Bridging the Gap: From CE Marking to Satisfying US FDA's Quality System Regulation
The MDD's full quality assurance route to CE marking may provide manufacturers with a shortcut to obtaining US FDA approval.
Jim Cusimano
European medical device companies that have met the requirements of the Medical Devices Directive (MDD; 93/42/EEC) and wish to market their products in the United States are faced with the challenge of satisfying US FDA's new regimen—Current Good Manufacturing Practices (CGMP) and quality system regulation (QSR). The stakes are high. With 260 million consumers, the US market for medical devices and diagnostic products is projected to reach $64 billion in 1999. The critical question for many device manufacturers is how to bridge the gaps between the two regulatory systems.
There is no simple, single answer. Although the new regimes are part of a trend toward harmonization of regulatory requirements designed to eliminate trade barriers, the two systems are not perfectly aligned. One manufacturer with a newly minted CE mark may be able to achieve FDA compliance relatively easily; another conceivably might have to start over from scratch.
Such anomalies are essentially the result of two primary misalignments between the systems. Both the European Union and the United States divide 
medical devices into different classes and provide for somewhat different requirements for each class. As a result, closing the gaps between US and EU requirements can vary by product classification.
US FDA's QSR offers one route to quality assurance for a given medical device class. By contrast, the European Union has adopted a modular approach to conformity assessment for quality assurance, with up to four different routes to quality assurance for a Class IIb device, three for a Class III product.
A European manufacturer that follows the EU route that most closely parallels US FDA guidelines could save considerable time meeting regulatory requirements.
A Tale of Two Systems
Underlying the complexity and differences between the two regimes are some fundamental similarities. "Both systems have the same two goals," explains Ron Belmont, director of food, drug, and healthcare support activities for Excel Partnership Inc., an international training and consulting firm based in Sandy Hook, CT, USA, with European headquarters in Nantwich, Cheshire, UK. "Their objective is to ensure that a medical device company produces a safe product and that it is able to provide quality assurance that it can manufacture this safe product consistently," says Belmont.
Both the European Union and the United States require the development of sufficient technical documentation to enable regulators to determine whether the product or product family as designed and conceived is safe.
The closest US FDA equivalents to the technical file for Class I, Class IIa and IIb products, and the design dossier for Class III devices is the premarket notification 510(k) evaluation and premarket approval (PMA) review. The former covers established devices and products that are largely similar to devices already on the market; the latter is generally required for Class III and high-risk Class II devices.
For US companies it can be very difficult to close the gap between the 510(k) and the technical file. For European manufacturers, however, the technical file should more than satisfy US FDA in most cases.
"Any company that has used the essential requirements (in Annex I of MDD) as a checklist in developing its technical file should have no problem meeting US FDA requirements," says James W. Kolka, international legal consultant and author of ISO 9000...A Legal Perspective (INFORM, Montclair, VA, USA, and ASQ Press, Milwaukee, WI, USA, 1998).
Kolka points out that US FDA addresses many of the same questions as do the essential requirements in its recently published Final Design Control Inspectional Strategy.
"Any manufacturer—whether American, European, or Japanese, for that matter—that is developing new devices for international markets is well advised to follow the essential requirements in creating technical documentation," he says. "By meeting CE-marking requirements, you will also largely satisfy US FDA, which readily accepts EU harmonized standards and European national standards to demonstrate compliance with its requirements. By following this course of action, you satisfy both regulatory regimes in one fell swoop," says Kolka.
The quality assurance system in both the European Union and the United States must cover both production and design control for Class II (both IIa and IIb) and Class III products. According to US FDA's QSR, this requirement can only be met by ISO 9001, the international quality system standard for both design control and manufacturing, and ISO 13486, which applies ISO 9001 to the medical device industry. The European Union has also adopted the same standards (designated as EN ISO 9001 and EN 46001) as a route to meet conformity assessment requirements. The option, called the full quality assurance system, is described in Annex II of the MDD.
However, the European Union also offers other options to manufacturers of Class II and Class III devices as part of its modular approach to conformity assessment for quality assurance. These options, which are described in Annexes III, IV, V, and VI of the MDD, were developed to give companies separate design control from manufacturing or production control. In some cases, European manufacturers might benefit from the flexibility inherent in these alternatives; unfortunately, none are acceptable to US FDA.
The Shortest Route to Quality Assurance
"Any European company that plans to do business in the United States should elect the full quality assurance system option when going for CE marking," explains Belmont. "Any other alternative is self-defeating, since the manufacturer would then have to meet the requirements of two systems."
The plot thickens somewhat for Class I devices. US FDA exempts most Class I devices from its design control requirements and requires manufacturers to satisfy the QSR by meeting ISO 9002 and ISO 13488 (EN 46002 in the European Union), the international standards that apply to production systems and exclude design control.
As with Class II and Class III devices, the situation with the MDD is more complex. For Class I sterile and measuring devices, the European Union offers several options. Only one of these overlaps with US FDA. It combines EN ISO 9002/EN ISO 13488 (Annex V, production quality assurance) with a self-declaration by the manufacturer that the product conforms to the design specifications in its technical file (Annex VII). This is the most reasonable option for EU manufacturers of Class I sterile and measuring devices seeking to sell their products in the United States.
Class I nonsterile, nonmeasuring devices are a separate case. The MDD accepts self-declaration (Annex VII), but US FDA requires compliance with ISO 9002 and ISO 13488. Thus, an EU manufacturer of CE-marked nonsterile and nonmeasuring devices would not automatically satisfy US FDA requirements.
"Although some European medical device manufacturers may have hurdles to overcome in introducing previously CE-marked products into the United States, manufacturers developing new devices can simultaneously meet the demands of both the European Union and US FDA," says Belmont. "So, in that sense, the two regimens are moving toward harmony, and trade barriers are coming down."
Jim Cusimano is a New York–based writer and communications consultant.
Illustration by Lael Henderson
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EU Recycling Laws May Cost Industry $10 Billion Per Year
EU recycling laws may cost industry at large billions of dollars per year in fees, data collection, and tracking, according to experts participating in a workshop on the price of compliance with European packaging mandates. Larger multinational companies will spend an average of US$500,000 annually to set up a package tracking system and another US$100,000 to maintain it, according to UK-based consultant Michael Coe who participated in the workshop.
Under take-back laws implemented in the European Union and a dozen other countries worldwide, manufacturers must join a collection organization (and pay concomitant fees) or retrieve their packaging. According to some workshop participants, compliance with the EU's packaging legislation, which will take effect in 2000, can be as high as US$10 billion per year. Preparing the documentation, according to the president of Environmental Packaging International Victor Bell, frequently is more onerous than the actual fee paid to the collection organization. Fees are paid to industry recovery organizations in Europe and Asia, but the definitions of packaging and composites, along with the dollar amounts vary wildly, he adds.
One thousand folding cartons with less than 5% coating, said Bell, would be assessed US$22.90 in Germany, US$1 in Belgium, and US$5.10 in France. A foil/plastic laminate would cost US$120 in Germany, US$40 in Belgium, but the same US$5.10 in France.
EU packaging legislation will require a written assessment that the package has been source reduced, that it is recyclable, reusable, or recoverable, and that it will not have a negative impact on the countries' recovery systems.
The workshop, held in Chicago, was organized by E-Tech Products Inc. (Denver, CO, USA). Proceedings can be obtained from Raymond Communications Inc., 5111 Berwyn Rd., #115, College Park, MD 20740 USA; phone: +1 301 3454237; fax: +1 301 3454768
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Software System Facilitates Medical-Image Transfers
Etiam (Rennes, France) has developed a software system for cooperative medical imaging. The system, called Mediem (medical imaging by e-mail), can be integrated as a component in imaging equipment and software.
Mediem allows for multimedia exchanges between healthcare professionals by enabling standard medical images to be transferred via the Internet. Current users of Mediem include healthcare companies, hospitals, and manufacturers 
of medical-imaging equipment and software. Although Mediem currently is not sold to physicians, the company is exploring this market. "The company is in a constant state of research and development," says Etiam sales engineer Florence Michelon. "We want our solution to become the standard."
At the system's core is its ability to send, query, retrieve, and view digital imaging and communications in medicine (DICOM) images of any form via e-mail. The DICOM format, a standard in telemedicine, begins all files with a header that includes an identification of the patient and the physician performing the diagnosis. Mediem can access DICOM images—from medical equipment, the Web, or a local network—and retrieve them for storage or modification. The files can be annotated with text, video, or audio commentary and accompanied by medical reports. Another significant feature is the software's incorporation of encryption techniques that permit secure, confidential transfers of medical images.
The software was developed in Java, a platform-independent Internet programming language, and supports several standard file formats and transfer protocols, including HTML, XML, RTF, HTTP, SMTP, POP3, and S-MIME. The DICOM medical-imaging standard is supported in all modalities, including black and white, compressed, and single-frame or multiframe.
Etiam was founded by Cerium, a group of engineers that have been responsible for software development in cooperation with the Signals and Medical Imaging (SIM) laboratory and hospital of the University of Rennes as well as industrial companies. Etiam strives to provide high-level software libraries to firms that are developing medical-imaging products. The company's clients include GE Medical Systems (Buc, France) and France Telecom. Etiam presented Mediem for the first time at the RSNA 1997 show hosted by the Radiological Society of North America in Chicago. Future versions of the system are in development and will include teleconference features.
The company anticipates the widespread use of Internet technology for medical imaging in the coming years and hopes that its software will play a key role in the development of this market. "We are really at a crossroads," says Michelon. "Etiam combines expertise in software engineering, communications, and medical imaging, so we are in a position to work on establishing standards for the integration of these three sectors."
For additional information or a demonstration copy of the Mediem software system, contact Etiam, Technopole Atalante-Villejean, 20 rue du Pr Jean Pecker, F-35000 Rennes, France; phone: +33 299 143388; fax: +33 299 143380.
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Nova to Manufacture Novel Neurodiagnostic Instrument
A full-service contract manufacturer of medical devices, Nova Biomedical Corp. (Waltham, MA, USA) announced that it has reached an agreement with NeuroMetrix Inc. (Cambridge, MA, USA) to manufacture, package, and distribute a neurodiagnostic instrument currently under development.
The NC-stat monitor will allow physicians to accurately, rapidly, and cost-effectively measure nerve-conduction parameters used to diagnose and evaluate systemic and entrapment neuropathies. A low-cost handheld microprocessor-based device, 
the system consists of single-use disposable biosensors and an electronic monitor. NeuroMetrix, a spin-off from the Harvard-MIT Div. of Health Sciences and Technology, announced that shipment of the product will begin early this year.
In addition to offering development, design for manufacture, production, distribution, and repair services to medical device OEMs, Nova Biomedical produces clinical chemistry analyzers for critical-care applications using its proprietary ISE sensors. These sensors are also used in OEM products that the company routinely manufactures for other diagnostic companies.
For more information, contact Nova Biomedical Corp., 200 Prospect St., Waltham, MA 02454, USA; phone: +1 781 8940800; fax: +1 781 8936998; e-mail: tlawrence@novabio.com.
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Ismeca Establishes Medical Device Assembly Unit
Automating assembly processes can reduce production costs while boosting quality assurance.
Norbert Sparrow
What is the biggest challenge facing potential suppliers to medical device OEMs? For Ismeca Europe S.A. (La-Chaux-de-Fonds, Switzerland), a company that manufactures automated assembly systems, neither complying with industry's stiff regulatory requirements nor engineering systems that can assemble delicate miniature components present a serious obstacle. "We have acquired the know-how to deal with those issues," says CEO Bernard Lacoste. The tough part, according to him, is acquiring name recognition and gaining industry's confidence. To show its commitment to the device industry and to earn its trust, Ismeca has established a global business unit devoted to medical device assembly.
The youngest of the company's three divisions—the other two are focused on back-end equipment for the semiconductor industry and assembly automation—the medical device unit is also the firm's fastest growing one. Within three years, Lacoste anticipates that it will generate approximately 25% of the company's revenue. The business plan is ambitious, he concedes, but realistic. His optimism is rooted in what he terms an unusually good match of industry's needs and Ismeca's capabilities.
Faster Processes, Smaller Assemblies
Initially a supplier of automation equipment to the watch-making industry, the 35-year-old company began producing back-end equipment for semiconductor applications in the 1970s. "From there we went into assembly automation, with an emphasis on small or delicate parts, and, increasingly, the assembly and processing of plastic parts," says Lacoste. "On the one hand we were pushed by the semiconductor industry to accelerate processes while increasing quality and reliability," he says. "But we have also demonstrated our expertise in designing systems that perform precision assembly operations of small components." In other words, adds Lacoste, a tailor-made résumé for a supplier to the device industry.
One feature of the company's assembly automation systems with great potential appeal to device manufacturers is the modular architecture. "The Smartflex concept lets manufacturers start small in size, say 2 X 1 m in floor space," says marketing and product manager for Medical Assembly Dirk Dauw. 
"As their needs evolve, they can easily add on to that initial piece of equipment." The average amortization time for Ismeca's automation equipment, adds Dauw, is two to three years. Under pressure from purchasers, device manufacturers are being forced to find new ways to reduce production costs, he adds. "The only way to bring down those expenses is through automation," he stresses. The other benefit of automating processes, Dauw adds, is the immediate gain in quality. "Manual assembly will never achieve the level of quality assurance that is required in the manufacture of certain medical devices," says Dauw.
Ismeca's systems also feature high reliability, according to Dauw, which is partly a result of the use of cams and servos in lieu of hydraulic components. The superiority of electronic systems over mechanical ones is borne out by Ismeca's track record in the semiconductor industry, "where reliability is just as critical as it is in device manufacturing," says Dauw.
To illustrate the company's expertise in devising automated solutions for complex assembly procedures, Lacoste described some of the company's recent projects. One application involved feeding, orienting, inserting, and bonding a 15-mm-long cannula to a hub. "The cannulae, which weighed very little and had a diameter of 0.25 mm, were difficult to process. So we had to develop novel approaches for most of the operations," he says. Compounding the difficulty, the tip had to be set at a precise distance from the hub. "We developed a vision-guided insertion method that achieved assembly tolerances of less than 0.025 mm."
Another medical application entailed the ultrasonic welding of a diagnostic cartridge to extremely stringent requirements on a high-speed pallet-based line. "The long weld path had to be hermetically sealed, and the melt rate and weld parameters had to be near perfect," says Lacoste. Ismeca determined that a weld of this quality could not be performed if the product remained on the pallet. "We built a rigid single-weld anvil," explains Lacoste. "The parts were transferred from the pallet onto the weld anvil, and with each cycle a previously welded assembly was returned to the pallet." The system, he adds, achieved essentially perfect welds at full line speed.
Flexibility and Speed
The company has also designed systems suited for the processing of a family of products. "We frequently run into situations where the production volume of one single configuration is not sufficient to justify automation," says Lacoste. Ismeca circumvents this problem by using electronic lockout systems that restrict access to station areas or side loops that route pallets along a "detour." Both of these solutions feature almost instantaneous changeovers. The company can also supply replacement stations, in which case changeover times can vary from 10 minutes to one hour.
In addition to Switzerland, Ismeca has manufacturing facilities in the United States and Malaysia, and sales offices in Switzerland, France, Italy, Germany, the United Kingdom, the United States, and Hong Kong.
For additional information, contact Ismeca Europe S.A., Medical Device Assembly Unit, 283, rue de l'Helvétie, CH-2301 La-Chaux-de-Fonds, Switzerland; phone: +41 32 9257648; fax: +41 32 9257575; e-mail: assembly@ismeca.ch.
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Rexam Medical Packaging Expands Capabilities
As part of its ongoing investment programme, Rexam Medical Packaging Ltd. (Stoke Gifford, Bristol, UK) recently added an air-knife coater and coating and lamination pilot line to its manufacturing facility.
The wide-width coater will enable the company to manufacture peelable coated Tyvek and paper products that were until now produced at the company's US facilities for worldwide distribution. The development and manufacture of new products will also be a priority, according to market manager Roger James. "Our development programme extending the range of air-knife coated products is nearing completion," he says, "and many of them will provide 
potential cost-reduction options." Air-knife coated products are typically used for packing large and heavy products or those with sharp edges such as dialyzer sets, cannulae, and syringes.
The new coating and lamination pilot line is designed to process Aclar products. This will enable the company to offer low-permeability moisture barriers from 0.12 to 0.34 cm3/m2/day using a range of barrier Aclar products. These products will complement Rexam's existing range of PVDC-coated polyvinyl chloride barrier blister-packaging materials. The company offers a variety of PVC products that meet differing contact and approval requirements.
A leading supplier of healthcare packaging materials, Rexam has production facilities in the United Kingdom, the United States, Ireland, Poland, Brazil, and Singapore. For more information, contact Rexam Medical Packaging Ltd., Winterbourne Rd., Stoke Gifford, Bristol BS34 8PT, UK; phone: +44 117 9872000; fax: +44 117 9872002; e-mail: rmpe.sales@rexam.co.uk.
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Guide to Medical-Grade Polymers Published
Materials suited for varied medical applications are reviewed in a reference guide published by Bayer Corp. (Pittsburgh, PA, USA, and Leverkusen, Germany). Bayer High-Performance Polymers for Medical Applications details typical uses of the materials along with performance requirements and recommends polymers supplied by the company that best meet specific requirements.
The booklet also indicates tests that the polymers undergo to meet US FDA–modified ISO 10993 Part 1 requirements for human tissue contact time of 30 days or less and provides charts for easy identification of compliant products. Other charts show acceptable sterilization methods, chemical resistance information, and suitable joining methods. Property data tables and processing profiles are also included.
To request a copy of the guide, contact Bayer Corp., Polymers Div., Marketing Communications Group, 100 Bayer Rd., Pittsburgh, PA 15205-9714, USA; phone: +1 412 7772000; fax: +1 412 7774889.
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IEC Video Explains Fast-Track Specifications
Industrialists and the president-elect and general secretary of the International Electrotechnical Commission (IEC) team up to explain the rationale behind IEC's 
high-speed specification process in a recently released video. Industry Technical Agreements (ITAs) are designed to meet an urgent market need for standards principally in fast-moving technology sectors where products tend to have short life cycles.
Large companies, a consortium, or indeed any group of interested parties are eligible to create an ITA, according to the IEC. Once a consensus has been reached by the group, the agreement becomes a de facto specification.
ITAs potentially apply to all domains of IEC work, including electrical equipment intended for medical use, says IEC information manager Dennis Brougham. "It should be stressed that ITAs are primarily intended for areas where the traditional standardization process occasionally has difficulty keeping pace," he adds. ITAs can be drawn up in a matter of months rather than years. "However, if someone suggested an ITA for electrical equipment in the medical domain, I feel that we would be receptive to the idea," says Brougham.
The first ITA, which is currently under way, is aimed at defining specifications for standardized multimedia platforms. When completed, it will allow end-users to access a range of multimedia services from a single platform. The Open Platform Initiative for Multimedia Access comprises more than 40 companies and organizations and is scheduled to be implemented by September 1999.
For information on ITAs and the video, contact the International Electrotechnical Commission, 3, rue de Varembé, CH-1211 Geneva 20, Switzerland; phone: +41 22 9190211; fax: +41 22 9190300; e-mail: info@iec.ch.
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Czech Group Offers Outsourcing Assistance
If you are an OEM looking for a supplier of contract services, the Czech Subcontracting and Partnership Exchange (S-Centrum; Prague) is eager to help. The organization will source suitable national partners for a nominal fee, according to Vlastimil Vejnar of the Confederation of Industry of the Czech Republic. The programme is supported by the European Union and the United Nations Industrial Development Organization.
"Companies interested in using this service simply need to provide us with information on the type of services they are looking for and the expertise that is required, and we will locate an appropriate enterprise," says Vejnar. S-Centrum has conducted comprehensive audits of its member companies and established a database to optimize the selection process. Information related to quality systems, manufacturing capabilities, capital equipment, and other data has been captured and coded in accordance with EU nomenclatures. "Consequently, we can select companies based on a combination of clearly defined criteria," says Vejnar.
S-Centrum can source suppliers involved in metal fabrication, plastic products, electronics, and textiles, among other sectors.
To find out more about the organization, contact Czech Subcontracting and Partnership Exchange, Mikulandská 7, 113 61 Prague 1, Czech Republic; phone: +420 2 24920035; fax: +420 2 24921035; e-mail: spcr@ova.pvtnet.cz.
