Testing: How to Approach Change in Orthopedic Device Manufacturing

Change is inevitable, and the orthopedic device industry is no exception. Manufacturers of orthopedic devices may experience change related to the device materials, and/or the process involved in the manufacture of the device. With either type of change, it is a requirement for the manufacturer to determine the impact of the change on patient safety.
 
Because change has the potential to introduce new compounds that may leach from device material (additives, plasticizers, colorants, etc.) and/or remain on the device as a production residual (oils, detergents, solvents, etc.), any change in the manufacture of an orthopedic device must be evaluated to determine the impact to biocompatibility. The most conservative option for determining the impact of a change would be to repeat the biocompatibility tests that were completed with the original regulatory submission. While this is the most thorough approach, it often means lengthy and costly in-vivo testing. One way to reduce this cost is to perform chemical characterization testing.

Chemical Characterization
Chemical characterization tests use analytical chemistry techniques to characterize the device material and determine what compounds may leach or extract from the device that may be harmful to the patient. Test methods such as these are most valuable when endeavoring to compare devices against one another to determine how the compounds on the new or altered device differ from the original configuration.

For example, device compositions or residuals/compounds that leach from the device can be compared to the original to show similarity. If devices are shown to be similar when evaluating a change, less biocompatibility testing may need to be repeated, meaning chemical characterization may help manufacturers reduce testing timelines while limiting repeat animal testing.

The key to any change evaluation is a strong risk assessment with a justification of the test plan. This means evaluating the impact of the change and developing a test plan that appropriately anticipates how the patient may be affected. This approach has been found to be successful in being accepted by regulatory agencies.

Various analytical chemistry techniques can be utilized when performing chemical characterization testing including: 

• Gas Chromatography/Mass Spectrometry;
• Liquid Chromatography/Mass Spectrometry;
• Inductively Coupled Plasma/Mass Spectrometry;
• Gravimetric Analysis;
• Physicochemical Testing;
• Fourier Transform Infrared Spectroscopy; and
• Differential Scanning Calorimetry.

Some of these test methods use direct material characterization, while others identify and quantify leachable and extractable compounds.  While there are no published acceptance criteria for these test methods, chemical characterization guidance is provided in ISO 10993-18, sample preparation guidance is provided in ISO 10993-12, and direction for setting limit values is provided in ISO 10993-17.

Clinical Significance
Changes often are beyond the control of the manufacturer, which is forced to react to a change such as the discontinuation of a material or subcomponent involved in the manufacturing process. Alternatively, the change can be implemented proactively as a means of improving the device or manufacturing process.

It is quite common for companies to change material suppliers. The change could be made simply because the new supplier can offer the same material at a reduced cost. How then would the medical device manufacturer evaluate the impact of this change?
Instead of repeating the biocompatibility testing, chemical characterization test methods could be used. Testing can be done to compare the existing and new material to show their similarities and differences—if any. If the results show the materials are similar, the manufacturer can elect to justify their decision to change suppliers without repeating costly biocompatibility testing.

Another common scenario device manufacturers encounter is the desire or need to use new technologies. For example, a manufacturer may be interested in updating its cleaning process to more effectively remove manufacturing residuals from a device; but to do so, it will need to determine what new residuals may be left behind from this change. Or, if a step in the cleaning process has been altered the manufacturer must demonstrate the new process is equivalent to the original process in its ability to effectively clean the device. These types of changes can effectively be evaluated with chemical characterization. 

It also is common for manufacturers to develop new products using the same materials and similar processing as devices of comparable application already on the market. In this situation manufacturers can elect to use chemical characterization to show equivalency between the new device and the predicate device that already has been shown to be safe.

No One Size Fits All
When a change has occurred, manufacturers must evaluate the impact of the change to the patient contacting portions of the device. To do so, orthopedic manufacturers experiencing a change might asses how much of the patient contacting portion of the device is changing and what the impact of the change will be to the overall surface area of the device. If the change affects only a small patient-contacting area or a small portion of the total surface area of the device, this may require less testing than a major change.

If a material changes, manufacturers might ask, “What is now being introduced from the new material that may adversely affect the patient?” If a step in the process has changed or been eliminated, the questions become, “Are there any new potential contaminants added that could be left on the device?” or “What is the impact of eliminating a step from the process?”

These questions are important in evaluating patient impact.

With change evaluations—such as those completed during chemical characterization testing—manufacturers have the ability to assess the impact of the change by comparing testing results to the original configuration. If the materials are characterized to be similar, and if there are no new compounds leaching/extracting from the device, manufactures can implement the change to the material or process with confidence that the change will have no impact on the patient.

The difficult aspect of change evaluations is that every change and every device is so unique that they require unique solutions. There is no “one-size-fits-all” path in regard to evaluating patient safety. Nonetheless, orthopedic device manufacturers are required to deliver a product that is biocompatible, and any time a change takes place in the manufacture of a device, the impact to biocompatibility needs to be evaluated.

The traditional approach to evaluating the impact of a change to the manufacturing of a device would be to repeat the device’s original in-vivo biocompatibility testing. However, to avoid the cost and delay of this type of comprehensive testing, chemical characterization should be considered. Whether a change assessment is necessary due to a change in materials, supplier, or manufacturing process, paired with select biocompatibility tests, chemical characterization potentially can reduce costs and save time in determining the impact of a change on patient safety. 

References

1. ANSI/AAMI/ISO 10993-12: 2012 Biological evaluation of medical devices—Part 12: Sample preparation and reference materials
2. ANSI/AAMI/ISO 10993-17: 2002/(R) 2012 Biological evaluation of medical devices—Part 17: Methods for the establishment of allowable limits for leachable substances
3. ANSI/AAMI BE83: 2006/(R) 2011 Biological evaluation of medical devices—Part 18: Chemical characterization of materials

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Thor Rollins is a certified microbiologist specializing in the selection and conduct of in-vitro and in-vivo biocompatibility tests at Salt Lake City, Utah-based Nelson Laboratories. He is a participating member on all Association for Advancement of Medical Instrumentation 10993 ISO committees and plays an active role along with the U.S. Food and Drug Administration and regulatory committees developing standards, discussing biocompatibility methods, and voting on changes to those standards.

Alexa Tatarian currently is a study director at Nelson Laboratories working in the chemistry department. Tatarian specializes in consulting on cleaning validations for newly manufactured medical devices and single-use implants as well as chemical characterization and extractable/leachable studies. She also is a member of the ASTM F04 technical committee for medical and surgical materials and devices.