Navigating the complexity of regulatory classification in bioprinting

Bioprinted products hold huge promise for medical breakthroughs, but developers must deal with regulatory classification complexities and many different factors can influence this.

The scope for 3D printing has expanded significantly in recent years thanks to its potential for creating and replicating diverse complex shapes with great precision.

One of the most exciting developments has been the growth of this technology into cell and tissue-based clinical applications – otherwise known as bioprinting. This rapidly emerging field refers to the printing of biological components to produce living tissue, bone, organs or parts thereof.

Among the more intricate examples is the bioprinted human ear. In 2012, a group of Chinese scientists performed auricular reconstruction in five patients with microtia using patient-specific chondrocytes in a biodegradable scaffold.

Meanwhile, in 2019, Tel Aviv University researchers printed the world’s first 3D vascularised engineered heart that used the patient’s own biological material and cells. These examples demonstrate the potential of the bioprinting for personalised tissue modelling.

While many more products using bioprinting technology are currently under development, complex regulatory classification must be considered early on because it will define the quality, non-clinical and clinical requirements for the product.

The classification of the bioprinted product may depend on function and the mode of action of product components, regulatory status of similar products and the current view of the regulatory agency. Classification approaches also differ between the major regulatory regions, the EU and US.

In both regions, medicinal products and medical devices are managed independently. In the US, medicinal products are divided into two classes, drugs and biologics, with cell- and tissue-based products regulated under a biologics policy. Any combination of a drug, biologic and medical device is seen as a combination product.

In the EU, the products containing living cells and tissue that underwent substantial manipulation are placed in a subcategory within biologics, which is advanced therapeutic medicinal products (ATMPs). Most bioprinted products fall under the definition of ATMPs in the EU. Furthermore, if such products are combined with a medical device, they can be seen as a combined ATMP.

The use of bioprinting may not be restricted to living cells, and the product function may be deployed by non-living cells or biological molecules. In this case the product may be considered a biologic but not an ATMP.

For the purpose of regulatory classification, the function of the cellular part and of the acellular bioprinted construct are regarded separately. The classification of the acellular bioprinted construct in the EU largely depends on its primary intended mode of action.

The classification difference between medicinal product and a medical device plays a crucial role here. If the mode of action of the bioprinted acellular construct is considered physical, mechanical or structural, it would be defined as a medical device and, consequently, the bioprinted product would be seen as a combined ATMP.

If it has a pharmacological mode of action, thus falling under the definition of a medicinal product, the bioprinted product would be considered a non-combined ATMP. One additional factor is if the matrix biodegrades prior to product implantation or shortly thereafter, the product is likely to be seen as non-combined, since the matrix is not part of the final product. The matrix that holds its shape for an extended time is likely to tilt the decision towards classification as a combined ATMP.

Similarly, the primary mode of action of the acellular bioprinted part defines the classification of such products in the US. When the bioprinted part has a medical device function, the final product is seen as a combination product. In the US, the indications from recent FDA decisions are that classification as combination product is more likely. The developer of such a product will need to follow both sets of FDA regulations, for medicinal products and medical devices, under consideration of specific combination product requirements.

Each case, however, needs to be considered on its own merits, and the developer should pay attention to the correct positioning of the bioprinted construct when discussing its proposed mode of action with the authorities.

Currently, most common examples of materials used for bioprinting are collagen, alginate and hyaluronic acid, but more alternative materials, including of non-biological origin, are in development. The crosslinkers, which are typically inorganic molecules, are added during bioprinting to solidify and stabilise the shape of the product.

Developers of bioprinting materials wanting to make their products available to a broad spectrum of users will also need to consider quality requirements that are potentially satisfactory for both a medicinal product and a medical device.

From a medicinal product perspective, the regulatory classification of the material depends on its use in the manufacturing and whether it can be used as a starting material, in-process material or excipient.

As a component of a medicinal product, the material would need to be compliant with relevant medicinal product regulations and compendial monographs, while as a material for manufacturing of a medical device, it would need to follow the requirements of ISO 10993 for biological evaluation of medical devices.

These two sets of regulations are not identical in their requirements. Furthermore, not all aspects can be addressed for a material or an acellular printed construct since the presence of cells tends to alter certain material properties. Therefore, it is advisable to identify a basic set of requirements that would allow adherence to quality requirements for various potential bioprinted products, including those that are more stringently regulated.

For example, a biocompatibility study could help to address some key questions regarding the material’s suitability for human use. A biodegradation study may also be useful but should take into account potential limitations of the study results in the absence of cells. Identification of other relevant parameters should be driven by a risk-based approach.

Independent of the product category, the origin and traceability of the bioprinting materials and other important factors for their human application. This is especially true for materials of biological origin, for which the assessment of viral and TSE safety according to relevant EU or US guidelines needs to be performed.

Furthermore, regardless of whether the material is used for a medical device or medicinal product, the printing will likely be carried out in an aseptic environment. Therefore, the acceptable limits for the material bioburden need to be elaborated.

Endotoxin levels also need to be evaluated to ensure that the material is manufactured in such a way that the final product specifications for endotoxin content can be met, no matter the product classification, route of administration or dose. And, finally, it is vital to have a reliable quality system in place to document and maintain the material quality.

Establishing the qualification programme for the bioprinting material is a balancing act of following the basic set of regulatory requirements from both the medicinal product and the medical device field, while keeping the material qualification costs reasonably low.

Elena Meurer and Mariya Gromova are from Biopharma Excellence.
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