Managing the Complex Regulatory Pathways for Bioprinting Breakthroughs

Manufacturing: 3D Bioprinting

Bioprinted products are already starting to demonstrate life-changing potential, but the path to commercialisation is complex, requiring developers to better understand the factors that impact regulatory classification

Elena Meurer and Mariya Gromova at Biopharma Excellence

In just 40 years since the first documented examples of 3D printing, the technology and its capacity in different applications has come a long way. In the medical world its potential is extraordinary due to the ability to create complex geometries, which are impossible to reproduce with conventional manufacturing technologies.

Now, innovations are being made possible by the emergence of one of the most exciting breakthroughs in the field: bioprinting. This is where materials of biological or synthetic origin are combined with cells to print an object used for clinical applications.

This intricate and life-changing technology has seen some extraordinary advances during recent years. After the first bioprinted human ear containing patient cells was developed in 2012 by a group of Chinese scientists, in June 2022 a 20-year-old woman was implanted with a 3D printed ear containing her own cells and developed by regenerative medicine company 3DBio Therapeutics (1, 2).

Another notable example is a 3D vascularised engineered heart that also used the patient’s own cells and biological materials. It was produced in 2019 by Tel Aviv University researchers and was the first successful example of an entire printed heart with cells, blood vessels, ventricles, and chambers (3). These examples demonstrate the potential of bioprinting for personalised tissue modelling.

Hugely promising though this field is, developers of bioprinted products must first ensure they understand and adequately address the complexity of regulatory classification during development, since this will define the quality, nonclinical, and clinical requirements of each product.

Classification Complexities and Differences

Many factors impact the classification of the bioprinted product. These include its function, the mode of action of product components, regulatory status of similar products, and the current view of the regulatory agencies.

There are also some notable classification differences between the US and the EU, and understanding these differences is crucial to successfully navigating the development process.

The US separates medicinal products into two classes – drugs and biologics – and regulates cell- and tissue-based products under a biologics policy. Any combination of a drug, biologic, and medical device is defined as a combination product.

In the EU, within the category of biologicals, any product that contains living cells and tissue that underwent substantial manipulation falls under a sub-category known as advanced therapy medicinal products (ATMPs) – and indeed most bioprinted products are considered to be ATMPs in the EU. If such products are combined with one or more medical devices, they are classified as combined ATMPs. While less common, if the bioprinted product’s function is enabled by non-living cells or biological molecules, the EU may define this as a biologic, but not an ATMP. From a regulatory classification perspective, the function of the cellular part and the acellular bioprinted construct are viewed separately. The classification of the acellular bioprinted construct in the EU largely depends on its proposed primary mode of action. If the mode of action of the bioprinted acellular construct is deemed to be physical, mechanical, or structural, it would be categorised as a medical device and the bioprinted product would be regarded as a combined ATMP. If it has a pharmacological mode of action, it is seen as part of the medicinal product, and the bioprinted product would be considered a non-combined ATMP.

Properties of the acellular bioprinted construct (for example, matrix or scaffold) also have a bearing on the product’s classification, since if the matrix biodegrades before implantation or shortly thereafter, the product is likely to be seen as non-combined as the matrix is not exhibiting its original structural functions in the final product. However, if the matrix holds its shape for an extended time, a classification of combined ATMP is more likely.

A reflection paper on classification of ATMPs from the EMA’s Committee for Advanced Therapeutics (CAT) offers examples of when bioprinted products containing cells are defined as combined or non-combined ATMPs (4). In one example, ‘isolated pancreatic beta cells and their accompanying endocrine cell populations embedded in an alginate matrix’ for the treatment of diabetes was considered a non-combined ATMP because, after development, the function of the matrix was no longer deemed to be linked to its structural properties. Conversely, an example of ‘autologous osteoprogenitor cells, isolated from bone marrow, which are grown within and around a bioresorbable scaffold that acts as physical support’ was considered to be a combined ATMP. The purpose of the product was to repair or replace bone defects through the use of living cells that grow within a lesion, and, while the matrix is gradually eliminated, it still served its intended function when implanted.

The US follows a similar approach where the primary mode of action of the acellular bioprinted part defines the classification of such products. If the bioprinted element has a medical device function, the final product is regarded as a combination product. Recent FDA decisions indicate that a bioprinted matrix is mostly seen as a medical device, and the classification as a combination product is therefore currently more likely. Explaining combination product types on the official web page, the FDA even provides an example of ‘live cells seeded on or in a device scaffold’ as a device coated or otherwise combined with biologic. Developers of bioprinted products classified as combination products are required to follow FDA regulations for both medicinal products and medical devices under considerations of specific combination product guidelines, and should adopt processes that allow them to satisfy both sets of requirements concurrently to limit duplication of effort. If the developer is not sure about the product classification, it is possible to obtain informal non-binding advice from the FDA through a so-called pre-Request for Designation procedure or submit an official Request for Designation that results in a formal and regulatory binding assignment.

Managing the Materials

Materials that are suitable for bioprinting are often referred to as bioinks. Currently, the most commonly used materials for bioprinting are collagen, alginate, and hyaluronic acid, but there are pioneering bioinks currently under development, including of non-biological origin. Typically, chemical crosslinkers are added during bioprinting to solidify and stabilise the shape of the product, though some novel bioinks may not require these in future.

Making the material usable for more end-users may sometimes be tricky for the manufacturers because they need to consider quality requirements that are potentially satisfactory for both medicinal product and medical device settings.

Material used in non-combined medicinal products might serve as:

A starting material when it is added at the beginning of the process and is reworked as an integral part of the final product or is biologically active
An in-process material where it is added at any point in manufacturing but is not an integral part of the final product
An excipient, where it is added with the purpose of drug product formulation and improved delivery. In each of these cases, the material would need to satisfy regulatory requirements valid for the relevant category and comply with applicable compendial monographs

If the bioprinting material is used within a combined product, or medical device, it would need to follow the requirements of ISO 10993 for biological evaluation of medical devices. Furthermore, when putting together a material qualification programme, the manufacturer needs to consider which quality attributes of the bioink can be studied on isolated material or an acellular construct, and which attributes may change due to the presence of cells.

Given these complexities, it is advisable to identify a basic set of requirements that would allow adherence to quality standards applicable for various potential bioprinted products, including those that are more rigorously 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 potential limitations of the study resulting in the absence of cells should be taken into account. Identification of other relevant parameters should be considered according to a risk-based approach.

For materials of biological origin, source and traceability are key for a medical setting, and requires assessment of viral and Transmissible Spongiform Encephalopathies safety to be performed under both EU and US guidelines.

Clear consideration also needs to be given to manufacturing standards. Given bioprinting will likely be carried out in an aseptic environment and used for implantation in humans, acceptable bioburden limits need to be established on materials. Endotoxin evaluation is needed to ensure that regulatory limits can be met, no matter the product classification, route of administration, or dose. And, crucially, it is important to have a reliable quality system in place to document and maintain the material quality, which is an important factor for the bioprinted product developer to decide on the use of a particular material. Therefore, manufacturing under GMP is highly preferrable.

While manufacturers of the materials need to ensure they are following basic regulatory requirements, they must also balance their investment in meeting those standards with qualification costs to remain competitive.

Successful commercialisation of a bioprinted product, and the materials used for bioprinting, requires development of a regulatory strategy taking into consideration regulatory requirements and possible development pathways. While this implies additional efforts for developers, these hurdles are worth tackling because of the great potential of bioprinting innovations to generate patient-specific tissue for targeted, personalised treatments.

References
1) Visit: pubmed.ncbi.nlm.nih.gov/33022554/
2) Visit: www.fiercebiotech.com/medtech/ear-3d-printed-patients-own-cells-implanted-successfully-first-human-trial
3) Visit: english.tau.ac.il/news/printed_heart
4) Visit: www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-classification-advanced-therapy-medicinal-products_en-0.pdf

Elena Meurer is a principal consultant at Biopharma Excellence, providing CMC and strategic advice for advanced therapies across all clinical phases and post-approval.

elena.meurer@biopharma-excellence.com

Mariya Gromova is a senior consultant at Biopharma Excellence, specialising in global regulatory strategy and regulatory interactions for biologics and advanced therapies in clinical development.

mariya.gromova@biopharma-exellence.com

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