设计质量的基本责任。
  • Manufacturing personnel have primary responsibility for producing devices that have the maximum level of quality that can be achieved based on the product and process designs.制造人员对基于产品设计和工艺设计基础上生产能达到的最高质量产品负有基本责任。
  • Quality system personnel have primary responsibility for the program's management, status reports, audits, problem identification, data analysis, etc., as described in the QS regulation and in this manual.质量体系人员对质量程序管理,状态报告,审计,问题确认数据分析,等等,如在QS法规和本手册所描述的那样负有基本责任。

A medical device manufacturer should NEVER try to operate on the basis that only the quality system organization has primary and direct responsibility for the quality of the products. To do so means that quality problems will not be solved in a timely manner because attention is directed toward the wrong organization. In reality, it is part of the responsibility of the quality system to see that attention is directed toward the correct department if a quality problem arises.


Where necessary, employees should be certified to perform certain manufacturing or quality system procedures. Records of training and/or certification shall be maintained. Personnel performing quality system functions should:


  • have sufficient, well-defined responsibilities and authority;接受足够的,明确定义职责和授权
  • be afforded the organizational freedom to identify and evaluate quality problems;有组织提供的自由度来识别和评估质量问题。
  • be able to formulate, obtain, and recommend possible solutions for quality system problems; and,能够简明阐述,获得和建议可能的质量体系问题的解决方案;
  • verify implementation of solutions to quality problems.验证质量问题解决方案的实施


After the quality system is operational, personnel should continue to look for problem areas or factors that can have an impact on product quality. Many factors that can have an impact on product quality include:



  • changes in, or absence of, personnel; 变动或缺少人员
  • uncomfortable working conditions (e.g., breakdowns in air conditioning); 不舒适的工作环境(例如,空调损坏)
  • increases in workload or production rates;增加工作负担或产量
  • introduction of new production or inspection equipment;引入新生产或检验设备
  • changes in company incentive techniques (e.g., placing hourly employees on piecework can cause deterioration of product quality); and公司奖励机制的变更(例如,引入计件制的小时工可引发产品质量劣化)
  • changes in sources for purchased components and materials, as well as changes in components, devices, or process techniques.变更采购元器件和原材料的货源,或者是变更元件,器具及工艺技术。

As noted, quality system audits and flow-charting of operations are excellent methods for determining the detailed status of the system. Correcting problems or responding to conditions identified by audits, operational analyses, and customer feedback data can result in quality system improvements.



FDA has promulgated regulations [803] for manufacturers, distributors, and initial distributor(s) requiring them to establish and maintain reports, including the Medical Device Reporting (MDR) reports for serious injuries, death, or certain other adverse incidents. If a manufacturer has a quality system as required by the QS regulation, the frequency of MDR reporting should be minimized.



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