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1、 1-1 1 THE QUALITY SYSTEM REGULATION INTRODUCTION .1-1 FLEXIBILITY OF THE GMP .1-2 MANUAL CONTENTS .1-3 GMP APPLICATIONS AND EXEMPTIONS.1-4 Exemptions .1-4 Component Manufacturers .1-5 Remanufacturers .1-6 Custom Device Manufacturers .1-6 Contract Manufacturers .1-6 Contract Testing Laboratories .1-
2、6 Repackagers,Relabelers,and Specification Developers .1-7 Initial Distributors of Imported Devices .1-8 INTRODUCTION The current Good Manufacturing Practices(GMP)requirements set forth in the Quality System(QS)regulation are promulgated under section 520 of the Food,Drug and Cosmetic(FD&C)Act.They
3、require that domestic or foreign manufacturers have a quality system for the design and production of medical devices intended for commercial distribution in the United States.The regulation requires that various specifications and controls be established for devices;that devices be designed under a
4、 quality system to meet these specifications;that devices be manufactured under a quality system;that finished devices meet these specifications;that devices be correctly installed,checked and serviced;that quality data be analyzed to identify and correct quality problems;and that complaints be proc
5、essed.Thus,the QS regulation helps assure that 1-2 medical devices are safe and effective for their intended use.The Food and Drug Administration(FDA)monitors device problem data and inspects the operations and records of device developers and manufacturers to determine compliance with the GMP requi
6、rements in the QS regulation.The QS regulation is in Part 820 of Title 21 of the Code of Federal Regulations(CFR).This regulation covers quality management and organization,device design,buildings,equipment,purchase and handling of components,production and process controls,packaging and labeling co
7、ntrol,device evaluation,distribution,installation,complaint handling,servicing,and records.The preamble describes the public comments received during the development of the QS regulation and describes the FDA Commissioners resolution of the comments.Thus,the preamble contains valuable insight into t
8、he meaning and intent of the QS regulation.The QS regulation is reprinted in the appendix of this manual.1-3 FLEXIBILITY OF THE GMP Manufacturers should use good judgment when developing their quality system and apply those sections of the QS regulation that are applicable to their specific products
9、 and operations.Section 820.5 of the QS regulation requires that,Each manufacturer shall establish and maintain a quality system that is appropriate for the specific device(s)designed or manufactured,and that meets the requirements of this part.The word appropriate means that the rule is a flexible
10、regulation.However,if manufacturers decide to not implement certain GMP requirements which are qualified by the term“where appropriate,”they should document their justification for nonimplementation.The justification should show that not implementing a requirement is not reasonably expected to resul
11、t in product that does not meet specifications or failure to carry out any necessary corrective action 820.1(a)(30.Operating within this flexibility,it is the responsibility of each manufacturer to establish requirements for each type or family of devices that will result in devices that are safe an
12、d effective,and to establish methods and procedures to design,produce,and distribute devices that meet the quality system requirements.FDA has identified in the QS regulation the essential elements that a quality system shall embody for design,production and distribution,without prescribing specific
13、 ways to establish these elements.Because the QS regulation covers a broad spectrum of devices and production processes,it allows some leeway in the details of quality system elements.It is left to manufacturers to determine the necessity for,or extent of some quality elements and to develop and imp
14、lement specific procedures tailored to their particular processes and devices.For example,if it is impossible to mix up labels at a manufacturer because there is only one label or one product,then there is no necessity for the manufacturer to comply with all of the GMP requirements under device labe
15、ling.The medical device QS regulation requires an umbrella quality system intended to cover the design,production,and distribution of all medical devices from simple surgical hand tools to very complex computerized axial tomography(CAT)scanners.It is not practical for a regulation to specify details
16、 of quality system elements for such a wide range of products.Rather,the QS regulation specifies general objectives such as use of trained employees,design reviews,design 1-4 validation,calibrated equipment,process controls,etc.,rather than methods,because a specific method would not be appropriate
17、to all operations.In most cases,it is left to the manufacturer to determine the best methods to attain quality objectives.In some cases,however,the QS regulation does specify the particular type of method to be used,such as written procedures or written instructions.This does not mean,however,that m
18、anufacturers cannot vary from the method specified if the intent of the GMP requirement can be met by another method such as using an engineering drawing plus a model device as manufacturing instructions.Written procedures are not restricted to paper copies.Written procedures may be filed and distri
19、buted by automated data processing equipment.This flexibility is allowed by section 820.180.Typically,large manufacturers will have a quality system that exceeds the medical device QS regulation.Small manufacturers will typically have a proportionally simpler system.FDA recognizes:that a small manuf
20、acturer may not need the same amount of documentation that a large manufacturer does in order to achieve a state-of-control;and,that some of records maintained to fulfill the GMP requirements for written procedures may not be as long and complex for a small manufacturer.After a manufacturer establis
21、hes a quality system,it should be maintained.Each manufacturer should assure that with growth and process or product changes their quality system is still adequate.This assurance is obtained through change control,day-to-day observance of operations,and by periodic audits of the quality system.The a
22、uditor should first identify the elements of the companys quality system.Next the audit should determine how well each element is functioning,and then determine its adequacy with respect to the intent of the device GMP requirements and meeting the companys quality claims.MANUAL CONTENTS To aid audit
23、ors,QA managers,and others,this manual provides guidance in the interpretation of the GMP requirements,and demonstrates the flexibility of the QS regulation in its application to 1-5 diverse devices,manufacturing processes,and manufacturers.In the absence of guidance from FDA,manufacturers may rely
24、on industry,national,and international consensus standards or guidances to meet GMP requirements.This manual was also developed to aid manufacturers in completing,maintaining,or expanding their quality system.Contents include educational materials,aids,and examples of how to implement elements of a
25、quality system,together with detailed examples of procedures,control forms,and associated data.The examples of typical procedures,drawings,and forms found in this manual were derived from quality systems in the device industry.These materials are not meant to describe universally applicable elements
26、 of a quality system that can be used unchanged by any manufacturer.Of course,a form or aid as presented in this manual may be suitable for direct use for a specific device and operation;however,in general,manufacturers will need to use care in adopting and modifying a selected form or procedure to
27、meet the specific quality system needs of their devices and operations.This manual is arranged as if the reader were starting a new business.That is,as if an entrepreneur were sequentially:1.obtaining information on GMP requirements;2.determining the appropriate quality system needed to control the
28、design,production and distribution of the proposed device;3.designing products and processes;4.training employees;5.acquiring adequate facilities;6.purchasing and installing processing equipment;7.drafting the device master record;8.noting how to change the device master records;9.procuring componen
29、ts and materials;10.producing devices;11.labeling devices;12.evaluating finished devices;1-6 13.packaging devices;14.distributing devices;15.processing complaints and analyzing service and repair data;16.servicing devices;17.auditing and correcting deficiencies in the quality system;and 18.preparing
30、 for an FDA inspection.If manufacturers perform these activities as required by the QS regulation and as expounded in this manual,they should be prepared for a GMP inspection of their operations by an FDA investigator.Manufacturers and importers of medical devices shall also comply with the Medical
31、Device Reporting(MDR)regulation,21 CFR Part 803,which requires that serious complaints be reported to FDA.MDR is related to the GMP complaint and failure investigation requirements,which are covered in Chapter 15.If manufacturers comply with the QS regulation and guidance in this manual and in other
32、 sources,there is a high probability that they will reduce the frequency of reportable events.GMP APPLICATIONS AND EXEMPTIONS The QS regulation applies to finished devices intended to be commercially distributed for human use unless there is an approved exemption in effect.GMP exemptions are codifie
33、d in the classification regulations 21 CFR 862 to 892.The exemption of most Class I devices from design controls is in section 820.30(a).Certain components such as blood tubing and major diagnostic x-ray components are considered by FDA to be finished devices because they are accessories to finished
34、 devices.The manufacturer of such accessories is subject to the QS regulation when the accessory device is labeled and sold separately from the primary device for a health-related purpose to a hospital,physician,or other user.1-7 The designation of a device as a custom or“customized”device does not
35、confer a GMP exemption.Contract manufacturers and specification developers shall comply with the sections of the QS regulation that apply to the functions they perform.Contract test laboratories are considered an extension of a manufacturers quality system and presently are not routinely scheduled f
36、or GMP inspections.The finished device manufacturer shall meet the requirement of the QS regulation,particularly 820.50,Purchasing,when they obtain products or services.Internal test laboratories,however,that are part of a corporate manufacturer that provides services to individual corporation facto
37、ries should meet GMP requirements.Internal laboratories are inspected as part of the FDA GMP inspection of the member factories.Situations are discussed in the remainder of this chapter where various manufacturers are exempt from the QS regulation or are not routinely inspected.However,these manufac
38、turers are still subject to the FD&C Act.If these manufacturers or any manufacturer render devices unsafe or ineffective,the devices are adulterated and/or misbranded and the manufacturers are subject to the penalties of the FD&C Act.Exemptions FDA has determined that certain types of establishments
39、 are exempt from GMP requirements;and FDA has defined GMP responsibilities for others.Exemption from the GMP requirements does not exempt manufacturers of finished devices from keeping complaint files(820.198)or from general requirements concerning records(820.180).Sterile devices are never exempted
40、 from GMP requirements.A device that normally would be subject to GMP requirements may be exempt under the following conditions:When FDA has issued an exemption order in response to a citizens petition for exemption,1-8 When FDA,in the absence of a petition,has exempted the device and published the
41、exemption in the Federal Register,When the device is exempted by FDA classification regulations published in the Federal Register and codified in 21 CFR 862 to 892,When the device is an investigational intraocular lens(IOL)and meets the requirements of the investigational device exemption(IDE)regula
42、tion for IOLs,and Through a policy statement,FDA may decide not to apply GMP requirements to some types of devices and processes although the devices may not have been exempted from GMP requirements.Manufacturers should be aware of the GMP exemption status of their devices.In addition,manufacturers
43、should keep on file records of any specific GMP exemption granted to them by FDA.Upon request during a factory visit,the exemption records need to be shown during normal business hours to the FDA investigator in order to verify that an exemption has been granted.Component Manufacturers A component i
44、s defined by 820.3(c)as any raw material,substance,piece,part,software,firmware,labeling,or assembly which is intended to be included as part of the finished,packaged,and labeled device.”Component manufacturers are excluded from the QS regulation by 820.1(a)(i).Current FDA policy is to rely upon the
45、 finished device manufacturer to assure that components are acceptable for use.Component manufacturers are not routinely scheduled for GMP inspections;however,FDA encourages them to use the QS regulation as guidance for their quality system.When finished device manufacturers produce components speci
46、fically for use in medical devices they produce,whether in the same building or another location,such production of 1-9 components is considered part of the device manufacturing operations,and the production should comply with the QS regulation.Accessory devices 807.20(a)(5)such as hemodialysis tubi
47、ng or major diagnostic x-ray components,that are packaged,labeled,and distributed separately to a hospital,physician,etc.,for health-related purposes are sometimes inappropriately referred to as components.However,FDA considers them finished devices because they are suitable for use or capable of fu
48、nctioning and are distributed for health-related purposes;and the QS regulation applies to their manufacture.Similarly,a device or component including software that is sold as an addition to a finished medical device to augment or supplement its performance is also termed an accessory.An accessory t
49、o a medical device is considered a finished device and,therefore,is subject to the QS regulation.Remanufacturers A remanufacturer is any person who processes,conditions,renovates,repackages restores or does any other act to a finished device which has been previously distributed to significantly cha
50、nge the finished devices performance or safety specifications or intended use from that established by the original finished device manufacturer.Remanufacturers are considered manufacturers.As such,these manufacturers are subject to inspection by FDA and shall meet the applicable requirements of the
