Medical Device Link.

Originally Published EMDM November/December 2002

SPECIAL REPORT

As the new ISO chemical characterization standard nears completion, European manufacturers face some big changes in biocompatibility assessment.

Leslie Lane

With the release of the final draft of the chemical characterization standard ISO 10993-18 scheduled for the next few months, now is an excellent time for device manufacturers to begin learning about the new norm.

For manufacturers who have been relying on animal testing to establish biocompatibility and who source proprietary materials for their products, the new part 18, "Chemical Characterization of Materials," of ISO 10993, "Biological Evaluation of Medical Devices," will represent a major shift in how biological safety for device registration is demonstrated. This change in approach will notably reduce the need for animal testing of known materials, and increase precision in materials manufacturing and safety assurance. It will also require, however, new and potentially costly testing and information gathering. In particular, part 18 will require that manufacturers be able to report the makeup and quantity of all chemical components used in devices that have contact with the body.

With the official release of the standard imminent, laboratories that specialize in medical device and materials testing are reporting that many manufacturers are raising questions and concerns about the new requirements. Among other things, manufacturers want to know when the standard will take effect, what it will require, and how the new requirements will affect them.

When Will the Standard Take Effect?

A formal set of requirements for chemical characterization probably won't be published for another one or two years, according to John Lang of Smith & Nephew plc (London, UK), the convener of the ISO working group on materials characterization.

"Formally, the standard will not affect device manufacturers in Europe until the national standards bodies of the countries in which they operate have published it as a national standard," says Lang. "For example, in the UK this standard would become BS EN ISO 10993-18, probably late in 2003 or early in 2004."

The document, which is currently in draft international standard (DIS) form, will shortly be undergoing a worldwide vote. "There is general agreement within the working group that the technical content of the DIS is now acceptable. The expectation is that the voting result will be positive and will allow movement quickly towards an FDIS (final DIS), which needs to go out for a two-month confirmation vote," Lang says. "The predicted earliest official publication by ISO will be by the end of 2003, but it could extend into 2004."

Although the standard will not be officially released for one or two years, Lang and many others in the regulatory field stress that manufacturers should be addressing compliance issues now rather than later. In fact, according to Lang, some manufacturers have already incorporated chemical and other types of materials characterization in their biocompatibility assessments. "For some companies, the new standard is a reflection of the approach they have taken for many years," says Lang.

Materials characterization is already required by ISO 10993, but only in a general way, points out David Albert, senior scientist and chief chemist at NAMSA (Northwood, OH, USA), a nonclinical medical device testing laboratory. Albert notes that part 1 of ISO 10993 states, "In the selection of materials to be used in device manufacture, the first consideration should be fitness of purpose having regard to characteristics and properties of the material, which include chemical, toxicological, and mechanical." This requirement has been in effect for more than a decade, says Albert, but because the language of part 1 is vague, many manufacturers have not yet addressed materials characterization at all. Part 18 will provide manufacturers with the specific guidance they need to implement chemical characterization.

Many of NAMSA's clients in the United States, as well as clients of the company's European facility, Biomatech (Chasse-sur-Rhône, France), have begun requesting materials characterization testing as well as education about the new standard. In response to these client requests and in preparation for the higher demand the lab anticipates, NAMSA has expanded its chemical testing facilities, developed a series of seminars on the standard, and published educational materials, such as the NAMSA Characterization Matrix. The document, which illustrates the materials tests that must be performed on medical devices depending on their level of exposure to the body, is available at www.namsa.com/select/ char_matrix.htm.

What Will the Standard Require?

Part 18 is "a framework for the identification of a material and the identification (and quantification, if necessary) of its chemical constituents," says Lang. This framework, he continues, consists of five steps that manufacturers may be required to follow, depending on the materials used. He notes that chemical characterization must take place in conjunction with risk assessment, because risk assessment is needed to enable manufacturers to decide whether to proceed with all five characterization steps.

To comply with the new standard, manufacturers may need to accomplish the following:

1. Perform qualitative identification of all materials present in the device, including any by-products of the manufacturing process.
2. Determine whether the materials are already in use for the desired clinical purpose and have been shown to be safe. If so, then no further chemical characterization is necessary, and the findings can be documented as part of the overall biological evaluation of the device.
3. If the materials are not already in use, quantify the amounts of the materials and their chemical components present in the medical device.
4. Using the quantitative information about the materials and the toxicology data, assess whether there is a cause for concern if any or all of the chemicals were to leach into the patient during clinical use.
5. If there are chemicals of concern, estimate the total dose that the patient will be exposed to, along with the rate of exposure.

If materials testing is then required, says Lang, "manufacturers should make the decision either to expand their in-house facilities or to consider external contract services." If choosing the latter, contacts and discussions with potential contract laboratories should take place soon, he adds. "As characterization work will be used to support safety and risk assessments, it is recommended that such work be compliant with good laboratory practices, and that it conform with an appropriate quality system to ensure that regulatory authorities will not reject the data on quality grounds."

How Will Part 18 Affect You?

One of the most important effects of the new standard for device manufacturers will involve the relationship between materials suppliers and OEMs. Many suppliers of materials are unwilling to disclose detailed information about their proprietary formulations, and device manufacturers may find that negotiating for this data will play an increasingly important role. It may become a key factor in their sourcing strategy.

"Manufacturers need to consider the quality of the chemical characterization data that they currently have for materials they plan to use in devices under development," says Lang. If materials are outsourced, manufacturers should take into consideration which suppliers provide the best characterization data. "They should discuss with potential materials suppliers the type and volume of characterization data they require," says Lang.

Finding suppliers who are willing to provide adequate characterization data, however, may be difficult or impossible.

Dana Olsen handles regulatory affairs for Polystan a/s (Vaerløse, Denmark), a medical device manufacturer specializing in cardiopulmonary and extracorporeal technology. She has had first-hand experience with chemical characterization in Japan, which began requiring materials assessment in August 2000.

Olsen appreciates the positive aspects of the requirement, such as a potential decrease in animal testing for biocompatibility purposes. However, she found that meeting the chemical characterization requirements in Japan was a difficult and time-consuming process, because many suppliers were unwilling to divulge detailed information. "Maybe 1 out of 10 [suppliers] was eager to cooperate and provide the information I needed," says Olsen. Without that information, she adds, the device manufacturer is required to shoulder alone the burden of the new testing requirements.

David Ingles, medical business manager at Rapra Technology Ltd. (Shrewsbury, Shropshire, UK), a research, technology, and information provider specializing in plastics and rubber materials that offers contract materials testing, is already noticing an increase in requests for chemical characterization testing. Ingles agrees with Olsen that most suppliers will not provide device manufacturers with the chemical characterization data they need. "Most manufacturers can't get the information from their suppliers at all," says Ingles. "If they want to use the materials, they have to take it upon themselves to do the testing."

Ingles also notes that the standard may be a first step in moving towards needed improvements in medical materials production. "The standard is an excellent start," says Ingles, "but it hasn't gone the whole way. Device materials are often quite variable because they are made by manufacturers of industrial polymers who really haven't gotten the control of their product that is required for specialized, critical medical device applications. Medical device manufacturers are often trying to eke out every last bit of performance possible from the materials, but more account has to be taken of the production processes that the materials go through. These processes often don't lend themselves to the depth of analysis required," Ingles explains.

For manufacturers who are using materials with known risk factors, there may be substantial savings in biocompatibility testing. "Manufacturers will be increasingly expected to adopt these new approaches, making the best use of existing toxicology and characterization information (or newly generated characterization information)," says Lang. "This is in contrast to the traditional checklist approach used in some countries to carry out in vivo preclinical tests regardless of the existing information on the materials involved. For materials and chemicals with existing good-quality safety and exposure data, a change of emphasis will be needed in the biological evaluation of medical devices," says Lang.

Of course, when using new materials for which there is no extensive available data, the need for testing will remain the same. "There will still be the need to perform in vivo testing where the materials and chemicals used are novel, where there is limited existing toxicology data, or where there is no history of safe human exposure," says Lang.

Getting Ready

Many device manufacturers are already preparing to meet the new ISO chemical characterization standard; those who have not begun yet would be well advised to do so. Meeting the new standard may require manufacturers to revisit their relationships with suppliers, and may even lead to new relationships. Manufacturers will also need to begin educating their analytical personnel and purchasing new testing equipment if they plan to conduct characterization testing in-house. If the testing will be outsourced, it's not too early to look for a contract testing laboratory that can provide both education about the standard and appropriate testing services. Whatever strategy you choose, putting in place a system to meet the standard will take time, and there is not much time left before the new standard takes effect.

Copyright ©2002 European Medical Device Manufacturer