Plastics in Medical Devices || Regulations for Medical Devices and Application to Plastics Suppliers

2 Regulations for Medical Devices and Applicationto Plastics Suppliers: History and Overview

2.1 History and Introduction

Over the past 2000 years, many devices have beendeveloped and used in the mitigation and diagnosis ofdiseases. The materials used in these devices haveranged from stone, wood, metal, ceramics, and mostrecently plastics. Medical devices have also evolvedin sophistication and complexity over time. With theformalization of the scientific method in the seven-teenth century such devices became more prevalent[1]. Many medical devices were manufactured bydoctors or small companies and sold directly to thepublic with no government standards or oversight.With the explosion of medical technology in the earlytwentieth century, several intermediaries had evolvedbetween the medical device industry and the public.In 1879, Dr E.R. Squibb, in an address to the MedicalSociety of the State of New York, proposed theenactment of a national statute to regulate food anddrugs [2]. It was not until 27 years later that the Foodand Drug Act of 1906 was introduced into theCongress and signed into law by President TheodoreRoosevelt [3]. At that time, devices that were harmfulto human safety and health proliferated the marketbut regulation of medical devices by the Bureau ofChemistry (the precursor to the Food and DrugAdministration–FDA) was limited to challengingcommercial products only after they had beenreleased into the market. Devices in the marketplacethat were defective, adulterated, or misbranded wereseized and the device manufacturers were prosecutedin a court of law, but only after the products were soldin the market and caused harm to the end users. Thus,there was a strong need for regulating the devicesbefore they entered the marketplace. An FDA report[4], issued in September 1970, detailed as many as10,000 injuries and 731 deaths from ineffectivemedical devices. The report recommended theformation of a regulatory system and body that wouldenforce the production and sale of safe and effectivedevices to the public. All medical devices already onthe market would be inventoried and classified into

Plastics in Medical Devices

Copyright � 2010, Vinny Sastri. Published by Elsevier Inc. All rights reserved

a three-tiered system based on their criticality of enduse. It also detailed requirements for records andreports, registration and inspection of establishments,and uniform quality assurance programs called goodmanufacturing practices (GMP). After muchlobbying by the FDA, Senate bill SR 510, ‘‘TheMedical Device Amendments of 1973’’ was intro-duced by Senator Edward M. Kennedy and waspassed by the Senate in 1975. House bill HR 11124,introduced by Representative Paul Rogers, waspassed by the House in 1976. These bills eventuallybecame the Medical Device Amendments of 1976,and were signed into law by President Nixon. TheMedical Device Amendments of 1976 became thebasis for the medical device regulation in the UnitedStates to control and regulate the production offinished devices and thus the device manufacturersthemselves.

The GMP requirements for medical devices cameinto effect on December 18, 1978. This regulationwas designed to specify general requirements for allmanufacturers as well as special requirements forwhat were termed ‘‘critical devices’’. Yet, between1978 and 1990 a number of studies and data fromrecalls of medical devices [5,6] indicated thata significant number of recalls were due to improper,faulty, or ineffective designs. On November 28, 1990,Congress passed the Safe Medical Device Act(SMDA), providing the FDAwith the authority to addpre-production design controls to the GMP regula-tion. This meant that device manufacturers wouldneed to have controls over their design and devel-opment processes including strict controls of the rawmaterials and components used to manufacture thefinished device. It also incorporated a provision toinclude the oversight of foreign countries sellingproducts into the United States. Quality SystemRegulation 21 CFR Parts 820 [7] was then drafted.Efforts were made to harmonize this regulation withboth the ISO 9001:1994 entitled ‘‘Quality systems:Model for quality assurance in design, development,production, installation and servicing’’ and with ISO

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12 PLASTICS IN MEDICAL DEVICES

13485:1996 entitled ‘‘Quality Systems – MedicalDevices – Particular requirements for the applicationof ISO 9001’’. This new regulation removed the term‘‘critical devices’’ and allowed manufacturers totailor their quality systems commensurate with therisk associated with their device during end use. Forexample, an implantable device will need morestringent (design, development, and production)controls compared to a simple tongue depressor andthese will differ in the level of detail and complexityof their respective quality system requirements.

The purpose of the regulations is to ensure thatmanufacturers of medical devices have the appro-priate procedures and processes in place to design,develop, and produce consistent, safe, and effectivedevices for their intended use. The regulations area framework for manufacturers and are flexibleenough to allow them to formulate and implementthose parts of the regulation that are applicable totheir products and processes and the risk of theirproducts.

2.2 United States Regulations

The design, development, production, distribution,and use of medical devices in the United States ofAmerica are regulated by the Federal Drug and

Table 2.1 FDA 21 CFR Part 820 and Its Subsystems

Section Title Descrip

Subpart A General requirements Definesquality s

Subpart B Quality System requirements Outlineseffectiveaudits, a

Subpart C Design controls Describstages idesign ivalidatio

Subpart D Document controls Review,appropr

Subpart E Purchasing controls Controlsproducts

Subpart F Identification and traceability Documein proceespecia

Cosmetics Act in the Code of Federal Regulations(CFR)d21 CFR Parts 820 [7]. This regulation isentitled ‘‘The Quality System Regulation’’. To sellmedical devices in the United States of America, all(domestic or international) finished medical devicemanufacturers must register with the Federal DrugAdministration (FDA), must be willing to complywith the regulation, and must be willing to let theFDA inspect their facilities.

The intent of 21 CFR Parts 820 is that ‘‘qualitymust be designed and built into components throughthe application of proper quality systems’’ [8]. Theregulation requires that medical device manufac-turers establish and implement an appropriate qualitysystem that encompasses the design, manufacture,packaging, labeling, storage, installation, andservicing of the finished device intended forcommercial use and distribution in the United States.Effective quality systems will ensure that manufac-turers are in a ‘‘state of control’’ and produceconsistent, safe, and effective devices for theirintended use. The FDA monitors and inspects thecomplaints, data, and records from both end usersand manufacturers to track and determine the safetyand efficacy of a device.

Table 2.1 details the various sections of theregulation with a brief description of each section.This regulation pays particular attention to the

tion

the scope and applicability requirements for theystem. Who needs to comply?

the methods of formulating, implementing anquality system via management reviews, qualitynd appropriate personnel.

es the process and controls during the variousn design and development of a medical device fromnputs, design outputs, design verification andn, design reviews, and effective design transfers.

approval, retention, accuracy, and accessibility ofiate documents.

and processes all raw materials, components,, and services.

ntation and process to identify and trace incoming,ss, and finished device products and components,lly those of high-risk devices.

(Continued )

Table 2.1 (Continued)

Section Title Description

Subpart G Production and processcontrols

The development, monitoring, and control of all processesused in production of the finished device.

Subpart H Acceptance activities Establishing and using acceptance criteria for the control ofincoming, in-process and finished device performance,quality, and consistency.

Subpart I Nonconforming product Developing and implementing procedures to assess andcontrol all products and processes that do not meetspecified requirements.

Subpart J Corrective and preventiveaction

Establishing and implementing procedures and processesfor sustainable corrective and preventive action of identifiedissues.

Subpart K Labeling and packaging Ensuring that there are procedures and processes in placeto include the requirements, design, production, and controlof device packaging and labeling into the quality system.

Subpart L Handling, storage,distribution, and installation

Having procedures for the handling and storage of allincoming, in-process, and finished device products.Ensuring proper distribution procedures for finished devicesand if applicable, procedures and processes for theinstallation of finished devices at the end user’s facility.

Subpart M Records Documents specific to this regulation include the DesignHistory File (DHF), the Device Master Record (DMR), theDevice History Record (DHR), and complaint files.

Subpart N Servicing If needed, maintenance and servicing procedures andprocesses must be included to continue and to ensuresafety and efficacy of devices at the end user.

Subpart O Statistical techniques The regulation encourages the use of statistical techniques(like sampling, data analysis, design of experiments) whereappropriate.

2: REGULATIONS FOR MEDICAL DEVICES AND APPLICATION TO PLASTICS SUPPLIERS 13

design controls that were added to the latest (1997)version.

Suppliers of raw materials or components do nothave to comply with the regulations, but are subjectto the purchasing controls of the regulations.Finished device manufacturers must establishprocedures and controls with their suppliers foressential raw materials that include quality metrics,material performance and purity specifications,assurance of supply, and notification of any formu-lation or process changes.

2.2.1 FDA Master Files

For the submission of a Premarket Approval(PMA) [9], a 510(k) [10] for substantially equivalentdevices or an Investigational Device Exemption

(IDE) [11] a finished device manufacturer submits anapplication to the FDA containing substantive data ofthe finished device including performance, chemicalresistance, biocompatibility, toxicity, and clinicaldata. In many cases, the finished device or compo-nents are made from a supplier’s product or rawmaterials. In order that a sound scientific evaluationmay be made of the PMA, 510(k) or the IDE,a review of data and other information related to thesupplier’s product, facility, or manufacturing proce-dures is required. While suppliers may be willing tohave the FDA review this information, they may notwant their proprietary information in the hands oftheir customers (the finished device manufacturers).A system for the submission of Master Files wasdeveloped by the FDA to permit the suppliers of thematerials to provide confidential product information


directly to the FDA for its review without disclosingthe confidential information to the customer ormanufacturer. If the same raw material is used invarious applications, components, or devices, onlyone Master File is required.

There are various types of master files dependingupon the intended use.

• Device master files (MAF)dSupporting data onmaterial used in medical devices (informationfor pre-manufacturing notices, 510(k)s andInvestigational Device Exemptions);

• Drug Master File (DMF)dSupporting data onmaterial used in drugs; (information for Investi-gational New Drug Applications (IND), NewDrug Applications (NDA), and AbbreviatedNew Drug Applications (ANDA));

• Biologics Master Files – Supporting data formaterial used in applications contacting bloodor blood products (information for notices ofclaimed Investigational Exemption for an Inves-tigational New Drug (IND) for biologics andbiologic licenses);

• Food Master Files (FMF)dSupporting data mate-rial used in food applications (information forFood Additive and Color Additive Petitions); and

• Veterinary Medicine Master FilesdSupportingdata for materials used in animal drug anddevices (Investigational New Animal Exemp-tions (INAD) and New Animal Drug Applica-tions (NADA)).

The content of a Master File includes thefollowing:

• Company Name,

• Product Name,

• Manufacturing Address,

• Statement of Commitment,

• Product Formulation,

• Product Specification, and

• Test methods and results (physical, chemical,biocompatibility, and toxicity).

The information provided in the master file givesthe device manufacturer and the FDA a level ofcomfort that the raw material being used in thedevice will pass the specific physical, chemical,

biocompatibility, and toxicity tests. The FDA must benotified of any changes to the formulation andsubsequent properties of the material and the MasterFile must be updated. Failure to notify and complywill render the finished device ‘‘adulterated’’ andmay not be subjected for sale or use.

MAFs may be submitted for various types ofoperations and products and can be grouped by thefollowing types:

• facilities and manufacturing procedures andcontrols;

• synthesis, formulation, purification, and specifi-cations for chemicals, materials (e.g., an alloy,plastic, etc.), or subassemblies for a device;

• packaging materials;

• contract packaging and other manufacturing(e.g., sterilization);

• nonclinical study data; and

• clinical study data.

2.3 ISO 13485 (European andGlobal Standard)

The international standard for medical devices isISO 13485:2003 entitled ‘‘Medical devices – Qualitymanagement systems – Requirements for regulatorypurposes’’ [12]. Though geared specifically towardmedical device manufacturers, the ISO 13485 stan-dard is harmonized with ISO 9001:2000 with somedifferences. ISO 13485:2003 includes particularrequirements for medical devices and excludes someof the requirements of ISO 9001:2000 that are notappropriate as regulatory requirements with respectto medical devices. Thus, organizations whichconform to ISO 13485:2003 cannot claim that theyconform to ISO 9001:2000 or vice versa unless theirquality management systems conform to all therequirements of ISO 9001:2000. Risk management isa key part of ISO 13485 [13]. Terms like customersatisfaction and continuous improvement have beenremoved from this document (compared to ISO9001:2000). The regulation consists of the sections asdescribed in Table 2.2. An ISO technical report (ISO/TR 14699) [14] provides guidance for the applicationof ISO 13485.

The primary objective of the regulation is toprovide harmonized guidelines to organizations so

Table 2.2 ISO 13485:2003 Sections and Their Descriptions

Section Title Description

1 Scope Defines the scope of the regulation, describes the requirementsfor exclusion to design and development where appropriate,and the applicability of the regulations

2 Normative references References ISO 9001:2000

3 Terms and definitions Provides the terms and definitions used in the regulation

4 Quality managementsystem

Focuses on procedures and processes for the implementationof an effective quality management system including thereview, approval, and control of records and documents

5 Management responsibility Emphasizes the involvement of management in the entireprocess, from customer needs, to product planning and productrealization. Use of effective reviews, communication to ensureimplementation and effectiveness of the quality system

6 Resource management Ensures that there are adequate resources that includepersonnel, infrastructure, and the work environment

7 Product realization A significant part of the regulation, includes product planning,product design and development, purchasing process andcontrols, production and service validation and controls, and,the identification and traceability of all products andcomponents used in the production of devices

8 Measurement analysis andimprovement

A separate section is devoted to the importance of goodmeasurement systems, monitoring products and processes,controlling nonconforming products, analysis of data, andcorrective and preventive action

9 Annex A Differences between ISO 13485:2003 and ISO 13485:1996

10 Differences between ISO 13485:2003 and ISO 9001:2000

11 Bibliography References


that they can consistently meet end user and regula-tory requirements. Compliance with ISO 13485 isrecognized as a first step in achieving compliancewith European regulatory compliance. Certificationof the Quality Management System allows themanufacturer to sell medical devices in the EuropeanUnion.

2.3.1 European Union MedicalDevice Directive

There are three directives for medical devices inthe European Union.

• The Active Implantable Medical Device(AIMD) Directive–90/385/EEC;

• The Medical Device Directive (MDD)–93/42/EEC; and

• The In Vitro Diagnostic Directive (IVD)–98/79/EC.

After June 14, 1998, medical devices could not beoffered for sale in the European Union without ‘‘CEmarking’’ and a ‘‘declaration of conformity’’. Theletters CE stand for ‘‘Conformite Europeene’’ inFrench literally meaning ‘‘European Conformity’’.For many products CE marking and a declaration ofconformity may only be affixed with proof ofa certified quality system and/or product testingbased on its end use. The quality systems certifica-tion, the CE marking, and the declaration ofconformity are provided by a ‘‘Notified Body’’ whichis an organization appointed by the national accred-itation authorities and which ‘‘notifies’’ the EuropeanCommission to approve products covered by theMedical Devices Directive. All medical device

Figure 2.1 The CE mark.

EC Declaration of Conformity

Council Directive 93/42/EEC concerning

medical devices

We (Name and address of manufacturer)

Certify that the product described is in conformitywith the applicable provisions of Council Directive

93/42/EEC concerning medical devices.

(Name, type or model, lot, batch or serial no. etc.)

(Description)

(Name of Responsible Person) (Signature of Responsible

Person)

(Date)

Figure 2.2 CE marking declaration of conformity.


manufacturers must designate a notified body tocertify and register their products. For all classes ofdevices, a detailed technical file must be submittedproviding objective evidence demonstrating compli-ance with the Medical Device Directive’s essentialrequirements and with appropriate harmonizedstandards which include ISO 13485:2003 and ISO10993 standards [8].

Products shipped must bear the CE marking toshow compliance with the directive (Figure 2.1). Ifa Notified Body is involved in the approval, thenumber of the Notified Body must also appearadjacent to the CE marking.

Additionally, the product must be shipped witha Declaration of Conformity, an example of which isshown in Figure 2.2.

Documentation can include the following:

• Evidence demonstrating compliance with essen-tial requirements detailed in the directive for theparticular product’s end use;

• Demonstration of design verification andvalidation;

• Risk assessment and analysis;

• Clinical evidence demonstrating effectivenessof the device;

• Procedures for post-market surveillance;

• Complete declaration of conformity;

• Technical information of the finished device–including toxicity and biocompatibility studies;

• Accurate product identification, labels, proce-dures, and user instructions; and

• CE mark or label on product or packaging.

2.4 Other Countries

2.4.1 Japan

The Japanese government, through the Ministry ofHealth, Labor, and Welfare (MHLW), regulates allmedical devices, whether manufactured in Japan orimported from other countries. In Japan, the term‘‘medical device’’ is used for any instrument, appa-ratus, or material as designated by the Japanesegovernment that is used in diagnosing, treating, and/orpreventing diseases in humans or animals and whichcan be used to affect the structure and functions ofhumans or animals. The Pharmaceutical Affairs Law(PAL) is the primary governing law for medicaldevices in Japan. Medical devices must undergothorough safety examinations and demonstratemedical efficacy before they are granted approval, or‘‘shonin,’’ to be sold in Japan. PAL regulations specifyvery detailed requirements for companies thatmanufacture or import medical devices for sale inJapan, ranging from infrastructure and facilities to


personnel and processes. For new medical devices forwhich there are no equivalent products alreadyapproved in Japan or for devices that have beenimproved or modified that might affect device safetyand efficacy, clinical trials are required. Clinical trialsmust be conducted to demonstrate the safety andefficacy of the product under strict Good ClinicalPractice (GCP) standards, and must be followed bystandard Post-Marketing Assessment (PMA) report-ing and a follow-up program.

In April 2004, the Pharmaceuticals and MedicalDevices Agency (PMDA) was established in an effortto create a more efficient and transparent medicaldevice registration review process. The PMDA wasformed by merging three already existing organiza-tions: (1) the Pharmaceuticals and Medical DevicesEvaluation Center (PMDEC), (2) the Organization ofPharmaceutical Safety and Research (OPSR), and (3)the Japan Association for the Advancement ofMedical Equipment (JAAME). Two of these threeagencies (PMDEC and JAAME) were previouslyinvolved in the medical device approval process,including the review of product registration applica-tions and clinical trial consultations. Prior to thecreation of the PMDA, the application and reviewprocess for new devices could take as long as 2 years.Over the next several years, the PMDA intends toshorten this process, although it has not had successin doing so thus far.

Under the New PAL, the Quality AssuranceController will be responsible for ensuring compli-ance with the new Good Manufacturing Practice(GMP) requirement, based on Japan’s own adaptationof ISO 13845:2003, as well as Good Quality PracticeOrdinance (GQP) standards [15]. The StandardOperating Procedures (SOPs) for GQP includeproduct storage controls, the release of products intothe market, quality control at local offices, ensuringthe maintenance of all quality assurance documentsand reports, the handling of product recalls, and audits.

Necessary Governmental Authorizations (for sale ofdevices into Japan):

• Manufacturing (or import) approval (‘‘Shonin’’)which guarantees the safety and efficacy of thedevice, obligatory for every product;

• Manufacturing (or import) license (‘‘Kyoka’’) ofa device, which the Japanese manufacturer andimporter hold, renewable every 5 years; and

• Reimbursement listing approval.

2.4.2 China

There are two main agencies in China that regulatemedical devices, the State Food and Drug Adminis-tration (SFDA) and the Department of MedicalDevices. The State Food and Drug Administration(SFDA) is the Chinese equivalent of the FDA in theUnited States. All imported medical devices must beregistered with the SFDA. The Department of MedicalDevices under the SFDA is responsible for the stan-dardization, product registration, safety, and supervi-sion of all imported devices into China. Some of thestandards used by the agency are ISO 10993 (BiologicEvaluation of Materials and Medical Devices), ISO14971 (Risk Management), and ISO 13485 (MedicalDevices–Quality Management Systems).

2.4.3 Australia

The medical device legislation has been estab-lished by the Therapeutic Goods Act 1989 as amen-ded by the Therapeutic Goods Amendment (MedicalDevices) Bill 2002 and the Therapeutic Goods(Medical Devices) Regulations 2002. The newframework also adopts the philosophies of the GlobalHarmonization Task Force on medical devices.

The new regulatory system has the followingfeatures:

• a device classification scheme based on differentlevels of risk for each class of device;

• essential principles for the quality, safety, andperformance of the medical device that must becomplied with before the product can be supplied;

• options as to how compliance with the essentialprinciples can be satisfied and assessed;

• manufacturer quality systems, type testing, anddesign evaluation;

• the use of recognized standards to satisfy therequirements of the essential principles;

• a comprehensive post-market surveillance andadverse incident reporting program;

• appropriate regulatory controls for themanufacturing processes of medical devices;

• the continued use of the Australian Register ofTherapeutic Goods as the central point ofcontrol for the legal supply of medical devicesin Australia; and

• chemical, physical, and biological properties.


2.4.4 India

The Central Drugs Standards Control Organiza-tion (CDSCO) under the Ministry of Health andFamily Welfare regulates the licensing, import,manufacture, and sale of medical devices into thecountry. Approvals can be facilitated by evidence ofapproval from the US FDA, the EU MDD (CEcertificate), and approvals from Australia, Canada,Japan, and other countries. ISO certification forspecific manufacturing facilities (ISO 13485) is alsoaccepted. Device master files must contain details ofgood manufacturing practices including componentsand materials used in the device. It must also includethe manufacturing and quality assurance processes,risk assessment, design verification, sterilization,stability, biocompatibility, and toxicological dataassociated with the materials and production of thefinished device.

2.4.5 South America

For most companies the access point to SouthAmerica is Brazil. Brazil has the second largesthealthcare market in the Americas (bigger thanCanada and second only to the United States). It isa member of Mercosur – the South American FreeTrade Area that includes Brazil, Argentina, Uruguay,and Paraguay. Separate submissions have to be madein each country. Registration of products or productfamilies must contain information on the manufac-turer, the materials and composition used, and theintended use.

Mexico has patterned its regulations after the USFDA and ISO requirements under the Secretarıa deSalud.

2.5 Global Harmonization TaskForce (GHTF)

The GHTF was conceived in 1992 and is aninformal grouping that was formed to respond to thegrowing need for the international harmonization ofregulations in medical devices. The members of theGHTF include government and industry officialsfrom the European Union, Japan, Canada, Australia,and the United States. These representatives workingwith medical device manufacturers and other orga-nizations related to medical devices try to harmonizeglobal approaches to the safety, efficacy, clinicalperformance, and quality of medical devices with the

goal of protecting public health, promoting innova-tion, and facilitating international trade. Globalharmonization is the aligning of the different regu-latory systems of the world making them globally onpar with each other to manufacture and sell safe andeffective devices. The GHTF is committed to devel-oping guidelines accepted in all GHTF countries andgives technical guidance toward a more coherentapproach on the interpretation of technical andquality requirements for medical devices. It has fourstudy groups, dealing with product approval-relatedissues, post-market surveillance, quality systemrequirements, and audits of quality systems.

2.6 Applicability of theRegulations to Material Suppliers

The regulations (FDA 21 CFR Parts 820 and ISO13485:2003) are applicable to the manufacturers of‘‘finished devices’’. Suppliers of raw materials are notexpected to comply with these regulations but mustmeet acceptable material requirements set forth by thedevice manufacturers (as per their purchasingcontrols). Finished device or component manufacturersexpect their material suppliers to have consistentlygood quality and process control in their facilities.

In July 1998 in the United States, the BiomaterialsAccess Assurance Act – BAAA (HR 872) was signedinto law by President Bill Clinton. The purpose of theact was to ‘‘establish rules governing product liabilityactions against raw materials and bulk componentsuppliers to medical device manufacturers, and forother purposes’’ [16]. This was a very important bill,as it protects the suppliers of biomaterials orcomponents of implanted devices from liability if anentire device results in injury or death, provided itwas not the fault of the material or component. Thisact was in response to a very serious concernexpressed by suppliers following many expensivelawsuits where it was found that the eventual cause ofthe problem was not with the material but with thefinished device itself. Many plastics suppliers arewilling to supply materials as long as their materialsare used in devices that are in contact with the humanbody for less than 29 days (minimal contact with andminimal residence time within the body). A fewplastics suppliers are willing to recommend theirproducts for implants and devices that are in the bodyfor more than 29 days (implantable devices) based onthe extensive studies and data that show their


materials pass all physical, chemical, biocompati-bility, hemocompatibility, and toxicity tests requiredfor implantable devices.

Finished device manufacturers are expected toestablish purchasing controls [17], providing mate-rial suppliers with acceptance criteria and materialspecifications and requirements needed for theirspecific devices and applications. Such requirementsmight include the following:

• Raw material performance specifications,

• Biocompatibility,

• Sterilization requirements,

• Material purity,

• Chemical resistance,

• Toxicity requirements,

• Product quality and consistency,

• Notification of formula changes,

• Adherence to good manufacturing practices, and

• Assurance of supply.

2.7 Conclusion

The purpose of regulations for medical devices isto ensure that the products are consistent, safe, andeffective for their intended use. The two majorregulations are the 21 CFR Parts 820 QualitySystems Regulations enforced by the Food and DrugAdministration in the United States and the globalstandard by the International Organization of Stan-dards ISO 13485:2003 ‘‘Medical devices – Qualitymanagement systems – Requirements for regulatorypurposes’’ enforced by the European Union. Mostcountries have adopted modified versions of the ISO13485 and/or the FDA regulations. Finished devicemanufacturers need to comply with the regulations.Suppliers of raw materials and components do notneed to comply with the regulations, but are subjectto the purchasing controls of the finished devicemanufacturers. Finished device manufacturers musthave stringent supplier qualification procedures thatinclude supplier audits, incoming raw material andcomponent specifications, and quality metrics.Plastic material suppliers must provide appropriatedata and information about their products that theregulatory bodies and the finished device manufac-turers can use to assess the performance and viabilityof the raw materials for their specific devices. This is

only required for high-risk devices. Such informationincludes the formulation, the performance specifica-tions, the test methods and release criteria, the qualitymetrics, material characteristics (physical, chemical,biocompatibility, and toxicity), the assurance ofsupply, and the notification of any formulationchanges. This information is typically maintained bythe regulatory bodies in master files, is kept confi-dential, and is accessible only to the regulatorybodies but not to the finished device manufacturers orthe public at large.

References

[1] N.F. Estrin, The Medical Device Industry. CRCPress, 1990. Marcel Dekker Inc, New York.

[2] E.R. Squibb, The collected papers of EdwardRobinson Squibb, M.D., 1819–1900. in:D. Porter, R. Earl (Eds.), Food Labeling:Toward National Uniformity, National Acade-mies Press, 1992, p. 39. Washington DC, USA.

[3] Federal Food and Drugs Act of 1906 (The‘‘Wiley Act’’) Public Law Number 59-384 34Stat.768 (1906) 21 U.S.C. Sec 1-15 (1934)(Repealed in 1938 by 21 U.S.C. Sec 329 (a)).

[4] Study Group on Medical Devices, MedicalDevices: A Legislative Plan. Department ofHealth Education and Welfare, Washington,D.C, 1970.

[5] FDA Office of Compliance and Surveillance,Device Recalls: A Study of Quality Problems.HHS Publication FDA-90-4235, 1990 WashingtonDC, USA.

[6] FDA Medical Device Regulation fromPremarket Approval to Recall–Department ofHealth and Human Services Inspector General’sStudy, 1990.

[7] 21 CFR Part 820–Quality Systems Regulation.[8] 21 CFR Parts 808, 812, 820 Medical Devices;

Current Good Manufacturing Practices(CGMP); Final Rule October 7, 1996, pp.52606, response #7.

[9] Premarket Approval (PMA) – is the FDA processof scientific and regulatory review of devices‘‘that support or sustain human life, are ofsubstantial importance in preventing impairmentof human health, or which present a potential,unreasonable risk of illness or injury’’.

[10] 510(k) application and submission – is the FDAscientific and regulatory approval process of


devices that a manufacturer thinks is‘‘substantially equivalent’’ to a similar devicethat was on the market prior to May 28, 1976.This is less involved than the premarketapproval defined in reference 9.

[11] Investigational Device Exemption (IDE) isissued by the FDA to allow the use of investi-gational devices in human subjects for clinicaltrials and investigation in order to evaluate thesafety and effectiveness of the investigationalmedical device.

[12] ISO 13485:2003, Medical devices – Qualitymanagement systems – Requirements forregulatory purposes.

[13] ISO 14971:2007, Medical devices – Applica-tion of risk management to medical devices.

[14] ISO/TR 14969:2004, Medical devices –Quality management systems–Guidance to theapplication of ISO 13485:2003.

[15] Ministerial Ordinance on Standards for QualityAssurance for Drugs, Quasi-drugs, Cosmetics,and Medical Devices MHLW, OrdinanceNumber 136 (September 22, 2004).

[16] Public Law 105–230, sect. 1, 112 Stat. 1519codified in 21 U.S.C. 1601–1606, 1999.

[17] Quality Management System–MedicalDevices–Guidance on the Control of Productsand Services Obtained from Suppliers.