Analysis of the Current Status of Personalized Medical Device Technology Review and Regulation

Meeting Personalized Needs Focus on Customization

In recent years, additive manufacturing technology has developed rapidly, and its characteristics of precise processing, low cost, high degree of automation, and customizable production have gradually emerged. Unlike the mass production characteristics of subtractive manufacturing technology, customized production perfectly matches the needs of precision medicine in the medical field. Domestic and international industries are increasingly calling for the use of personalized medical devices to replace existing standardized products, which has gradually become a consensus in the medical community.

In the face of this situation, domestic and foreign regulatory authorities and academia have conducted explorations and reflections. The United StatesThe FDA has issued guidelines for personalized additive manufacturing medical devices, and Europe has also conducted relevant thinking and discussions. Recently, the National Medical Products Administration and the National Health Commission jointly issued the "Regulations on the Supervision and Management of Customized Medical Devices (Trial)".

"Regulations on the Supervision and Management of Customized Medical Devices (Trial)" Officially Released

Content Summary

Based on the existing key points of review and approval for personalized dentures, customized orthoses, and the first domestically produced additive manufacturing personalized knee orthosis, this article draws on the regulatory ideas of the United StatesFDA and the EU on patient-matched design for additive manufacturing medical devices, and proposes a regulatory approach to ensure the safety and effectiveness of personalized medical devices through design and production process control. It clarifies the regulatory key points such as material control requirements, design and manufacturing process validation and confirmation, and sterilization process requirements for reference by regulatory agencies and enterprises.

Currently, the United States and the European Union have issued 510K market licenses for some medical devices using3D printing technology. For example, Oxford Biomaterials and OsteoFab have obtained FDA product market licenses or CE certificates. In the view of the FDA, 3D printing technology, as a manufacturing process, is allowed for use in the mass production of standardized medical devices as long as its process parameters and manufacturing process are verified and confirmed. The FDA requires companies to conduct clinical trials and animal experiments to demonstrate the stability and reproducibility of the materials and printing process. It also requires the provision of design verification materials.

Due to insufficient number of clinical cases, personalized medical devices cannot provide the number of clinical cases that meet statistical requirements according to conventional clinical trial requirements. Enterprises andThe FDA strengthens the output of the design process to prove the physical safety and effectiveness of the product. Enterprises provide finite element analysis reports of data models. Finite element analysis is a data simulation analysis method widely used in the engineering field to verify the physical properties of products (such as stress distribution and tensile strength), and it has been widely used in aerospace and automotive manufacturing.

Enterprises performCT and/or magnetic resonance imaging scans on the human body to obtain data structure models of the human body. Product structure is designed based on these data models. After obtaining the product structure, finite element division and static and dynamic stress simulation analysis are performed. The resulting finite element analysis report, along with the corresponding design and development documents (such as product design drawings, structural feature descriptions, product intended use descriptions, user manuals, clinical trial data, animal experiment reports, product biocompatibility reports, etc.), are submitted to the FDA to demonstrate that the design parameters have been verified and confirmed. Currently, the market response to the product is positive.

China has publicly solicited opinions on the "Technical Review Guidelines for Registration of Customized Additive Manufacturing Medical Devices" and has issued regulations on the supervision of customized medical devices. At the same time, it has issued the "Medical Device Production Quality Management Specifications Appendix Customized Dentures." In the entire review process, for relatively mature personalized denture products, the review is conducted based on the product's structural performance indicators, and good results have been achieved through strengthening the supervision of product raw materials and process verification. According to existing laws and regulations, the recently published product classification announcement has clearly stated that additive manufacturing personalized models and surgical guides are all Class II medical devices.

Overseas Review Ideas and Methods

In 2014, the FDA established an additive manufacturing working group and held relevant discussions. Subsequently, the discussion content was published on the FDA website, from which we can see the FDA's thinking direction regarding 3D printed personalized medical devices. In December 2017, the FDA released the "Guidelines for Additive Manufacturing Medical Devices." EU regulators have also conducted relevant reflections on the regulation of 3D printed personalized medical devices and published articles.

Material Control AspectsBoth the FDA and the EU require that the stability of the properties of raw materials during processing be clearly defined. Enterprises should clarify whether the materials have undergone modification changes during the production process, and the stability and changes of different polymer systems during the manufacturing process. Clarify the composition of additives and changes in material composition during printing, and the impact of various processing aids (crosslinking agents, photoinitiators, etc.) on the final physical and biological properties of the product; clarify the impact of the number of times materials can be reused on the biocompatibility and oxygen content changes of the materials.

The FDA clearly requires enterprises to provide material analysis certificates for raw materials in its official guidelines, and proposes control indicators for different types of raw materials.

Design Process AspectsThe FDA requires that design software should have error-prevention functions to prevent designers from exceeding design specifications. Clinicians and engineers should communicate to select features, and the ease of use for doctors and the convenience of using tools should also be considered. The EU clearly states that different software used in the 3D printing process should be designed for verification and confirmation to avoid the gradual amplification of data errors. The FDA has clearly defined the concept of patient-matched device (PMD) design in its official guidelines. PMD design should clearly define the range of all design parameters (i.e., maximum and minimum values) and emphasize the importance of imaging effects, considering the impact of soft tissue changes and disease progression on the effectiveness of PMD design. At the same time, in the interaction of the design model, it is crucial to clarify the safeguarding of personal information. The FDA has clearly defined the entire software workflow of image scanning, digital model design, slicing, and path planning in its official guidelines.

Currently, the 3D reconstruction and product design software used domestically and internationally are different, and the 3D reconstruction algorithms used are also different. This increases the risk of exceeding the tolerance for size errors generated after the data model has undergone 3D reconstruction and design.

Shelf LifeBoth the FDA and the EU consider the need to determine the shelf life of 3D printed raw materials and finished products. Due to the personalized characteristics of "for a specific patient" for 3D printed personalized medical devices, the shelf life of such products should be different from the shelf life requirements of mass-produced products. The FDA clearly states in its official guidelines that the PMD validity period should be set from the patient's imaging date or design confirmation date.

Anisotropy ConsiderationsThe FDA has clarified the problem of anisotropy caused by the layered characteristics of 3D printing and its impact on products, and clearly stated that anisotropy should be avoided in the design to prevent product performance degradation. The performance of the product in the Z-axis direction is inconsistent with the performance in the XY-axis direction, so it is necessary to consider using this characteristic to ensure product performance during the design process.

Process Parameter Verification and ConfirmationThe FDA and the EU both clearly state that the process parameters of the 3D printing process should be determined for validation, confirmation, and batch-to-batch variation range. Because the 3D printing process is a manufacturing process conducted under computer-aided control, involving many different processes such as laser manufacturing, UV curing, and thermoplastic melting, clarifying the corresponding process parameter ranges according to different processes is an important confirmation aspect. Only by ensuring

the stability of the process parameter window can the batch-to-batch variation be ensured to fluctuate within a controllable range.

The FDA clearly states in its official guidelines that software changes, material changes, and process changes all require re-validation and confirmation of the process.

Post-processingThe FDA and the EU both clearly indicate that heat treatment, polishing, and other post-processing processes should be validated and confirmed. The 3D printing process has a layered characteristic, and the product surface has water ripples after printing. Considering the aesthetic requirements of the product, surface polishing is required, and the polishing process will harden the surface. If 3D printed products undergo heat treatment, the structural strength of the components can be further improved, and the material properties can be improved, so heat treatment will be performed on some structural load-bearing parts.

Sterilization and Cleaning Process ConsiderationsDue to the irregularity of the product, the corresponding sterilization process parameters should be determined.3D printed personalized products are customized parts, and the product structure shape corresponding to each sterilization may be inconsistent. The FDA clearly states in its official guidelines that the worst-case sterilization and cleaning validation scenarios should be considered.

DetectionThe FDA and the EU both believe that personalized products have the inherent characteristic of being "one-of-a-kind" and that non-destructive testing technologies should be considered for product factory testing. These technologies include a variety of detection methods such as ultrasound, computed tomography, dye penetration, confocal microscopy, and hyperspectral imaging.

The FDA clearly states in its official guidelines that test samples should be used for worst-case validation, including setting samples in boundary areas and setting samples as the most complex structure for destructive testing.

Review Suggestions for China

In terms of materialsThe changes in material composition should be emphasized, and the biocompatibility of raw materials and products should be clarified. According to different printing processes, clarify the biological evaluation data of different printing additives. Only by ensuring the biocompatibility of raw materials, processing aids, and finished products can the entire3D printing process controllability and product safety be ensured.

For personalized denture materials, each material has a corresponding product registration certificate and has undergone biological evaluation and physical and chemical property testing. Therefore, there are already quite mature regulatory control requirements for personalized denture materials, and the above regulatory model can be used as a reference for controlling the raw materials of personalized medical devices.

In terms of designIt should be clarified that when carrying out3D printing design, communication between enterprises and clinicians should be based on a clinical sample simulation analysis database of various specifications and sizes. Enterprises can take values in different ranges for data simulation analysis, clarify the stress conditions and corresponding stress distribution, and ensure product safety.

Design specifications can be generated based on the characteristic values provided by the clinical sample database to confirm the different software used. Physical size analysis is performed based on the finished product model to ensure that the design error is within an acceptable range. At the same time, communicate with the doctor about the established tool channel to ensure the convenience of doctor operation.

In the review and approval of additively manufactured personalized knee joint orthoses, considering the characteristics of medical-engineering interaction in personalized medical devices, it is required to validate all the software used in the entire design process (scanning software, modeling software, slicing software, etc.) to achieve design control.

The quality management specification for personalized denture production has already clearly stated that the software used in the design process, such as the tooth arrangement software and scanning software, should be design-validated to meet the accuracy requirements.

Regarding shelf lifeReal-time and accelerated aging experiments should be conducted on the characteristics of raw materials simultaneously. During the aging experiment, the physical, chemical, and biological properties of raw materials and finished products should be clarified.3D printed personalized products are targeted at specific patients, and the shelf life can be significantly shortened to the date of design confirmation to the scheduled surgery date. If the patient's condition changes rapidly, the product design confirmation should be re-performed.

In the design process of additively manufactured personalized knee joint orthoses, the fatigue test method is used to obtain the limit usage frequency of the product, and then the shelf life of the product is determined.

Anisotropy ConsiderationsBecause3D printing uses layered stacking along the Z-axis, the physical properties in the Z-axis direction are inconsistent with the x-axis and y-axis. During the design validation stage, considering the subtle changes in the Z-axis direction, the stress concentration is analyzed to prevent cracking and other situations.

Validation and Confirmation of Process ParametersDifferent processes, equipment, and environments all have different degrees of influence on the process. Due to the normal fluctuations in the process, various key process parameters need to be grouped for orthogonal experiments. The process parameters need to be validated and confirmed for different equipment and operating locations to ensure that the range of process parameters and batch-to-batch variation fluctuate within the allowed range. It is emphasized that enterprises should confirm the process window of the product and accumulate data.

Additively manufactured personalized knee joint orthoses mainly use laser cladding nylon printing technology. Different additive manufacturing processes and different materials will all lead to changes in the entire parameters, and process parameter control and verification are required.

About post-processingFor hot isostatic pressing and other heat treatment technologies used, the influence of the design structure of the hot isostatic pressing mold, the applied pressure, temperature, heating rate, holding time, and cooling rate on the later microstructure, hardness, and surface roughness should be clarified.

Personalized denture post-processing includes grinding and polishing processes. Personalized additive manufacturing knee joint orthosis post-processing includes support removal and grinding. A large amount of dust will be generated during the entire post-processing process, and a dedicated grinding and polishing workshop is required.

Sterilization processDuring the sterilization process, a challenge item should be used to clarify the most complex product structure. A complex multi-microporous structure should be made using the same process as the challenge item, and a bacterial slice should be placed during printing. After sterilization, the bacterial slice is subjected to sterility testing. If the test results are qualified, the effectiveness of the sterilization process parameters can be further proven.

If conditions permit, for complex porous implants, it can be considered to print in a sterile working environment to ensure a low bioburden level from the production process itself.

DetectionClearly ensure product quality through process control, and conduct physicochemical and biological performance tests on furnace samples. Microscopy can be usedCT, single-photon CT scanning and other detection technologies can be used to obtain the internal structure of the product and make quantitative judgments.

It is not recommended to use test blocks for worst-case analysis, mainly for three reasons: First, it will increase the patient's surgical costs; second, there is a difference between the worst-case scenario that the block can simulate and the mechanical structure of the entire product, and it cannot be simulated and judged as a whole; third, the mechanical performance test of the block cannot represent the worst-case scenario of the product itself.

It is recommended to use computer simulation to analyze the mechanical properties of the product, and test blocks can also be used for chemical composition analysis and basic interlaminar bonding strength analysis.

Post-market SurveillancePersonalized medical devices have personalized characteristics and cannot evaluate product quality through product re-inspection. It is necessary to strengthen in-process and post-market supervision, requiring enterprises and clinicians to track post-market products and evaluate their safety and effectiveness.

For personalized dentures, Shanghai has adopted a traceable system for post-market supervision, which can trace back to the corresponding manufacturer of each denture, the main raw materials used, etc., through the system.