I recently had the opportunity to visit the Lichtenstein Castle in southern Germany. The original castle was built in approximately 1100 A.D. The foundation of the current edifice was constructed in 1390 A.D. and appears to be dangerously close to the edge. Though these places were built for security, this location lends an ironic feeling to this aim.
 
The biocompatibility regulatory arena has also started to feel like it is on edge, and we are at a tipping point. Recently, we have seen changes in the Medical Device Regulations (MDR) in Europe, a new guidance document from FDA, and soon we will have the new versions of ISO 10993-1, -17, and -18.
 
Though there appears to be significant changes to the landscape regarding how regulatory bodies view biocompatibility, a deeper look into the documents and regulations uncovers many similarities. Leveraging these similarities helps manufacturers develop a plan to meet the needs of today’s complex global marketplace—including the need to develop a Biological Evaluation Plan (BEP) that centers on the foundation of risk assessment. The “check box” approach to biocompatibility is no longer appropriate (e.g., we must now understand the materials and process residuals of a device to accurately mitigate the biocompatibility risks to the end user). The following represents the highlights of a deeper look into each of the documents:
 
Changes to the MDR
The latest MDR draft directives stick to the same basic framework; however, more detail has been added to almost every section. For example, the original 14 essential requirements are now replaced with 23 “General Safety and Performance Requirements” that are more thorough than previously published. Some other important points in the draft are:
 

• Comprehensive requirements were added for risk management, post-market monitoring, and clinical evaluation. These fundamental aspects of regulation are now more tightly integrated.
• Controls for reprocessing of single-use devices were added.
• Classifications were reworked, including new devices that are now categorized as Class III and the introduction of special requirements for Class I reusable surgical instruments.

FDA Guidance on the Use of ISO 10993
FDA released the highly-anticipated guidance document regarding the use of ISO 10993. The document doubled in length, so I have listed ten significant changes.
 

1. Device Examples: The document includes more communication and examples to support device companies in their submissions. Evidence is in the five additional attachments and the 30-page increase over the previous draft.
2. Practitioner Contact: Assessing risk based on practitioner contact with devices now falls under ISO 10993-1, which expands the scope beyond patient safety.
3. Recognized Standards: It is important to note U.S. FDA references other standards that are relevant to biocompatibility testing (ASTM, OECD, ICH and USP).
4. Risk Management Guidance: Section III Risk Management for Biocompatibility Evaluations is a new lengthy 10-page section with great examples and discussion of how to approach and assess risk.
5. Decision Trees: As described in the document, assess risk BEFORE testing begins.
6. FDA ISO Biocompatibility Matrix Updates: FDA Modified matrix is “…not a checklist…” Added separate column for Material-Mediated Pyrogenicity.
7. Cytotoxicity Tests: Extraction time for cytotoxicity testing is identified as 24-72 hours extraction. This differs from the standard and possibly implies that all permanent implants should be extracted for longer periods (72 hours).
8. Hemolysis Tests: Only indirect hemolysis testing is now allowed for devices with indirect blood contact. Complement Activation no longer requires analysis of C3a. Serum is now preferred over plasma.
9. Genotoxicity Tests: Genotoxicity testing may be waived if chemical characterization testing and literature research indicate that a genotoxic risk does not exist. However, genotoxicity testing and research cannot be used to mitigate carcinogenic risk.
10. Pyrogenicity Tests: Pyrogenicity testing is expanded to include the Bacterial Endotoxin Test (BET) for sterile devices having direct/indirect contact with the cardiovascular system, lymphatic system, or Cerebral Spinal Fluid (CSF)—regardless of contact duration.

 
New Drafts of ISO 10993-1, 10993-17, and 10993-18
These essential medical device evaluation guidelines are currently undergoing needed updates. Though I cannot go into the details of the upcoming changes to the documents, I can say that medical device manufacturers can expect to see heightened scrutiny around both the risk assessment and the use of chemistry to evaluate risk. These assessments will be a paramount part of biocompatibility testing.
 
Step Away from the Edge
In response to the changing landscape, my peers and I developed a three-tiered approach to help medical device manufacturers satisfy the updated (and upcoming) regulatory requirements. This process is comprehensive and available today: identify risk, mitigate risk through testing, and compile the results.
 
A Biological Evaluation Plan (BEP) is developed to identify the risks associated with a medical device including: considerations for its intended use, failure possibilities, construction materials, and processing impact. Once these risks have been identified, a testing plan is established to mitigate the risks. Upon completion of the testing, a Biological Evaluation Report (BER) summarizes the identified risks, reviews the results of the testing, and outlines a conclusion of safety for the device. Going through this process puts manufacturers in harmony with the new regulations and ensures that they are on solid ground with regulatory biocompatibility burden—and not living too close to the edge.