The regulatory challenge of 3D bioprinting

The 3D printing industry has grown dramatically over the last decade and continues to challenge and re-shape the health technology field today [1,2]. 3D printing (also known as additive manufacturing) is the process of making a physical object from a digital model through the automated addition of material. This manufacturing method has the potential to disrupt the medical device sector in particular because it enables the production of functional parts tailored to an individual patient [3]. The advent of such ‘mass-customized’ medical devices presents a major challenge for regulators as the current regulatory frameworks are designed for mass-manufactured, standardized products, and are not generally suited to patient-specific devices [4–7]. In response, regulators have taken steps to modify regulatory processes in ways that account for the unique challenges presented by 3D printed medical devices [8–10]. However, these modifications do not generally account for the added complications associated with an important subset of additive manufacturing technologies: 3D bioprinting [11].

3D bioprinting technologies employ additive manufacturing principles, but also incorporate living cells within the inks or resins being printed, thereby creating living 3D constructs for regenerative medicine or disease modelling applications [6,11]. From the translational and regulatory point of view, 3D bioprinted products inherit all the complexities of 3D printed devices, in addition to those encountered with regenerative medicine, tissue engineering, biomaterials and stem cell technology [12]. This added complexity means that any new regulations regarding 3D printed products may not necessarily be applicable to 3D bioprinted products. This gap in the regulatory net is problematic as it generates uncertainty around translational research.

The world's first human clinical trial of a 3D bioprinted product commenced in 2022 [13], thus adding urgency to the need to adapt or rework current regulatory systems. Historically, the development and implementation of regulations for new medical technologies has tended to follow years after those devices have been developed, a phenomenon known as ‘regulatory lag’ [8,10]. The importance of assessing the regulatory systems proactively, rather than reactively, has been recognised as key to avoid hampering the pace of future translation [10].

In this perspective, we overview the challenge of regulating 3D bioprinting. This work is intended as a primer, aimed at the bioengineers, scientists and clinicians who are actively working toward translating and commercializing 3D bioprinting technologies, with the goal of highlighting potential hurdles on the path ahead. After a brief description of our methodology, we begin the main body of the article with an introduction to regulation, followed by a summary of how regulation has been applied to 3D printed devices to date, and to cellular therapies. We then turn to 3D bioprinting, surveying a range of specific challenges pertaining to 3D bioprinting, including: classification, quality control, software, point-of-care manufacture, materials and standardization. In general we highlight how current regulatory systems are ill-suited to the 3D bioprinting process. In contrast to previously published analyses, we discuss the challenge of regulating 3D bioprinting with respect to three classes of medical therapies: conventional devices, custom-made 3D printed medical devices and cell therapies. We also discuss how the lack of clarity around 3D bioprinting regulation, as it currently stands, may hamper clinical translation in this sector.

Methodology

This perspective is based upon the experience of the authors (a regulatory expert in the medical device industry, an orthopedic surgeon, a materials scientist and a bioprinting/biofabrication specialist) who have been engaged in translating bioprinting technologies for over 7 years. The literature search was conducted using various platforms including Google Scholar and PubMed, using keywords relevant to each section, and was not conducted as a systematic review. The literature reviewed included a combination of published academic articles, international standards, regulatory guidelines, advice, and discussion papers, as well as various industry white papers, roadmaps and strategic reviews.

Regulation of 3D printed medical devices

An introduction to regulation

A regulation is typically defined as a “rule or directive made and maintained by an authority” setting legal requirements [14,15]. Within a medical device context the purpose of regulation is to foster patient protection, for example by mandating a certain standard of quality in device design, manufacture, and pre-clinical testing, thereby reducing the risks of poor performance or device failure. Medical device failure can also have systemic impacts felt across the industry – especially where devices are already in use, meaning they must have received market authorization from regulators. Prominent failures and recalls are widely reported in world media, eroding trust in regulatory systems or the medical device industry as a whole [16–19]. The public perception of new technologies can be tainted by such prominent failures, which may impact uptake [20]. On the other hand, while regulating against the potential risks of new medical devices, regulators must strike a balance which retains freedom to innovate in the sector, since overly tight regulations might serve to stifle development of products that would ultimately benefit consumers [10]. In emerging technology areas, such as 3D printing in medicine, this challenge is most problematic since the potential risks are uncertain [10].

Regulatory processes differ around the world and so resist general description. In the USA, regulation is enacted by the Food and Drugs Administration (FDA); and in Australia by the Therapeutic Goods Administration (TGA) [14,15,21,22]. In Europe conformity can be assessed by any one of many accredited European Notified Bodies (ENBs) in a regulatory process coordinated by the European Medicines Agency (EMA) [23,24]. While the regulation of medical therapies differs across international jurisdictions, there is a drive toward better alignment and standardisation, for example between Australia and Europe and between Australia and the United States [5,25–27].

Regulation of 3D printed devices to date

3D bioprinting technologies employ additive manufacturing principles and have the potential to produce bespoke implants tailored to a particular patient. In this fashion, some of the regulatory challenges posed by bioprinting are similar to those which have been encountered by manufacturers who are already using 3D printing to create patient-specific medical implants (e.g., from metals or polymers) [28–32]. With a view to highlighting how 3D bioprinting industry might navigate these common issues, we will now briefly review the regulation of 3D printed devices to date.

The first 3D printing technologies were developed in the 1980s for creating models out of various plastics (such as thermoplastics and light-curable resins), and have been in use in industrial prototyping ever since [33]. The advent of new techniques (such as selective laser melting of titanium in the 1990s) paved the way for the 3D printing of medical implants [33], and 3D printing has been used as a technique for creating dental implants and custom prosthetics since at least the early 2000s [28]. The US FDA has approved several 3D printed medical devices for clinical use, including orthopaedic devices, patient-matched implants, surgical guides and restorative dental bridges [29]. According to a recent systematic review 3D printed medical devices have been shown to be clinically effective in a number of medical fields such as musculoskeletal surgery, oral and maxillofacial surgery and anatomical model fabrication for surgical training [30–32]. A 2016 analysis of additively manufactured devices approved by the FDA through the 510(k) pathway (where the device is substantially equivalent to an existing approved device, as defined in Section 510(k) of the Federal Food, Drug and Cosmetic Act (FD&C Act)) found that adverse events reported for additively manufactured devices were at a similar rate to those observed with the use of the comparative, traditionally manufactured devices [34]. Current market size estimates that the rate of use is rapidly increasing with the 3D printing medical devices market size now projected to reach USD $6583.50 million by 2028 from $2123.11 million in 2021, and grow at a compound annual growth rate of 17.5% during this period [35]. The output and uptake of additively manufactured devices was further accelerated during the COVID-19 global pandemic, where supply chain disruptions and high numbers of respiratory patients made 3D printing of some medical device components and personal protective equipment essential [36].

Despite their wide uptake, patient-specific 3D printed devices have been implanted largely without close regulatory oversight because they fit under the remit of the ‘custom made’ exception. In several jurisdictions, the regulatory process defines an exception excluding patient-specific devices under the expectation that they would be lower risk or used in exceptional cases rather than as a standard treatment [5,7,37]. In Europe, for example, the Advanced Therapy Medicinal Product (ATMP) Regulation includes a ‘hospital exemption' for non-routine, custom-made products not intended to be marketed [38]. Specifically, Article 28 of the ATMP 1394/2007 (EC) Regulation allows the application of regulatory exemptions to advanced medicinal products, including cell-therapy medicinal products, that 3D bioprinting may potentially be covered by (and thus be exempt) [39].

In Australia custom-made medical devices were specifically defined in the Therapeutic Goods (Medical Devices) Regulations 2002, and up until February 2021, the TGA exempted devices if they were: (i) made specifically in accordance with a request by a health professional specifying its design characteristics or construction, or (ii) intended to be used only in relation to a particular individual, or by a health professional to meet special needs arising in the course of his or her practice [9,12]. As such, bespoke 3D printed devices were exempt from being included in the Australian Register of Therapeutic Goods, did not need to follow the full conformity assessment process and were only required to meet limited regulatory activities, without any regulatory or third-party oversight of their evidence of compliance.

Regardless of jurisdiction, these exemptions exist without regard to the manufacturing techniques employed. Historically, these regulations were drafted when personalised devices were rare. However, with the development and uptake of 3D printing technology, personalization has become both scalable and economically viable. This paradigm shift raises that the ‘custom made’ exemption may no longer be acceptable from a risk-perspective [7,9,12,32]. Recent analysis of the EU countries ‘hospital exemption’ pathway example described above, confirm that a significant challenge now exists in balancing commercial development and innovation while consistently and transparently safeguarding public health [40–42]. Prompted by similar concerns several regulators have initiated reviews or are already actively updating the various regulatory guidance for 3D printed technology.

As per the Australia example above, in 2021 the TGA, after extensive consultation and consideration of the impact to industry weighed against patient safety, decided to close the broad exemptions pathway and increase the regulatory oversight of these types of devices by subdividing and expanding on the definition of ‘personalized medical devices’ into new subcategories of ‘custom-made’, ‘patient-matched’ or ‘adaptable’ [43,44]. The new, updated sub-definition for ‘custom-made’ is significantly more comprehensive and, while still exempt, it requires a ‘true’ custom-made one-off device where no other options exist, rather than a ‘patient-matched device’ that is customized and matched to a patient's anatomy within a specified design envelope. These kind of patient-matched and adaptable devices (mass-produced devices that are adapted in accordance with the manufacturer's validated instructions at the point of care, to suit the patient's anatomy) are no longer exempt from the regulation as ‘custom-made’ devices and are now required to undergo full conformity assessment and inclusion on the Australian Register of Therapeutic Goods (ARTG) [43,44].

The challenge of regulating 3D printed devices

Several regulatory challenges associated with 3D printed devices arise from technical aspects of the automated fabrication process [45]. For example, the nature of the fabrication process may also produce particular kinds of surface, edge or interlayer defects, the risk of which needs to be specifically mitigated [45]. In addition, since the digital processing is so central to advanced fabrication, regulation must also extend to the computer aided design process and the associated software system chain [45,46]. Some commentators downplay the regulatory challenge associated with the manufacturing process itself, arguing that existing regulations may be adequate for 3D printed products [47]. Regardless, there is still potential for regulatory disruption owing to new capabilities that the process realises, for example personalization and decentralization [47]. There are also further legal issues around legal liability, such as who should be potentially liable for a defective 3D-printed product? In the absence of precedent, it is unclear exactly how the law will deal with such questions [6].

Regulation of cell therapies

Cell therapies concern the use of cells to address medical conditions, especially those that occur as a result of cellular dysfunction. Bioprinted constructs must, by definition, include living cells and so can be categorized as cell therapeutic products. To sensibly discuss the regulatory complexity of bioprinting, it's important to first consider those challenges associated with advanced cell therapies which will also be inherited by prospective bioprinted therapies.

Historically, the first cell therapies were blood transfusions (which dates back several hundred years) and the direct transplantation of bone marrow stem cells (which dates to the 1950s). Regulation of therapies follows similar lines to the regulation of other transplanted tissues, with a focus on issues such as the screening of prospective donors, and on the storage and transportation of the biologic. However, a new wave of cell therapies began to be developed in the 1970s which involved more complicated ex vivo manipulations of the donor cells. These new cell therapies heralded great promise as a so-called “fourth pillar of medicine” [48], but this potential also came with a slew of new risks. The first of such cell therapies on the market was Epicel (1988), which is a kind of skin graft made by culturing autologous cells for burn patients. In a classic example of regulatory lag, this commercialization occurred almost a decade before the development of FDA regulation on cell therapies (which came into effect in 1997). Thousands of clinical trials for cell therapies have now been conducted, with targets including cardiovascular disease, neurological disease, liver disease, bone conditions and cancer [49]. Despite the huge number of trials, the list of approved cell therapies is short. As of 2022 the FDA has approved only 27 cell or gene therapy products [50], while the EMA has approved just 15 advanced therapy medicinal products (ATMPs) as of 2021 [51]. The regulation of cell therapies has presented several challenges arising from various technical and ethical complexities [52,53].

One challenge arises from the wide diversity of cell therapy products since each requires its own set of cell preparation processes and delivery mechanisms, and can be challenging to cover under one regulatory policy [52]. Such products include direct administration (e.g. injection of stem cells), the transplantation of differentiated cells (i.e., where the cells are first cultured in vitro to differentiate them down a particular lineage before implantation), and tissue engineering (where cells are seeded on scaffolds and cultured to form a lab-grown tissue). Risk profiles can greatly differ depending on the cell type being administered. Mesenchymal stem cells, for example, present risks associated with their expansion in culture, such as the onset of senescence and dedifferentiation. Meanwhile induced pluripotency stem cells (iPSCs) are associated with risks of teratoma in vivo, and may also involve genetic manipulation by oncogenes. Regardless of cell type used, there are risks associated with the ex vivo manipulation of cells, including early cellular senescence, as well as spontaneous malignant transformation [54]. To mitigate some of these risks, regulators typically require that cell phenotype be tested to confirm purity, potency, and identity in product lot release specification. Genotypic analyses can screen cells prior to reimplantation, for example to ensure undesirous markers are not upregulated. However, quantifying potency of a cell product can be a challenge as the defining characteristics of potency (such as a gene expression profile) are not always known, and may be difficult if not impossible to discern in a heterogeneous cell population. For tissue engineered products, maturation of the printed construct may also be required through the use of dynamic stimulation (mechanical, electrical etc.) all inside tissue-specific bioreactors [29,55,56]. This goes beyond standard tissue culture, and as such, it may require specialized facilities and have an impact on regulation.

Regulatory requirements can also differ depending on whether the source of cells is autologous (from the patient themselves) or allogeneic (from other human sources) [57]. The above mentioned cell phenotype screening can be performed for therapies where there is a well-defined product being sold (such as a population of allogeneic cells). Such screening is more challenging for autologous cell or tissue therapies where clinicians perform the extraction, manipulation and reimplantation steps. Such cases fit the cell therapy dogma: ‘the process is the product’. Regulation for such therapies can follow process-based approach: in the form of guidelines on procurement and quality, requirements for good manufacturing practice (GMP) compliance, and inspections of production premises [57].

Another challenge arises from the lack of harmonization across the regulatory structures of different countries, especially in whether or not they not have a specific regulatory category for biologics, and how they classify combination products [52]. The lack of harmonization has contributed to the growth of stem cell tourism, where patients are lured by the promise of unproven stem cell treatments to cure serious conditions such as brain tumours [58].

In the United States Human Cell or Tissue based products (HCT/Ps) are regulated through a risk-based approach [48,52,53]. The degree of regulatory oversight depends on the level of manipulation performed on the cell or tissue product prior to implantation. For example, cells or tissue which undergoes a sub threshold level of processing, which does not change its biological characteristics, can be regarded as “minimally manipulated” [53]. These products are regulated under section 361 of the PHS Act and are not subject to any premarket review requirements [48]. Examples include bone marrow, blood transfusions and organ transplants. On the other hand, biological products which do not meet the minimal manipulation criteria may be regulated under Section 351 of the PHS Act [48]. Approval of such products requires an extensive pre-market review including data from preclinical and clinical studies that demonstrate the safety and efficacy, as well as details on the manufacturing facilities and procedures, including the implementation of a quality control system.

In the European Union, the EMA's ‘Advanced therapy medicinal product’ classification includes three kinds of product: a gene therapy medicinal, a somatic cell therapy medicinal product and a tissue engineered product. While in Australia, the TGA's regulatory framework depends on risk, extent of manipulation, and whether the cell or tissue product will be used in its usual biological function [59]. Australia has recently (2018) introduced regulatory reforms around autologous stem cell products aimed at curbing the rise of unscrupulous business practices offering unapproved and unproven therapies [60].

In general, therapies including live cells adds a significant degree of complexity and uncertainty as it pertains to risk [7,9,12,32]. Developing a cell therapy is a lengthy process, requiring significant funding and uncertain regulatory processes have been seen as contributing to the challenge of translating and commercializing cell therapies. For example, Genzyme's Carticel procedure, an autologous cell therapy for treating articular cartilage defects, was first launched in the USA as a surgical device, before the FDA required it to be withdrawn and licensed as a biologic [57]. This kind of precedent highlights the regulatory challenges that arise when a new type of medical treatment is developed.

Regulation of 3D bioprinting

What is bioprinting?

A subset of the application of additive manufacturing and 3D printing technology is the 3D printing of living cells, known as 3D bioprinting, where layers of cells are deposited instead of, or in addition to, structural biomaterials. 3D bioprinting is defined by its ability to manufacture 3D structures with living biological elements, most commonly of human origin [9,61]. Where the bioprinted construct is an implant, the strategy typically aims for the biomaterials to be reabsorbed by the body and replaced by native tissue, removing the need for permanent artificial implants [61–64]. The proponents of 3D bioprinting underline its potential to form functional tissues and organ constructs for transplantation [65–67]. Bioprinting has the potential to address conditions such as microtia [68], volumetric muscle loss [69], articular cartilage defects [62], and heart disease [70], and is also being pursued for the creation of disease models and to aid drug development [71,72]. 3D bioprinting is rapidly growing and can be considered as a disruptive technology for traditional health regulatory systems [38], including by bodies such as the International Coalition of Medicines Regulatory Authorities (ICMRA) [73] and the European Parliamentary Research Service [74].

Creating 3D structures using living cells without impacting viability or phenotype is a considerable technical challenge and has been addressed through a disparate array of bioprinting technologies, including: ink-jet bioprinting (where cells are delivered in tiny droplets dispensed through an ink-jet print-head), laser-assisted bioprinting (where pulses of laser are used to eject cells from a cell-coated ribbon onto a substrate) and extrusion bioprinting (where cells are encapsulated in a gel and extruded through a robotically controlled syringe) [33]. The various suites of software used to process 3D medical images and to control the bioprinter are also central to the bioprinting process [33,75]. To date the organisations developing 3D bioprinting techniques and materials have primarily been university research labs. However, the commercial landscape is growing rapidly with more than 100 bioprinting companies now operating globally, alongside many more start-ups aimed at commercializing the technology for medical treatments, as well as the increasing uptake by established medical device and pharmaceutical companies [66].

The first human clinical trial involving a 3D bioprinted tissue was commenced in 2022 by US based 3DBio Therapeutics [13]. The phase 1/2a trial is a study of the safety and aesthetic properties of a bioprinted outer ear implant incorporating patients' own cartilage cells and has conducted the procedure on its first participant. This pioneering study, along with the increased pace of 3D bioprinting research [9,64,76] illustrates that new medical products are being developed before a fit-for purpose regulatory structure has been established to deal with them.

The 3D bioprinting process itself involves several general steps, which can be varied and amended [29,56,77]. While various options for sources of stem cells are available, including allogeneic cells from a cell bank, many applications use autologous primary cells harvested from the patient for whom the implant is intended. In the example of orthopedics a generic process is envisioned where: (i) 3D medical imaging of the afflicted anatomy (e.g. bone or cartilage defect) is taken to define a 3D model of the defect site: (ii) this image is used to inform the design of a personalized implant which may be tailored according to the patient's anatomy as well as to the expected biomechanical loading; (iii) meanwhile a suitable population of stem cells are collected from the patient and cultured in a lab, expanded in number, and taken through an appropriate differentiation pathway (if required); (iv) these cells are incorporated into a suitable biomaterial ink, often a hydrogel, whereby the cells and material together comprise the ‘bio-ink’; (v) the bio-ink is loaded into a 3D printer which is programmed to fabricate the chosen design by depositing patterns of cells and biomaterials in 3D; (vi) the printed constructs are matured under specialised cell-culture conditions, possibly including biomechanical, electrical and/or biochemical stimulation; (vii) the 3D bioprinted tissues can now be used in medical research, or as transplant material. A simplified workflow of this process is pictured in Figure 1 below.

The challenge of regulating 3D bioprinting

3D bioprinting generates a very different risk profile compared with traditional 3D printing, requiring inherently different policy considerations [11]. The differences range from fundamental philosophical and bioethical questions to issues of practical risk, biosafety and security. Several of these, more technical, considerations are summarized in Table 1, and discussed in more detail below.

Classification

Regulatory agencies typically define particular standards and guidelines for therapeutics depending on whether they are classed as pharmaceutical, a biological, a medical device or any combination thereof. In some jurisdictions, this product category designation can also determine the marketing authorization procedures, as well as post-market registration and the liability in case of defective products. Accurately determining the classification of a new product is critical from a commercialization perspective as it is core to regulatory strategy development, that is, establishing appropriate costings, timelines, investment in terms of evidence and documentation generation, as well as detailed regulatory risk assessment to the business. The regulatory strategy and the associated downstream effects are critical when fundraising and planning timelines for product development and market launch. Any potential ambiguity in classification is a source of risk, especially for early-stage businesses with fewer resources for regulatory consultants and assessment submissions. By itself, or even as a subcategory of 3D printing, 3D bioprinting does not currently fit well into any existing regulatory framework and there is little specific guidance provided by regulators [2,96].

One consequential question is whether the bioprinter is itself considered a medical device, or as simply a tool aiding in the manufacture of medical products. Currently most regulatory systems would place bioprinters in the latter category, and instead examine the construct itself as the medical product. This classification reflects the status quo, product-focussed nature of current frameworks. However, some jurisdictions are considering a more process-focussed framework. In Australia, the Therapeutic Goods Administration is considering adopting a ‘Medical Device Production Systems’ (MDPS) approach which would cover the end-to-end manufacture of a bioprinted product [78,97]. In such a scheme the printer itself would be assessed, approved and regulated as a medical device, allowing for its use in a healthcare facility without the need for each individual construct to be included on the ARTG. Product and process focussed regulatory frameworks are considered in more detail below.

Regardless of the classification status of bioprinters, another significant challenge is that bioprinted constructs often manifest as a combination products including cells along with biomaterial scaffolds and/or growth factors. Such products are likely to straddle several product categories comprising disparate regulatory pathways. The usual approach in such cases is to assess the product according to its indication for use and its principal or primary mode of action (PMOA). Since the PMOA is determined on a case-by-case basis, it may not be clear to the manufacturer what classification their prospective device will fall under – with implications for their ability to chart a regulatory strategy. The issue of defining and categorising 3D bioprinting products and processes has thus been identified as one of the potential challenges of regulating 3D bioprinting [38,77,98]. It has also been noted that the language used within and about the field is still evolving, with clear definitions of terminology and consistent usage also being important for advancing regulatory process [99]. While some jurisdictions have added nuance to the classification system to clarify the regulatory pathways for combination products, the complexity of prospective bioprinting therapies can still challenge regulatory systems which have dedicated systems in place. The EU, for example, defines Advanced Therapy Medicinal Products (ATMPs) as a special class of medicines, which include gene therapies, somatic cell therapies and tissue engineered products. Products which feature two or more of these components are called ‘combined ATMPs’ and may also include a medical device. Stanco et al. recently analysed how a 3D bioprinted product would most likely be classified in Europe under the scope of ATMPs [38]. The authors found that bioprinted products would most likely be defined as tissue engineered products within this scheme, based on a European Medicines Agency (EMA) recommendation regarding products containing viable cells cultured within a 3D structure. However, the authors also underlined some complexities and ambiguities around this classification. For example, while a 3D bioprinted meniscus incorporating induced pluripotency stem cells would be classified as a combined ATMP, the scaffold component would itself also need to demonstrate compliance with applicable medical device regulations. The ATMP definition is also subject to the cell-induced changes to the construct during the in vitro maturation phase. For example, a bioprinted product where a biomaterial matrix has been substantially remodelled by cells might be considered to be a somatic cell therapy, rather than a tissue engineered product. The complex interdependencies evident here illustrate the challenge of regulating combination products in a strictly categorical system. A more flexible ‘process based’ approach may be better suited, as we discuss later in our section on regulatory processes below.

Quality control aspects

In the medical therapies industry, ‘quality’ is an integral part of the manufacturing, validation and product release processes and is audited by regulators in terms of its compliance with standards. Some requirements, such as the maintenance of a certified Quality Management System (QMS), are common across many different classes of products. A business's QMS sets out the policies and protocols around the manufacturing process and provides the management framework and procedures to produce a product. It is unlikely that this requirement will be any different for future bioprinted products. However, maintaining a certified QMS system is not sufficient, by itself, to guarantee a compliant end product that will get regulatory approval under existing frameworks. Further, specific requirements depend on the product's regulatory classification and use case. For example, compliance with ISO 21973:2020 “General Requirements for Transportation of Cells for Therapeutic Use” may be required for bioprinted products which involve transporting live cells between the hospital (where they are harvested from a patient) and the lab (where they are bioprinted into a tissue construct). But that same standard might not be applicable if the same tissue construct is bioprinted within the hospital site (see the 'Point of care manufacture' section below).

Additional practical aspects of quality control are inherent to the bioprinting product pipeline, especially the challenge of demonstrating the performance of patient-specific (‘batches of one’) products made on demand [45]. Complete characterisation is likely not possible and so more extensive preclinical and in vivo safety testing and in-process controls will be required to provide sufficient information on risk versus benefit [45]. This aspect is particularly challenging since current approaches to detailed biological and biomechanical characterisation are destructive – destroying the very sample which needs to be characterised—though some non-destructive techniques are in development [100]. There may also be questions of product safety, standardisation in terms of the manufacturing process and the product, customisation, traceability, GMP and lack of standard review pathways [77,82]. The current regulatory and standard frameworks around cell therapy and stem cell research are continually evolving (as evidenced by the recent introduction of the entirely new standard ISO 21973:2020) and these developments could directly impact the strategy around bringing a bioprinting product to market. For example, the financial cost of complying with the standard for live cell transportation might influence the decision as to whether to perform the printing in a dedicated lab off-site, or at the point of care.

Software

As with 3D printing of medical devices, digital processing is central to the bioprinting process. The bioprinting software system chain includes software for: digital reconstructions of 3D medical imaging, anatomical segmentation and artefact detection, computer aided design, finite element analysis, slicing of a 3D digital object into printable layers and toolpath generation appropriate to the particular bioprinter, among others [11,65,77,82]. Much of this software system chain is common with conventional 3D printing. In the case of bioprinting, additional software associated with dynamic culture systems (such as those which provide a period mechanical load to a printed construct) are an additional consideration as they can control a potentially critical step in the tissue maturation pipeline.

The regulatory requirements for software strongly depend on whether bioprinting is classified as a medical device, as may be the case in certain jurisdictions (see Classification section above). Medical device software is subject to regulatory oversight, and may be required to comply with standards such as IEC 62304:2006 “Medical device software – Software life cycle processes”. In general, many of the software programs currently in use across the bioprinting and bioreactor fields are open source or developed in-house by the research lab or company and, are unlikely to meet the requirements of IEC 62304:2006. Where bioprinting is considered a tool of manufacturing, on the other hand, software would not need to comply with such medical device oriented standards and demonstrations of compliance of the manufacturing process to certain performance criteria (e.g., as per ISO 13485 or ISO 9001) [83,93] may be sufficient.

Point of care manufacture

The definition of the ‘manufacturer’ is a fundamental issue in the regulation of medical therapies, as this role defines who is liable for product failure. The assignment of this role may be ambiguous in cases where the bioprinting and culture steps occur at the hospital site, rather than at a dedicated biotech facility (such point of care [POC] manufacture may be advantageous where autologous cells are being harvested and reimplanted). If, in these situations, the healthcare facility is considered to be the manufacturer, it could be subject to standard requirements for conformity assessment (e.g., auditing of GMP and their quality management system) especially if the product would be deemed to be a therapeutic good. This issue relates to an ongoing debate around how to regulate POC manufacture of medical products more generally [101,102].

Some therapeutic products are already produced at POC, but these have been typically seen as bespoke therapies and afforded regulatory exemptions (e.g. through mechanisms similar to those described above for 3D printed devices). However, such schemes are not suited to the ongoing expansion of POC manufacture aided by the development of new automated instruments [103]. Such a scenario could be interpreted as a form of distributed manufacture, where the products are being made across multiple sites, rendering quality control a major challenge [102].

These issues motivate the development of more tailored regulatory frameworks. In the UK, a new regulatory framework has been specifically designed for POC manufacture [102]. In that framework, the designer of the manufacturing system (i.e. the biotechnology company) would in effect assume the role of manufacturer: they would secure marketing authorization, would recruit hospitals and would provide the equipment and training. In Australia, the TGA is considering a framework for regulating POC manufacture through a medical device production system (MDPS) – defined as a “collection of the raw materials and main production equipment specifically intended to be used together and by a healthcare provider, or healthcare facility, to produce a specific type of medical device, for treating his, her or its patients.” [104] The MDPS itself would be considered to be a medical device, and would be listed on the ARTG. Such a scheme would allow healthcare providers or healthcare facilities to produce medical devices without taking on the role of ‘manufacturer’, and so would not need conformity assessment certification. This scheme, if formalised, would be an example of a “process-based” regulatory approach, as discussed below.

Materials

In the traditional medical device industry, material properties are well defined and standardized. Most raw materials come from a qualified supplier with a medical grade certification, known risk profile and a Certificate of Analysis or Certificate of Conformance demonstrating their compliance. In contrast, there is a paucity of ‘medical grade’ bioprinting materials on the market certified for human clinical use. Some components, such as cell culture media, bioinks and biomaterials may have significant safety concerns and/or may contain regulated materials.

Multiple sterilization methods available such as Ethylene Oxide, Gamma radiation and autoclaving all come with corresponding standards. Bioprinting components can be difficult to effectively sterilise and scale up. The majority of standard sterilisation methods can be destructive and may have detrimental effects on bio-ink properties such as viscosity, printability and cytocompatibility, dictating fabrication in a sterile environment [84].

Standards

Another obstacle to the regulation of bioprinted products is the relative paucity of specific standards for characterizing bioprinting processes [38]. In the medical device industry, these standards include GMP, International Council for Harmonization (ICH) standards, International Organization for Standardization (ISO) standards and other technical standards, such as those prepared by ASTM International.

To date standards have only been proposed for extrusion based bioprinting (such as, New Test Methods for Printability of Bioinks and Biomaterial Inks [ASTM WK65680] and Printability of Bioinks for Extrusion-based Bioprinting [ASTM WK72274]). There is also the ASTM International F2900 – 11: Standard Guide for Characterization of Hydrogels used in Regenerative Medicine. These standards do not take into account the latest developments in embedded bioprinting, such as the FRESH technique (Freeform Reversible Embedding of Suspended Hydrogels), which works by extruding a cell-laden hydrogel into a hydrogel support bath, thus allowing more complex and high-resolution patterns to be created [105]. To our knowledge, no standards yet exist for light-based bioprinting techniques such as stereolithograpy digital light processing or volumetric photopatterning. These techniques work through the selective photo-crosslinking of liquid resin, and are of increasing interest owing to their advantages in achievable resolution and pattern complexity [106,107]. Thus the development of standards lags behind the development and use of new techniques. The need to adopt and update standards is regarded as especially important for point-of-care production, considering that existing standards have been established to serve centralized production settings [73].

What can be done? The case for a tailored regulatory system

Despite evidence for efficacy, patient interest and the large potential market for 3D bioprinted products, it is increasingly clear that the policies and procedures for regulating bioprinting are one of the key issues stalling the translation process [56,108]. It is therefore imperative that the regulatory environment is comprehensively reviewed from the 3D bioprinting perspective and any shortcomings are clearly identified [1,2,64].

A tailored regulatory system may be required. Li et al. have advocated for a ‘process-based’ approach to regulations as safer than a ‘product-based’ approach while scientific supporting evidence is still being built [80]. A process-based approach is where regulators pay particular attention to the risks posed by the process used to produce the final product. This precautionary and risk-averse approach has previously been adopted for novel manufacturing processes presenting unknown risk profiles, though at a cost of potentially slowing innovation. For example, genetically modified organisms (GMOs) are regulated according to a ‘process-based’ regime in the EU/UK, where close regulatory attention is paid to the potential risks arising from the GMO cultivation process. The ‘product-based’ approach is more conventional for medical devices and is where regulators place emphasis on the risks posed by the final product itself, regardless of the manufacturing process used. Such a regime can favour innovation as it is more permissive of novel processes, but is more exposed to risk since issues associated with the manufacturing process may only come to light when the product is already in the field, e.g. through device failures. Nielsen et al., also considered the potential for a process-based approach, but ultimately concluded that the product-based system is likely more appropriate [10].

Conclusion

Despite the positive and enthusiastic portrayal of 3D bioprinting in the media, there is currently no commercial case of a 3D bioprinted product for clinical use [20]. There are, however, some promising patents, and some success with the tooling technology and the broader applications of the 3D bioprinting machines themselves [66,109]. The advent of the first-in-human clinical trial of a bioprinted therapy is also a strong sign that 3D bioprinting has a promising future [13]. For the technology to mature and gain its first market authorisations, it will be critical to overcome the regulatory challenges around 3D bioprinting. Regulation is considered to be one of the major barriers to commercialization [1,56,110] In the biomaterials field specifically, overcoming regulatory barriers is identified as a major challenge when developing new implantable therapies [111]. The apparent complexities around 3D bioprinting regulation, as we have discussed, can only increase the height of this barrier from a business planning perspective, with the potential for raising a roadblock to commercialization in this sector.

3D bioprinting has inherited many of the challenges around 3D printed devices, and adds others from the tissue engineering, stem cell and biomaterial fields. All the existing challenges with 3D printing are now amplified and further complicated by the additional challenges of working with living cells which are normally regulated under a different, separate pathway not necessarily in alignment with medical devices [7]. It is therefore imperative that the regulatory environment is comprehensively reviewed from the 3D bioprinting process as well as product perspective and any shortcomings are clearly identified [1,2,64]. Any 3D bioprinting research translation program needs a regulatory plan with a supported regulatory approach to minimize the risk of failure. The advent of bioprinting products will be a challenge to the current regulatory systems which are more product centric, as opposed to process focused, when responding to risks.

In the rapidly evolving field of personalized medical products, new process-based regulatory frameworks could offer an effective solution for ensuring safety and efficacy. Rather than trying to apply a standard set of criteria to a diverse array of unique products, a process-based approach allows regulators to ensure that every product – no matter how unique – comes from a reliable, safe, and thoroughly vetted production process. In the context of 3D bioprinting, regulating the ‘process’ could include regulating the printer and printing-related software as medical devices. It may also include the validation of the process through non-destructive characterization of the resulting tissue. This approach inherently caters for the variability and customization inherent in personalized medicine, ensuring that the processes generating these unique solutions meet strict standards for safety, efficacy, and quality, irrespective of the individualized product outcome. For this technology to realise its potential, it is critical to anticipate these challenges now, and to proactively prepare existing systems to adapt.

Future perspective

Future regulatory challenges in 3D bioprinting domain are multifold, and go beyond what we have discussed above as they stem from larger shifts in the biomedical industry brought about by the integration of technologies, the incorporation of artificial intelligence into production processes and the increasing pace of research.

In the coming years we expect distinctions between software, hardware and biological products will continue to blur as increasingly complex combination products emerge. The potential addition of artificial intelligence driven personalised design could dramatically reduce the economic cost of bespoke implants [112], although the use of artificial intelligence technologies in medicine comes with its own suite of technical and regulatory considerations [113]. Meanwhile the potential integration of in vitro tissue models and/or organ-on-a-chip systems in the R&D pipeline, either as a precursor to or a substitute for animal models [114], has the potential to enable the screening and development of novel therapies with unprecedented rapidity. We anticipate the increasing pace of R&D could produce a new wave of regenerative therapies with the potential to outrun the current product type-led regulatory framework. As a result, regulations could become increasingly outdated, inadequate, and potentially obstructive to the rollout of promising new therapies. A lack of global harmonization leaves open the prospect for medical therapy tourism to become more prevalent in unregulated jurisdictions, as previously seen with stem cells [58]. With the increasing use of software in healthcare delivery, cybersecurity also becomes of paramount concern. These future developments underscore the urgent need for a regulatory framework which is inherently more agile; being able to adapt to rapid progress while ensuring the safety and efficacy of these promising medical technologies.