Additive Manufacturing (AM), commonly known as 3D printing, is increasingly being used in the manufacture of medical devices, including orthopedic and cranial implants, surgical instruments, dental restorations, external prosthetics, and printing of physical anatomical models for surgical planning. In 2013, the market for 3D printing (products and services) was $3.07 billion. As of December 2015, more than 85 AM devices had been cleared by the U.S. Food and Drug Administration (FDA or the Agency). The 3D printing market is forecasted to exceed $21 billion by 2020.1
In recognition of the rapid growth and advantages of using this technology, on May 10, 2016, FDA released a new draft guidance entitled, “Technical Considerations for Additive Manufactured Devices” (the “draft guidance”). The draft guidance builds on an earlier workshop2 held by the Agency and outlines the Agency’s initial thinking regarding the technical aspects of AM devices that should be considered for devices manufactured with at least one AM fabrication step. Relevant considerations extend to the development, production, process validation, and final testing of finished devices. The guidance focuses on devices, such as implants, produced using AM techniques.
The draft guidance is divided into two sections: Design and Manufacturing Considerations and Device Testing Considerations. Design and manufacturing considerations are intended to provide technical considerations for fulfilling quality system (QS) requirements for the finished device, while device testing considerations are intended to describe the type of information that should be submitted in premarket submissions for AM devices. It is important to note the Agency cautions that "point-of-care device manufacturing may raise additional technical considerations" not addressed in the current draft guidance.
A summary of the major points of the draft guidance is provided below.
I. Design and Manufacturing Process Considerations
Nearly all medical devices, including those made with AM techniques, must be made in compliance with FDA’s quality system regulation (QSR), which describes the processes, procedures and controls required for the manufacturing of medical devices. As a starting point, FDA suggests development of a production flow diagram that identifies all critical steps involved in the manufacturing of the device, from the initial device design to the post-processing of the final device, to describe the AM process and to ensure product quality. Further recommendations touch on device design, software workflow, material controls, post processing, process validation and acceptance activities, as well as quality data, as described below.
Considerations for Device Design
Standard-Sized Device Design. For standard-sized devices, AM may be employed in the manufacturing of features that are too complex to be produced by other techniques. FDA recommends that manufacturers take into account the degree to which AM may introduce variability into the design process by comparing the minimum possible feature size of the AM technique and the manufacturing tolerances of the machine with the desired feature sizes of the final, finished device. In the Agency’s view, this comparison will help ensure that devices and components of the desired dimensional specifications can be reliably built using the chosen additive technology.
Patient-Matched Device Design. Patient-matched devices—sometimes referred to as “customized” devices—can be developed using a standard template model that can then be matched to a patient’s anatomy. The overall design 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 and what parameters can be altered for patient matching.
In addition to the considerations for standard-sized device design, FDA recommends 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 fit of the finished AM device.
Considerations for Software Workflow
File Format Conversions. Errors in file conversions can negatively impact a final finished device and component properties, including dimensions and geometry. Such errors may be introduced when converting a computer tomography (CT) file to a format that can be used by Design Manipulation Software, which is software that allows a medical device design to be modified for specific circumstances, such as patient-matching FDA recommends that manufacturers test all file conversion steps using simulated, worst-case scenarios to ensure expected performance.
Digital Device Design to Physical Device. The draft guidance provides recommendations for development of 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: The draft guidance provides recommendations for ensuring that the orientation and placement of the device within the build volume is adequate.
- Addition of Support Material: FDA recommends ensuring the location, type, and number of temporary support structures needed to print certain devices given the layer-by-layer printing process. In addition, manufacturers should address the adequacy of the supports in achieving accurate geometric and mechanical properties of the device, as well as the methods by which the temporary support structures are removed.
- Slicing: Manufacturers should document the appropriate layer thickness for their device.
- Creating Build Paths: The draft guidance provides recommendations for ensuring that the build path between identical devices and components are maintained and consistent.
Machine parameters and environmental conditions also can impact the quality of an AM device or component. FDA has provided specific considerations for manufacturers to consider for ensuring proper calibration and machine settings, performing preventative maintenance, and adequately controlling environmental conditions.
Starting Material. Because the starting material can have a significant impact on the AM build cycle, FDA recommends that manufacturers tightly control and appropriately document each starting material, as well as any processing aids, additives, and cross-linkers.
Material Recycling. Manufacturers should describe any recycling process employed for the reuse of materials and document evidence that such process does not adversely affect the final device.
The draft guidance recommends that all post-processing steps, or manufacturing steps that occur after the printing process, be documented and analyzed to determine how the post-processing affects the materials and the final device.
Process Validation and Acceptance Activities
FDA has outlined specific considerations for performing process validation to ensure the quality of “all devices and components built in a single build cycle, between build cycles, and between machines,” where results cannot be fully verified by subsequent inspection and tests. Once validated, the guidance recommends methods for process monitoring and control. In addition, changes to the manufacturing process may require revalidation. The draft guidance provides a list of changes to the AM process that may require revalidation.
The Agency also recognizes that some acceptance activities for devices or components can be performed through non-destructive evaluation (NDE). Recommended techniques for NDE include, but are not limited to, ultrasound, computed tomography (CT), x-ray, confocal microscopy, and hyperspectral imaging.
FDA recommends that coupons be used for process validation and to identify worst-case conditions in the manufacturing process. Test coupons may also be useful for in-process monitoring.
The draft guidance recommends that appropriate quality data, such as build volume location, be maintained for analysis to identify quality problems and investigate the cause of any product nonconformities.
II. Pre-Market Device Testing Considerations
In the draft guidance, FDA summarizes the type of information that is recommended to be included in a premarket submission for a device manufactured using AM. As with devices manufactured using non-AM techniques, the type and amount of data required by FDA will depend on the intended use, risk profile, and classification of the AM device.
In general, if specific testing is required for a device manufactured using non-AM techniques, the same testing information should also be provided for an AM device of the same device type and classification. In addition, the following types of information may need to be provided in a premarket submission for an AM device:
- Device Description. For AM created intermediate and customized device sizes, which do not have discrete sizes, sponsors should identify the range of dimensions of the device, 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 devices manufactured using traditional methodologies. However, for AM-manufactured products specifically, worst-case combinations of dimensions and features (e.g., holes, supports, porous regions) should be evaluated. Also, the build orientation of the devices should be identified for each performance test as the effect of orientation can vary based on the manufacturing technology used. A build space baseline study also should be conducted to determine whether build location has a significant effect on device characteristics or performance. If there is a significant effect, build location should be considered in the identification of worst-case samples for mechanical testing.
- Dimensional Measurements. Similar to mechanical properties, 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 additively manufactured component to demonstrate consistency and reproducibility between build cycles.
- Material Characterization. All sources of the material should be identified. Material properties known to affect inter-layer bonding should be characterized and should be representative of the final finished device.
- Cleaning and Sterilization. The cleaning process validation and sterilization process should account for the complex geometry of AM devices under worst-case conditions.
- Biocompatibility. Biocompatibility should be evaluated per ISO 10993, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing.
- Additional Labeling Considerations. In addition to meeting standard device labeling requirements, additional labeling is recommended for AM devices that are patient-matched. Specifically, labeling for patient-matched AM devices should include:
- Patient identifier,
- Details identifying use, such as anatomical location, and
- Final design iteration or version used to produce the device.
Although FDA’s Guidance on Technical Considerations for Additive Manufactured Devices is only a draft at this time, it does provide insight into FDA’s current thinking about 3D printing and the AM-specific considerations that should be acknowledged through the product development process. Based on our experience with FDA’s review of regulated, 3D-printed medical devices and as outlined further in the draft guidance, FDA's overall criteria for evaluation and testing of 3D-printed medical devices are similar to those associated with traditionally manufactured devices. However, with 3D-printed products, FDA will review new manufacturing considerations in the device evaluation, such as the orientation of a printed object and the printing location.
What the draft guidance does not address is where FDA intends to draw the line between the medical device and the ‘manufacturing’ process involved in the creation of the 3D-printed medical device. In past 510(k) clearances, we have seen some variability in where FDA has drawn this line. This can become an extremely complicated issue for companies from a software perspective, as in many instances, multiple software programs (including custom software, third party off-the shelf-software or third-party cleared software programs, etc.) are used, either together or independently, in the overall process flow involved in the creation of the 3D-printed device.
The draft guidance introduces the concept of two types of software involved in the additive manufacturing process, i.e., Build Preparation Software and Design Manipulation Software, to distinguish between software used in the initial design phase to create the 3D digital file versus the software that would be used subsequently to take the 3D digital file and convert it into a format that is used to actually build the AM device. However, the draft guidance addresses both of these types of software 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 be viewing such software as part of the device design that needs to be described or included in a premarket submission for a 3D-printed medical device. Additional clarification is needed from the Agency on this point, including where FDA draws the line; the software and associated documentation that may be required for programs employed in the design, manufacture, and build of the device; and acceptable approaches to software validation when multiple software programs are employed in different phases of the process.
In sum, the draft guidance emphasizes that manufacturers of AM devices should consider the special characteristics of such products and provides guidance on FDA’s expectations for development, production, process validation, and final testing of finished AM devices.
Public comments on the draft guidance should be submitted to Docket No. FDA-2016-D-1210 by August 8, 2016.