FDA's draft guidance addresses considerations for additive manufacturing in medical devices, but stops short of answering some key questions.
Yarmela Pavlovic, Jennifer Henderson, Kelliann Payne, and Danielle Humphrey
Additive Manufacturing (AM), commonly known as 3-D printing, is increasingly being used in the manufacture of medical devices, including orthopedic and cranial implants, surgical instruments, dental restorations, prosthetics, and physical anatomical models for surgical planning. As of December 2015, more than 85 AM devices had been cleared by the Federal Food and Drug Administration (FDA or the Agency). The 3-D printing market is forecasted to exceed $21 billion by 2020.
In recognition of the rapid growth and advantages of AM, on May 10, 2016, FDA released a draft guidance entitled, "Technical Considerations for Additive Manufactured Devices." The document, which builds on an earlier FDA workshop, outlines a basic framework for considering FDA regulatory obligations in light of the differences presented by AM technologies.
The draft guidance includes important information about FDA's current thinking, but also stops short of clearly addressing many key questions raised by the use of AM in medical devices, such as where one draws the line between the manufacturing process and the finished regulated device, considerations for point-of-care manufacturing, or who should be considered the "manufacturer" of the finished device under different scenarios. Moving forward, further guidance from FDA on these issues will be helpful to manufacturers who choose to take advantage of what AM has to offer.
The Draft Guidance
The draft guidance is divided into two main sections. First, the document provides Design and Manufacturing Considerations, which address technical considerations for fulfilling quality system (QS) requirements. Second, the document outlines Device Testing Considerations, describing the type of information that should be included in premarket submissions for AM devices.
Design and Manufacturing Process Considerations
Nearly all medical devices, including those employing AM techniques, must be made in compliance with FDA's quality system regulation (QSR), which describes the processes, procedures, and controls required for manufacturing medical devices. The QSR, while complex, provides flexibility to manufacturers in developing a robust system to ensure the quality of their products. Because each type of medical device has unique requirements for design, development, and manufacturing, it is essential that manufacturers understand relevant design considerations and ensure appropriate manufacturing controls. As a starting point for AM devices, FDA suggests development of a production flow diagram that identifies all critical steps involved in manufacturing the device, from the initial design to post-processing of the final device. Further recommendations address device design, software workflow, material controls, post processing, process validation and acceptance activities, as well as quality data.
The draft guidance notes that for standard-sized devices, AM may be employed to manufacture features that are too complex to be produced by other techniques. Because AM may introduce variability into the design process, FDA recommends that manufacturers compare the minimum possible feature size of the AM technique and the machine's manufacturing tolerances with the desired feature sizes of the finished device. This will allow manufacturers to confirm that devices and components of the desired dimensional specifications can be reliably built using additive technology.
Patient-matched or "customized" devices, which are developed using a standard template model matched to a patient's anatomy, are also addressed in the draft guidance. The overall design of patient-matched devices may be modified using various clinical inputs, including individual measurements, clinical assessments, and/or patient imaging. FDA recommends that the manufacturer clearly identify clinically-relevant design parameters, including which parameters can be altered for patient matching. FDA also recommends that manufacturers of patient-matched devices address the effects of imaging on the manufacturing process. For example, poor image quality or resolution, smoothing or image processing algorithms, or the clarity of anatomic landmarks used to match the device to the patient's anatomy may affect the fit of the finished AM device. Robust process validations will help to prevent small changes in size or geometry that can lead to issues with the finished AM device fit.
In addition, the manufacture of AM devices often requires use of multiple software programs at various stages of the process. The draft guidance provides specific considerations for the development of both Design Manipulation Software, which allows a medical device design to be modified for specific circumstances, such as patient-matching, and Build Preparation Software, which is used when a digital device design is finalized and additional preparatory processes are needed before the device is additively manufactured. The draft guidance divides these additional processes into the following four steps and provides specific recommendations for each: build volume placement; addition of support material; slicing; and creating build paths.
Finally, the draft guidance provides specific considerations for ensuring proper calibration and machine settings, preventative maintenance, and adequately controlling environmental conditions, all of which can impact quality.
Premarket Device Testing Considerations
Device-specific controls for a firm's quality system has always been required; however, for devices manufactured using standard manufacturing (i.e., non-AM) techniques, information related to device manufacturing is not typically required in 510(k) premarket notifications. The guidance is clear, however, that some degree of 'manufacturing' information will be required for 510(k) notices describing AM devices.
As with devices manufactured using non-AM techniques, the data required to be provided in a premarket submission will depend on the intended use, risk profile, and classification of the AM device. In general, if specific testing is required for a traditionally-manufactured device, that testing will also be expected for an AM device of the same type. In addition to traditionally required information, the following may be required to support premarket submissions for AM devices:
- Device Description. For intermediate and customized devices without discrete sizes, sponsors should identify the range of device dimensions, as well as any design variations, critical dimensions, or features that are intended to be altered or matched to the patient, the type of AM technology used, and a flow chart describing the AM process.
- Mechanical Testing. The performance testing conducted for AM devices generally should be the same as for devices manufactured using traditional methodologies; however, for AM-manufactured products, worst-case combinations of dimensions and features should be evaluated. The device build orientation should be identified for each performance test, as the effect of orientation can vary based on the manufacturing technology. If build location has a significant effect on device characteristics or performance, it should be considered in the identification of worst-case samples for mechanical testing.
- Dimensional Measurements. Device dimensions may be affected by orientation and location within the build space. Dimensional tolerances should be specified, and dimensional measurements should be performed for each AM component to demonstrate consistency and reproducibility between build cycles.
- Material Characterization. All material sources should be identified. Material properties known to affect inter-layer bonding should be characterized and should be representative of the finished device.
- Cleaning and Sterilization. The cleaning and sterilization process validations should account for the complex geometry of AM devices under worst-case conditions.
- Additional Labeling Considerations. In addition to standard device labeling requirements, labeling for patient-matched devices should include: patient identifier; details identifying use, such as anatomical location; and final design iteration or version used to produce the device.
The most unique aspect of using AM for manufacturing of medical devices is that the processes used may ultimately be regulated as part of the finished product. FDA requires that manufacturers establish robust quality systems that govern all aspects of the manufacture of finished medical devices, irrespective of the type of manufacturing processes employed. From a premarket submission perspective, however, the focus is largely on the safety and performance of the final device for its intended use. In this regard, one might question why AM devices require special consideration. When looking at the various processes and techniques employed with AM, including powder fusion, stereolithography, fused filament fabrication, and liquid-based extrusion, it becomes clear that AM introduces nuances to the manufacturing process that can impact the finished device. These nuances, which require specific consideration, can extend to all phases of the manufacturing process, from development, production, and process validation to final, finished device testing. The draft guidance provides a useful framework for evaluating these issues.
Based on experience with FDA's review of regulated 3-D printed medical devices, and as outlined in the draft guidance, FDA's overall criteria for evaluation and testing of 3-D printed devices are largely similar to those associated with traditionally manufactured devices. In the premarket device evaluation of AM devices, however, the draft guidance makes it clear that FDA will expect to review certain new 'manufacturing' information, such as the orientation of a printed object and the printing location. While the need to address such considerations in the premarket context is not unreasonable, this can quickly become complex in the absence of a clear policy regarding where to draw the line between the regulated medical device and the 'manufacturing' processes involved in its creation.
Over the years we have seen variability in FDA's handling of this issue in its review of 510(k) notices for AM devices. Some past 510(k) reviews focused exclusively on the finished device, without delving into AM aspects of the manufacturing process. Other 510(k) reviews for digital and physical anatomical outputs have delved deeper into the AM manufacturing processes and specifically discussed the additive manufacturing equipment and processes. Still other 510(k) clearances have limited use of the 3-D printed device to visualization and education purposes, with only the software functionality outlined in the indications for use. Based on very recent experiences, it appears that FDA is continuing to evolve their views on what is considered in the scope of the 510(k) review. While many factors may have contributed to prior variability, our more recent experience, coupled with the new draft guidance, signals an effort by FDA to better define this scope.
However, until clear direction is provided, this issue can be extremely complicated for companies to manage in the context of a 510(k) submission, particularly from a software perspective. In many instances, multiple software programs (including custom, off-the-shelf, or third-party-cleared software programs) are used in the overall process flow involved in the creation of 3D printed devices. As discussed above, the draft guidance introduces two types of software involved in the additive manufacturing process--Design Manipulation Software and Build Preparation Software--both of which are discussed only in the context of the design and manufacturing of the AM device. This suggests that, while certain software validation and revalidation activities should take place from a quality system perspective, FDA may not view such software as part of the device design to be included in a premarket submission. This interpretation is consistent with recent experience, but provides little guidance on FDA's expectations for documentation of programs employed in the design, manufacture, and build of the device, or acceptable approaches to software validation when multiple software programs are used in different phases of the process. It is our hope that future versions of the guidance may address this more clearly as it significantly impacts premarket submission requirements.
The draft guidance is a useful first step for establishing special characteristics relevant to FDA's regulation of AM devices, including expectations for development, production, process validation, and final testing of finished AM devices. But, many questions remain unanswered, and additional guidance is needed in this area. Until such guidance is available, we continue to recommend that AM device manufacturers consult with FDA on a case-by-case basis prior to submission of a marketing application.
Yarmela Pavlovic is a partner in Hogan Lovells's San Francisco office. Her practice focuses primarily on FDA regulation of medical devices.
Jennifer Henderson is counsel in Hogan Lovells's Washington, D.C. office.
Kelliann Payne is counsel in Hogan Lovells's Philadelphia office.
Danielle Humphrey is a senior associate in Hogan Lovells's Washington, D.C. office.
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