PerspectiveRegulatory Science

Regulating 3D-printed medical products

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaan6521
DOI: 10.1126/scitranslmed.aan6521

Abstract

Additive manufacturing [also known as three-dimensional (3D) printing] is the layer-wise deposition of material to produce a 3D object. This rapidly emerging technology has the potential to produce new medical products with unprecedented structural and functional designs. Here, we describe the U.S. regulatory landscape of additive manufactured (3D-printed) medical devices and biologics and highlight key challenges and considerations.

INTRODUCTION

Three-dimensional (3D) printing is a form of additive manufacturing (AM) in which materials are joined to make parts from 3D model data, usually layer upon layer, as opposed to subtractive manufacturing and formative manufacturing methodologies (1), and has been increasingly used for medical product research and development in the last decade. Recent forecasts predict that by 2022, the 3D-printed medical devices market will near $26 billion (2) and the bioprinting market will top $1.3 billion (3). Bioprinting is the process of printing of biological materials, including cells, biomaterials, and biomolecules, into 2D layers to form a 3D structure (4).

Digital design files and the use of 3D imaging technologies to create complex structures, including medical products that may require patient-specific anatomic structures, are at the core of AM (5). The AM process uses digital blueprints to deposit material, allowing for incorporation of complex geometric features during building including intricate internal structures that couldn’t otherwise be created. The major categories of 3D printing technologies include powder bed fusion (selective laser sintering) (6), stereolithography (7), extrusion (fused filament modeling) (6, 8), and inkjet (6, 8). All of these types of printing have been used for 3D printing of medical devices or biological materials intended for regenerative medicine.

Differences in manufacturing methods between 3D printing and traditional manufacturing approaches have added specific technical considerations for 3D-printed products into U.S. Food and Drug Administration (FDA) scientific evaluation. To date, marketed medical products manufactured using AM have been reviewed and regulated under the premarket notification [510(k)] (9) and new drug application (NDA) (10) pathways in the United States (Table 1). As more complex additive manufactured products are developed, including biologics, other regulatory pathways such as premarket approval (PMA) (9) and biologics license application (BLA) (10) may also be used. The FDA is committed to fostering innovation in the space of AM through scientific discussion, public outreach, and stakeholder engagement. Here, we provide our perspectives on additive manufactured medical devices and biologics intended for use in regenerative medicine. Not all aspects of 3D printing of medical products are covered in this perspective, such as printing of drugs, class I devices, and anatomic models. For the FDA’s current thinking on 3D-printed anatomic models, please refer to the FDA/Center for Devices and Radiological Health (CDRH)–Radiological Society of North America Special Interest Group (RSNA SIG) joint meeting on 3D-printed, patient-specific anatomic models (11).

Table 1 Common FDA pathways for regulating additive manufactured medical products.
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ADDITIVE MANUFACTURED MEDICAL DEVICES

We searched and analyzed the FDA internal database on medical devices, using specific keywords relevant to AM to track trends in the use of this technology. The keywords “additive manufacturing,” “3D printing,” “rapid manufacturing,” “additive fabrication,” “electron beam melting,” and “selective laser sintering” were searched for devices cleared through the 510(k) pathway (found substantially equivalent to a legally marketed predicate device) during the time span January 2000 to April 2016. There are many types of AM technologies and a diverse lexicon used to describe each. In addition, the type of manufacturing is not a required aspect of the public 510(k) summary. Search results were manually verified for applicability and to filter misidentified entries. To ensure confidentiality of data, all results were limited to the described keywords, deidentified, and aggregated. The goal of this analysis was to provide a useful snapshot of the types of cleared AM devices, and AM processes used to produce these devices, for the recent history of this emerging technology. The timeline and search terms were selected accordingly. Therefore, this dataset does not represent a complete catalog of FDA-cleared AM devices.

Within the limitations of the described search, more than 80 devices have received 510(k) clearance (Fig. 1). A majority of the FDA-cleared additive manufactured devices found in this search were made using powder bed fusion techniques (83%), which include selective laser sintering (66%), electron beam melting (25%), and other laser-based technologies (9%) (Fig. 1A, printing technology). These printing technologies can create intricate geometries having relatively good spatial resolution. Furthermore, a variety of standard metallic and polymeric materials are amenable to the high temperatures that are required for these printing processes. Other printing technologies less frequently used in cleared devices found in this search include stereolithography (12%), extrusion (3%), and inkjet (2%). The line graph in Fig. 1B shows a snapshot of the number of cleared devices from 2010 to 2015, which indicates that there was a steady increase in the number of additive manufactured devices.

Fig. 1 Additive manufactured medical devices cleared through the FDA 510(k) pathway between 2010 and 2015.

(A) Concentric pie charts showing the types of printing technologies, devices, materials, and material porosity used to make 3D-printed devices. Analyses were performed using the information gathered from the search conducted for additive manufactured devices cleared through the 510(k) pathway from January 2000 to April 2016. EBM, electron beam melting; Ti6Al4V, titanium-6 aluminum-4 vanadium; CoCrMo, cobalt-chromium-molybdenum; CpTi, commercially pure titanium. (B) Line graph of the number of AM devices cleared between 2010 and 2015. (C) Materials used for AM of porous devices. (D) Technologies used for AM of porous devices. This chart does not show porous devices made with other methods.

CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

Analysis by clinical application revealed that 53% of the cleared devices identified in these results were orthopedic implants and 34% were surgical guides (Fig. 1A, device type). The remaining devices were for dental (6%) and craniofacial (7%) applications. Of the 3D-printed orthopedic implants, most were for knee (35%) and hip (26%) replacements (subset analysis of orthopedic devices in Fig. 1A, device type) with a majority of those being patient-specific bone cutting guides or acetabular cups (used to replace the cup-shaped socket of the hip joint), respectively. Other orthopedic applications include spine (11%) and shoulder (6%).

Of the identified devices, proportions manufactured using metal and polymer materials were approximately evenly split (Fig. 1A, printing material); however, the choice of material was highly dependent on application and intended use. A majority of the 3D-printed metal devices were manufactured using the same materials as traditionally manufactured devices, including alloys such as titanium-6 aluminum-4 vanadium (Ti6Al4V), cobalt-chromium-molybdenum (CoCrMo), and commercially pure titanium (CpTi). 3D-printed polymer devices mainly consisted of photocurable resins or polyamide materials that could, for example, be used for dental applications (such as temporary crowns), surgical support structures, or surgical cutting guides. These polymeric devices were predominantly patient-matched based on medical imaging and digital design files. It is important to note that the FDA evaluates a material within the context of a medical product and its intended use and does not clear or approve materials alone for general medical use. Proprietary information regarding a specific material may be submitted to the FDA in a Master File by the material supplier.

An advantage of AM is its capability to fabricate complex parts. Many (67%) of the devices identified in the current analysis were designed with internal or surface porosity (Fig. 1A, porosity). Porous structures have been shown to be conducive to tissue in-growth and integration of implantable medical devices (12). Although the inclusion of a porous structure in a medical device does not necessitate the use of AM, the capabilities of the printing process have made the generation of porous structures easier. Parsing the porous devices further through manual inspection of each file, 79% were made of a metallic material (Ti6Al4V 72%, CoCrMo 2%, CpTi 5%), whereas 21% were made of a polymeric material (Fig. 1C). Of the nonporous devices (33%), most were patient-matched surgical guides that help to ensure intraoperative cuts match the presurgical plan and implant shape precisely.

Our analysis revealed that the AM industry is rapidly expanding, with the orthopedic device industry being an early adopter of AM, specifically powder bed fusion technologies. Many of the first products to be cleared were in the area of dental devices. Many of the cleared AM devices incorporate porous structures and/or are patient-specific, capitalizing on some of the advantages that AM can offer over traditional manufacturing techniques, such as additional design freedom.

ADVERSE EVENTS FOR ADDITIVE MANUFACTURED DEVICES

To better understand potential safety and technical issues associated with 3D-printed medical devices, we conducted a postmarket analysis of the cleared devices identified in the previous section using the publicly available Manufacturer and User Facility Device Experience (MAUDE) database (13). We collected and reviewed medical device reports (MDRs) reported in MAUDE during 2014, which was the most recent year with complete MDR information at the time of analysis. We found 836 reports associated with cleared AM devices within the analysis described earlier in this manuscript. These MDRs were screened to compile data about adverse events (AEs) associated with additive manufactured devices relevant to product issues, use error, and therapeutic failures. Because the reporting of MDRs by manufacturers, importers, and device user facilities is mandatory but reporting by device users such as health care professionals, patients, and consumers is voluntary, and because the search comprised only devices found in the previous retrospective review, the scope of the MAUDE database review was limited. Despite limitations, this review can help identify parameters predictive of device failure or AEs specific for additive manufactured devices.

Of 836 MDRs submitted in 2014 for the identified additive manufactured devices cleared through the 510(k) pathway, 59 were product-related (Fig. 2). The primary reasons for the product-related AEs, in rank order, were improper size or incompatibility with other components of the device, device fracture or shavings, inadequate or incorrect device sizes for the patient, implant wear, and use error (incorrect device implanted). Many of these AEs are consistent with AEs observed with the use of traditionally manufactured devices. Because of the study scope and limited completeness of the data, it is difficult to conclude whether any of these AEs are directly related to the manufacturing process or workflow. The current review indicates that although only a small percentage (7.1%) of the overall AEs are product-related, the complexity of AM devices may bring special attention to additional technical and design considerations needed to prevent product failures. Unlike stock devices, which are produced in one of several sizes and extensively analyzed before production, patient-matched devices [see FDA Guidance on the Custom Device Exemption for more information (14)] can incorporate any combination of shapes within a cleared set of size parameters such as thickness, angle, length, etc. This is known as the design envelope. Testing the worst-case design within the envelope and assessing the capability of the anatomical matching process may be crucial to prevent device failure based on this review.

Fig. 2 Adverse events associated with cleared additive manufactured devices based on MDRs reported in 2014.

Stacked bar chart of the reasons for 59 product-related AEs for additive manufactured AM devices based on 836 MDRs reported to the MAUDE database in 2014 related to 510(k)-cleared AM devices. MAUDE, Manufacturer and User Facility Device Experience.

CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

ADDITIVE MANUFACTURED BIOLOGICS AND 3D BIOPRINTING IN REGENERATIVE MEDICINE

In addition to advancing medical devices, AM also drives innovation in biological and tissue-engineered products for regenerative medicine, including bioprinting of tissue scaffolds and constructs containing living cells (1517). There has been a rapid increase in the number of peer-reviewed research publications (18) and in abstracts presented at scientific conferences on bioprinting in the past few years. Current scientific trends suggest that bioprinting is a heavily invested research and development area, especially applied to tissue engineering and laboratory testing. Although there are currently no FDA-approved or cleared biologic products made by AM in the United States, the Center for Biologics Evaluation and Research (CBER) at the FDA has received numerous inquiries related to bioprinting and bioprinted (additive manufactured) cellular products and tissue-engineered constructs and has provided individual feedback for each inquiry.

The technical workflow for bioprinting is similar to that of printing medical devices, although there may be additional steps, such as selection of a design approach (biomimicry, self-assembly), cell type, and biological material to contribute to the proposed therapeutic mechanism. Because of the increased complexity of biological products, more extensive technical considerations may need to be taken into account compared to the printing of medical devices (8). Some of these considerations include, but are not limited to, the printing parameters and consistency, material selection, finishing steps, vascularization of the construct, biocompatibility, mechanical and physicochemical properties, and biological function of the finished product. For example, printing parameters (printing temperature, resolution, and speed) should be compatible with biological materials as they may affect the properties of the finished product and should be easily applicable to scale-up or scale-out.

Printing technologies explored for use with printing biological materials include extrusion, inkjet, and laser-assisted (8). The most common bioprinting applications use extrusion or inkjet printing because these technologies are more compatible with biological materials. These technologies are also capable of printing multiple materials during a single print, facilitating creation of tissue constructs with multiple cell types and extracellular matrix materials arranged in specific patterns and geometries. It is imperative that biological materials remain active and functional during and after printing and thus additional environmental conditions, such as air composition, humidity, and available nutrient sources, are also of concern. Because most biological materials are not amenable to terminal sterilization, maintaining sterility through the use of sterile materials and aseptic processing during printing is often necessary. If these conditions are not optimized, then, without proper mitigations, biological materials may no longer be viable, functional, or sterile by the time the build is completed.

The materials should be suitable for the printing technology and the final application so that material properties and biological activity can be maintained. The specifications for input materials and test methods should be based on the AM technology used (material specifications will be different for extrusion, powder, and stereolithography machines), the intended use of the final medical product, and the information available. The input materials (powder, polymers, “inks”) should be validated to produce a final material with reproducible mechanical, biological, and other material properties relevant to the intended use. Additional material considerations may include the adhesion of print layers and changes in part integrity due to material swelling or contraction. The cell source and type should be well characterized, including evaluation of cell viability and function after printing. Heterogeneous cell populations may need to be deposited in defined spatial locations to print complex tissue structures. Finishing and cleaning steps, including bioreactor incubation, gelation of material, and removal of support materials, should be performed and evaluated when necessary.

Although bioprinting is more complex compared to printing of conventional materials, AM can provide advantages over traditional tissue engineering techniques, such as simultaneously printing cells and biomaterials with more precise spatial control to produce constructs with desired geometric, biological, and other relevant properties. Known applications of AM technologies in biologics include skin (16), cartilage (19), bone (20), nerve (21), and blood vessels (22).

CONSIDERATIONS FOR EMERGING TECHNOLOGIES

The use of AM technologies is changing the medical product landscape by facilitating innovation, and the FDA is committed to fostering AM technologies in all medical product areas—devices, drugs, and biologics. There has been a relative increase in the number of AM products being marketed and many more new AM products being studied and developed with a promise to bring unprecedented, personalized benefits to patients. Currently, products manufactured by AM technology are regulated using the same regulatory pathways as nonadditive manufactured products (2325). There may be additional technical considerations for additive manufactured products, some of which were discussed during the public workshop held at the FDA in October 2014 (26) and are presented in FDA web content, in documents on additive manufactured devices (27), and in a recent technical review (28). The FDA workshop and documents focus primarily on medical devices, including some key considerations for evaluating additive manufactured devices, such as the effect of build orientation and location on final device performance, including mechanical and physical properties, process validation of the AM systems to ensure consistency between print jobs, sterilization and removal of residual materials, and characterization of material properties before and after printing. Each FDA Center has programs to help innovators and medical product developers (Table 2), and the agency has created an agency-wide internal working group to facilitate intra-agency communication and external interactions with research and development partnerships and consortia.

Table 2 Resources available to stakeholders regarding 3D printing and interacting with the FDA.
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To date, the FDA has had fewer opportunities to evaluate additive manufactured biologics (including cellular constructs) relative to medical devices because AM biologics is an emerging area of development. The FDA is committed to building a comprehensive understanding of scientific trends in bioprinting and to developing useful tools for evaluating and regulating AM biologics. This regulatory science framework is needed to undertake regulatory challenges and seek new regulatory opportunities in bioprinting. Because of the complexity of printing biologic constructs, additional considerations such as the compatibility of the printing process (cell viability/function, material properties) may need to be evaluated. Like traditionally manufactured biologics, the maintenance of sterility of printed parts needs to be demonstrated through appropriate testing. The integrity of the product after postprinting steps and the consistency of the manufacturing process, including, but not limited to, cell distribution, construct dimensions, and mechanical and physicochemical properties, are considerations for assessment. In vitro and in vivo evaluation of the finished product to demonstrate the biological activity and function are additional considerations. This is not an exhaustive list of factors or challenges for bioprinted biologics but rather some of the key issues for consideration. Consequently, AM technologies and materials may need to be adapted to print biologics for medical use.

With ongoing advancement in the field of additive manufactured medical products, the FDA continues to communicate with the public regarding regulatory considerations for such products (Table 2). Through ongoing research, collaborations, and discussions with stakeholders, the FDA is committed to fostering safe and effective innovation in 3D-printed medical products.

REFERENCES AND NOTES

Acknowledgments: We acknowledge K. Wonnacott for his involvement in the conception and initial stages of this project. Competing interests: The authors declare that they have no competing interests.
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