Originally Published IVD Technology April 2005
Anniversary Essays
8. International regulatory issues
A review of international IVD regulations: 1994–2004.
Kay Setzer
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Kay Setzer is manager of external standards at Abbott Laboratories (Abbott Park, IL). She can be reached at kay.setzer@abbott.com. |
Many IVD industry observers would assert that FDA’s regulation of IVDs has changed dramatically over the past 10 years. Others might argue that, despite some changes, an atmosphere of business as usual has prevailed. The perception differs depending upon point of view; that is, the position the observOver the last 10 years, industry observers have witnessed a tremendous increase in the number of countries regulating IVD medical devices, as well as in the breadth and depth of existing regulations. While many countries are currently developing new regulations for IVD devices, others such as Canada, Australia, China, Brazil, Taiwan, and Japan, have made major changes or are in the process of making changes to existing regulations.
In many cases, these new regulations have led to a more costly and complex registration process: the amount of documentation required to register a product has increased with time, as has the number of steps needed to prepare legal documents. These cost increases have been seen throughout the world.
Global Harmonization
Any review of international IVD regulations over the past decade must begin with a discussion of the Global Harmonization Task Force (GHTF) and its contribution to the harmonization of regulations throughout the world.1 The GHTF was established in 1992 with five members—Australia, Canada, the European Union (EU), Japan, and the United States.
Specific topics that have been discussed within the GHTF include quality system concepts, auditing, classification of devices, submission requirements, labeling of devices, and reporting of adverse events, to name a few. The industry has seen the harmonization of government requirements for IVD devices across the five founding member countries as well as more-recent GHTF participants, setting up a win-win scenario for the IVD industry.
Having consistent requirements, which are then adopted by individual governments, benefits all. The benefit for government agencies is a consistent set of requirements used across borders. This improves communication, especially for registration of devices, auditing for compliance to regulations, and adverse-event reporting. For the IVD manufacturer, requirements are harmonized throughout the world, offering a straightforward, consistent approach to product classification, registration, quality system requirements, and adverse-event reporting.
This consolidation of requirements reduces the overall cost of bringing products to the market and sustaining them, thus affecting the manufacturer, the user, the patient, and the government. The laboratory receives devices on a worldwide basis with consistency, and products reach the market in the quickest amount of time, improving the health of the patient and the larger population.
Regulation in the United States
In the last 10 years, the United States has gone from a good manufacturing practice (GMP) regulation to the new quality system regulation.2 This change has helped harmonize requirements and make compliance to worldwide requirements much easier for manufacturers marketing products within the United States. It has eliminated conflicts that once existed between the old GMP regulation and the ISO 9001 quality concepts.
European Union IVD Directive
While countries throughout the world were writing their own country-specific regulations, the EU consolidated its multiple-country regulations into a harmonized set of requirements under the IVD Directive.3 Before the EU IVD Directive became effective, a manufacturer would have to satisfy each European country’s product submission requirements. This added to the overall complexity of moving products to the market. Each government had its own classification of devices, and the requirements varied by country. As a result, the manufacturer had to prepare different submissions for each country and negotiate with each for successful product registrations.
As of December 2003, there has been a set of requirements that harmonize with the GHTF essential requirements for safety and performance and the quality system requirements of ISO 9001 and the GHTF.4 Although manufacturers still often find these challenging to meet, doing so is not as difficult as trying to stay abreast of evolving requirements from multiple countries.
Rather than write specific requirements into the IVD Directive, a new approach was instituted: that of writing standards. The idea behind these standards was to provide guidance to manufacturers. Every five years, at a minimum, they would be updated, thus keeping up to date with evolving technologies. Some of the standards that have been developed include guidelines for IVD stability testing, labeling, risk assessment, calibrator traceability, and performance characteristic requirements.
In addition, common technical specifications (CTSs) have been developed, setting minimum performance characteristics for blood-screening products. In the past, these products were tested by government agencies (e.g., Germany and the United States) on a lot-to-lot basis. The testing verified that each lot recovered accurate results and was known as lot-release testing.
One might have expected that with the advent of the CTS that this lot-to-lot testing was no longer necessary. To the contrary, this testing remains in effect today. In fact, more testing is occurring today to cover the market demand throughout the EU.
Although regulations and the requirements from each European country were consolidated and standardized in the IVD Directive, the industry lost ground regarding the number of languages required in device labeling. In the early 1990s, the industry could market products in Europe whose labels contained only five languages (i.e., English, French, German, Spanish, and Italian). A sixth language—Portuguese—was added just before the IVD Directive took effect.
Since then, Directive countries have all determined that instructions should appear in their native language. Currently, products must be labeled in 15 languages to be marketed in the EU.
Quality Systems Convergence and Divergence
If one compares ISO 9001:1994, guidance from the GHTF, the U.S. FDA quality system regulation, the Japanese quality requirements, and the EU’s IVD Directive, harmonized concepts can be seen throughout.5 These cover such topics as management responsibility, design control, document control, purchasing materials control, product identification and traceability, process controls, control of inspection and test equipment, control of nonconforming product, corrective and preventive action, handling, storage, packaging, delivery, internal quality audits, servicing, and statistical techniques.
ISO also developed another standard to provide specific requirements for quality system certification of IVD manufacturers. This document, ISO 13485:1996, used ISO 9001:1994 as a base and added more detail for IVD manufacturers.6
In 2000, a new version of the ISO 9001 quality system requirements was developed. The changes focused attention on customer satisfaction, continual improvement, and management responsibility.7 The new ISO 9001 eliminated some of the recordkeeping and documentation requirements that were contained in the 1994 version of the standard. Through the development of these changes, it was determined that ISO 13485 should become a stand-alone document for certification of IVD manufacturers.8 As a stand-alone document, it no longer relied upon the requirements in ISO 9001 for ISO quality system certification.
This divergence from the ISO 9001 requirements has caused most manufacturers doing business worldwide to certify to both ISO 9001 and ISO 13485 quality system standards. What an IVD manufacturer gained in the harmonization of quality system requirements in the mid-1990s is now becoming diluted. In fact, many countries today require not only certification to the two ISO standards, but also to country-specific quality system requirements.
Risk Assessment and Postmarket Surveillance
Gaining acceptance around the world is the concept of using risk assessments to focus resources on those products that present the most risk to the public. Risk determination is being used when deciding how to classify certain devices, which devices should have submissions sent to the government or notified bodies, which devices should be followed more closely after being placed on the market, and for which devices it is most critical to perform quality system evaluations and audits.
Significant change has been seen in the rapid communication that now occurs between government agencies regarding product recalls, notifications, and postmarket surveillance of products. In the past, there might have been some sharing of information between countries that shared a border, but now with the advent of the competent authorities, there is occurring an immediate communication on issues. In fact, other governments demand to know what is happening even on products outside their borders. The GHTF has spent a lot of energy in developing systems that will allow this sharing of information to occur seamlessly.
Kaizen, CAPA, and
Continual Improvement
From the Japanese concept of kaizen to the U.S. corrective and preventive action (CAPA) principles and the ISO 9001:2000 term of continual improvement, the root concept is the same: Manufacturers should make efforts to continuously improve their processes and products.
In the past, manufacturers concentrated on correcting problems that arose in finished products. Now, under the universal concept of continual improvement, it’s not appropriate to limit responses to corrective action of the immediate problem. Rather, manufacturers must investigate the root causes and take a global, active approach to eliminating potentially related issues from occurring in the future.
Constant monitoring of product performance during manufacturing as well as while in the hands of the user is the order of the day. Whether a manufacturer does this as an opportunity to measure customer satisfaction, or as part of customer complaint resolution, continual improvement is a requirement of ISO 9001:2000.
The Next 10 Years
In the future, we will see consolidation of laboratory quality systems as a result of U.S. Clinical Laboratory Improvement Amendments of 1988 regulation, the ISO 17025 quality system for reference laboratories, and the newest laboratory quality system standard, ISO 15189. As these concepts gain acceptance worldwide and their utility becomes well established, it is hoped that as manufacturer quality-systems documents have been harmonized, so too will the quality systems of the laboratory.
ISO and GHTF will continue their work on regulation harmonization and standards. Standards in the future will contain requirements for IVD labeling as well as risk assessment of devices. The future of adverse-event reporting and postmarket surveillance will further evolve so that reporting to one government agency will report the event to all relevant agencies. New regulations emerging from countries just beginning to regulate IVD medical devices will hopefully follow the work begun by GHTF and ISO.
Areas that will pose challenges soon include the regulation of genetic testing and combination products, which straddle borders between the IVD regulations, medical devices, and pharmaceutical product requirements.
The industry is becoming more and more sophisticated, not only in the technologies being offered in IVD devices, but also in the recognition of materials that affect the user (for example, mercury content). In the last 10 years, these discoveries have caused changes in product composition, and additional warnings and precautions for users.
Although predicting the future is often uncertain at best, one thing that is certain is that the IVD industry will continue its path of change and improvement.
References
1. The Global Harmonization Task Force, “Guidance on Quality Systems for the Design and Manufacturing of Medical Devices,” GHTF.SG3.N99-8, June 29, 1999.
2. Code of Federal Regulations, 21 CFR 820.
3. “Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices,” Official Journal of the European Communities L 331/1 (1998).
4. The Global Harmonization Task Force, “Essential Principles of Safety and Performance of Medical Devices,” GHTF.SG1.N020R5, June 30, 1999.
5. ISO 9001:1994, “Quality Systems—Model for Quality Assurance in Design, Development, Production, Installation, and Servicing.” (Geneva: International Organization for Standardization, 1994).
6. ISO 13485:1996, “Quality Systems—Medical Devices—Particular Requirements for the Application of ISO 9001.” (Geneva: International Organization for Standardization, 1996).
7. ISO 9001:2000, “Quality Management Systems—Requirements.” (Geneva: International Organization for Standardization, 2000).
8. ISO 13485:2000, “Medical Devices—Quality Management Systems—Requirements for Regulatory Purposes.” (Geneva: International Organization for Standardization, 2000).
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