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1、FOOD AND DRUGADMINISTRATIONGUIDE TO INSPECTIONS OFQUALITY SYSTEMS1August 119992Guide to Inspections ofQuality SystemsThis document was developed by the Quality System Inspec-tions Reengineering Team MembersOffice of Regulatory AffairsRob RuffGeorgia LayloffDenise DionNorm WongCenter for Devices and
2、Radiological HealthTim Wells Team LeaderChris NelsonCory TylkaAdvisorsChet ReynoldsKim TrautmanAllen WynnDesigned and Produced by Malaka C. Desroches3ForewordThis document provides guidance to the FDAfield staff on a new inspectional process thatmay be used to assess a medical devicemanufacturers co
3、mpliance with the QualitySystem Regulation and related regulations. Thenew inspectional process is known as the“Quality System Inspection Technique” or“QSIT”. Field investigators may conduct an ef-ficient and effective comprehensive inspectionusing this guidance material which will helpthem focus on
4、 key elements of a firms qualitysystem.Note: This manual is reference material for investi-gators and other FDA personnel. The document doesnot bind FDA and does not confer any rights, privi-leges, benefits or im4munities for or on any person(s).Table of ContentsPerforming Subsystem Inspections. . .
5、 . . . . . . . . . . . . 7Pre-announced Inspections. . . . . . . . . . . . . . . . . . . .13Getting Started. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15Management Controls. . . . . . . . . . . . . . . . . . . . . . . .17Inspectional Objectives18Decision Flow Chart19Narrative20Design
6、Controls. . . . . . . . . . . . . . . . . . . . . . . . . . . .31Inspectional Objectives32Decision Flow Chart33Narrative34Corrective and Preventive Actions (CAPA). . . . . . . .47Inspectional Objectives48Decision Flow Chart49Narrative50Medical Device Reporting61Inspectional Objectives62Decision Flow
7、 Chart63Narrative64Corrections & Removals67Inspectional Objectives68Decision Flow Chart69Narrative70Medical Device Tracking73Inspectional Objectives74Decision Flow Chart75Narrative76Production and Process Controls (P&PC). . . . . . . . 79Inspectional Objectives80Decision Flow Chart81Narrativ
8、e82Sterilization Process Control9s1Inspectional Objectives92Decision Flow Chart93Narrative94Sampling Plans. . . . . . . . . . . . . . . . . . . . . . . . . . . 103Instructions104Tables (Backpage)1075This reference is intended to be used in conjunction withthe:rCompliance Program Guidance Manual for
9、Inspection of MedicalDevice Manufacturers (CP 7382.845).rInvestigations Operations Manual (IOM).rCode of Federal Regulations, Title 21 (21 CFR) Part 820 QualitySystem Regulation; Part 803 Medical Device Reporting; Part 806Medical Device Corrections and Removals; Part 821 Medical DeviceTracking.rComp
10、liance Policy Guides (CPG) for devices (Sub Chapter 300).rGuideline on General Principles of Process Validation, FDA, May1987.Other references include:rThe Federal Food, Drug, and Cosmetic Act; The Safe Medical DevicesAct (SMDA) of 1990 and the Medical Device Amendments of 1992.rMedical Device Quali
11、ty Systems Manual: A Small Entity ComplianceGuide.rThe FDA Worldwide Quality System Requirements Guidebook forMedical Devices.rOther device specific guidance documents prepared by CDRH for themedical device industry.rFDA Recognized Standards.These additional guidances are posted to the CDRH Internet
12、World Wide Web Home 6Page hattt p:/www.fda.gov/c.drhSee IOM Chapter 10, References, for additional information.Performing SubsystemInspectionsThe Guide to Inspections of Quality Systems provides in-structions for conducting medical device quality system/GMP inspections. It is to be used in conjuncti
13、on with thecompliance program entitled Inspections of Medical DeviceManufacturers (7382.845). The guide was prepared bythe Food and Drug Administration (FDA) Office of Regula-tory Affairs (ORA), and the Center for Devices and Radio-logical Health (CDRH). It provides guidance for inspectingmedical de
14、vice manufacturers against the Quality SystemRegulation (21 CFR Part 820) and related regulations.This process for performing subsystem inspections is basedon a “top-down” approach to inspecting. The subsystemapproach is designed to provide you with the key objec-tives that can help determine a firm
15、s state of compliance.The process was designed to account for the time con-straints placed on field investigators when performing de-vice quality system inspections. If you can focus your ef-fort on key elements of a firms quality system, you canefficiently and effectively evaluate that quality syst
16、em.7When you begin an inspection by looking at one or moreinstances of quality problems, such as nonconforming de-vice reports, and work your way back through the firm'squality system, you are doing a “bottom-up” inspection.This method has been helpful in zeroing in on specific prob-lems, and e
17、valuating the firms actions relating to thoseproblems. However, with the “top-down” approach, weare looking at the firms “systems” for addressing qualitybefore we actually look at specific quality problems. In the“top-down” approach, we “touch bottom” in each of thesubsystems by sampling records, ra
18、ther than working ourway from records review backwards towards procedures.The “top-down” approach begins each subsystem reviewwith an evaluation of whether the firm has addressed thebasic requirements in that subsystem by defining and docu-menting appropriate procedures. This is followed by ananalys
19、is of whether the firm has implemented the require-ments of that subsystem.The illustration provided inside the front cover of this bookshows the seven subsystems, along with related satelliteprograms. Based on discussions between the device in-dustry and the agency, we have chosen four major sub-sy
20、stems that are the basic foundation of a firms qualitysystem. Those four major subsystems are ManagementControl; Corrective and Preventive Actions (CAPA) (withsatellites Medical Device Reporting, Corrections and Re-movals, and Medical Device Tracking); Design Controls;and Production and Process Cont
21、rols (P&PC) (with satel-lite Sterilization Process Controls). We have provided a8suggested technique for inspecting each of these four sub-systems. In addition, following the chapter of the relatedsubsystem we have provided suggested techniques forinspecting the satellite programs.The satellite
22、programs were included in the QSIT Inspec-tion due to their correlation in the inspection process withthe related subsystem. For instance, the CAPA subsystemis the logical “jumping-off” point to begin inspecting forMedical Device Reporting, Corrections and Removals, andMedical Device Tracking progra
23、ms which relate to a firmspostmarket activities. In the case of the CAPA subsystem,if you are covering the satellite programs in your inspec-tion, approximately half a day should be added to yoursubsystem inspection timeframe.Rather than check every aspect of the firms quality sys-tem, the subsystem
24、 approach focuses you on those ele-ments that are most important in meeting the requirementsof the quality system regulation and which are key qualityindicators. Between 6-15 inspectional objectives are pro-vided for the review of each subsystem. The review in-cludes both a (broad) review of whether
25、 the firm has pro-cedures in place, and appears to meet the requirements,and a closer (detailed) review of some records to verifythat the requirements have been implemented in actualproduction, design and daily quality assurance situations.One similarity between “top-down” and “bottom-up” inspec-tio
26、nal approaches is record review. Both approaches in-volve review of raw data, or individual records. In the“top-down” approach, however, we are asking you to use9a sampling approach to the record review. With the “top-down” approach, you will sample records in many of thesubsystems to verify whether
27、 or not the firm is in compli-ance. In other words, you are doing the raw data reviewas you did in the past, but in a more controlled manner.We have provided sampling tables to assist you in deter-mining how many records you need to review, and whatconfidence you can have in the potential prevalence
28、 ofthe observed conditions.One new feature in the “top-down” inspection techniqueis the use of inspectional objectives and flow diagrams toguide you during the inspection. We have provided in-spectional objectives and flow diagrams that are useful ininspecting the four major subsystems. The flow dia
29、gramsprovide a quick overview of how the inspection of eachsubsystem should occur.In addition to the inspectional objectives and flow dia-grams, we have provided a narrative description describ-ing how to perform the inspection of each subsystem. Thenarrative description includes a discussion on how
30、 toachieve each inspectional objective and reflects the ques-tions contained within the flow diagrams. You are notbound to follow each and every sentence in the narrative.Rather, you should inspect the subsystem with the narra-tive guidance in mind.The Quality System Regulation (21 CFR 820.3(k) de-f
31、ines “Establish” as “define, document (in writing or elec-tronically), and implement”. The Quality System Inspec-tion Technique uses the “establish” approach in conduct-10ing the inspection. For each subsystem, you will first deter-mine if the firm has defined and documented the require-ments (CAPA,
32、 Design, etc.) by looking at procedures andpolicies, and then you will bore down into records, using thesampling tables, where appropriate, looking at raw data todetermine if the firm is meeting their own procedures andpolicies, and if their program for executing the requirementis adequate.The durat
33、ion of inspection is related to the depth of the in-spection. Keep in mind that the subsystem approach pro-vides you with the key inspectional objectives that can helpdetermine a firms state of compliance. At the same time,the guidance was designed to accomplish a complete re-view of all four subsys
34、tems in approximately one week.While the length of your inspections will vary, using key in-spectional objectives will help assure that you look at themost important elements of the firms quality system duringthe inspection.Most device firms are inspected more than once. By prob-ing different subsys
35、tems, different devices or different pro-cesses each time, FDA will eventually have covered mostof the firms quality system. You are not expected to covereverything in the firm and in the narrative each time. Youare expected to evaluate the firms quality system, but alsoto do it in an efficient and
36、focused manner. Thus, you shouldlimit the depth of coverage when necessary to meet thetime frame suggested. As a general rule of thumb, one dayshould be sufficient to cover each subsystem when usingthe “top-down” approach described within this document.In practice, you may find that the inspection o
37、f a certain11subsystem may take half a day, while another may takeone and a half days. This situation would still reflect anoverall one day per subsystem time frame.By directing your attention to the major areas in a firmsquality system, you should be better able to determine ifthe firms quality sys
38、tem is in control. Using the subsystemapproach, you may find less opportunity to cite minor de-viations from the quality system regulation than in the past.However, you will be citing more serious (systemic) devia-tions from the regulation.12PREANNOUNCEDINSPECTIONSThe ORA Medical Device Industry Ini
39、tiatives program en-compasses preannounced medical device inspections, FDA483 Annotation and Postinspectional Notification.The instructions for Preannouncement (including the crite-ria to be used in determining when preannouncement isappropriate), FDA 483 Annotation and Post-inspection No-tification
40、 were provided in an April 3, 1996, Federal Regis-ter Notice (Volume 61, Number 65). Refer to the Investiga-tions Operations Manual (IOM) for further information.When contacting the firm for the preannounced QSIT In-spection, the investigator should ask for a copy of the firmsQuality Policy and high
41、 level Quality System Procedures(including Management Review Procedures), QualityManual, Quality Plan or equivalent documents to previewprior to the inspection. The firm is not required to supplythese documents. The investigator should tell the firm thatthe preview of these procedural documents woul
42、d facili-tate the inspection. The documents would be returned atthe time of the inspection. If you find deficiencies in thesedocuments, you should request copies of the original docu-ments after you initiate the inspection.1314GETTING STARTEDIt is essential that the firm establishes and maintains a
43、qualitysystem that is appropriate for the specific medical devicebeing manufactured and meets the requirements of theQuality System Regulation. The Management Represen-tative has the responsibility to ensure that the requirementsof the Quality System Regulation have been effectively es-tablished and
44、 maintained. Prior to your review of any sub-system, interview the Management Representative (or des-ignee). The objective of this interview is to obtain an over-all view of the subsystem as well as a feel for managementsknowledge and understanding of the subsystem. An im-portant linkage for this ac
45、tivity is Management Controls(820.20 Management Responsibility).1516ManagementControlsSubsystem17Management ControlsInspectional Objectives1.Verify that a quality policy, management review andquality audit procedures, quality plan, and quality sys-tem procedures and instructions have been defined an
46、ddocumented.2.Verify that a quality policy and objectives have beenimplemented.3.Review the firm's established organizational structureto confirm that it includes provisions for responsibili-ties, authorities and necessary resources.4.Confirm that a management representative has beenappointed.
47、Evaluate the purview of the managementrepresentative.5.Verify that management reviews, including a review ofthe suitability and effectiveness of the quality system,are being conducted.6.Verify that quality audits, including re-audits of deficientmatters, of the quality system are being conducted.At
48、the conclusion of the inspection.7.Evaluate whether management with executive respon-sibility ensures that an adequate and effective qualitysystem has been established and maintained.1819Management ControlsNarrativePurpose/ImportanceThe purpose of the management control subsystem is to provide adequ
49、ateresources for device design, manufacturing, quality assurance, distribution,installation, and servicing activities; assure the quality system is functioningproperly; monitor the quality system; and make necessary adjustments. Aquality system that has been implemented effectively and is monitored toidentify and address problems is more likely to produce devices that functionas intended.A primary purpose of the inspection is to determi
