Bioprinting has the potential to revolutionize medicine, as illustrated recently when patients with microtia, a congenital condition in which one or both outer ears are missing or incomplete, were given an ear implant using their own cellsi.
This rapidly emerging field has wide-ranging clinical applications, enabling the printing of biological components to create living tissue, bone, organs, or parts thereof.
In 2019, Israeli researchers printed the world’s first 3D vascularized engineered heart with cells, blood vessels, ventricles and chambers, using the patient’s biological material and cellsii.
While these are powerful examples of the life-changing role bioprinting could play in medicine in the future, this evolving technology requires developers and manufacturers to navigate complicated regulatory classifications, which, in turn, significantly affects the requirements for the materials used in bioprinting.
Many different factors have a bearing on the classification of the bioprinted product. These include its function, the mode of action of product components, the regulatory status of similar products and the current view of the regulatory agencies.
There are also some important classification differences between the United States and the European Union, and understanding these is key to successfully navigating the development process.
In the US, medicinal products are divided into drugs and biologics, with cell and tissue-based products regulated by a biologics policy. Any combination of a drug, biologic and medical device is defined as a combination product.
In the EU, any product containing living cells and tissue that has had substantial manipulation falls under a sub-category of biologicals known as advanced therapy medicinal product (ATMP), making up the majority of bioprinted products in the EU. If combined with a medical device, they are known as combined ATMPs, unless the product function is deployed by non-living cells or biological molecules, which may impact the classification, making it a biologic rather than an ATMP.
The implications of regulatory classification for the bioprinted products on the regulatory requirements for the materials used in bioprinting need to be understood by manufacturers of these products.
Often known as bioinks, the most common materials used in bioprinting are collagen, alginate and hyaluronic acid, though non-biological bioprinting materials are also under development. Typically, crosslinkers are added during bioprinting to solidify and stabilize the product shape.
It is recommended that manufacturers of bioprinting materials identify and implement quality requirements early in development to ensure the materials can be versatile and can be used in both the combination and non-combined medicinal product settings in the EU and US.
This allows companies to make their material more attractive to a greater number of bioprinted product developers and thus improve their commercial viability.
To identify this set of requirements, a number of factors linked to the material’s regulatory classification need to be considered.
As a component of a medicinal product, the material’s regulatory classification depends on its function in the manufacturing process, whether it is being used as:
If the bioprinting material is classified as part of medical device within a combined product, the requirements of ISO 10993 for biological evaluation of medical devices need to be considered.
In addition, the manufacturer should determine which quality attributes of the bioink can be studied on isolated material or an acellular printed construct, and which material characteristics need to be studied later, in the presence of cells.
Establishing a basic set of quality requirements that adhere to regulatory standards from the get-go is good risk management. Key questions about the material’s suitability for human use need to be addressed from the outset, which can be done by carrying out a biocompatibility study.
The source and traceability of bioprinting materials are also important considerations for use in human applications. For example, both the EU and the US require the assessment of viral and TSE (Transmissible Spongiform Encephalopathies) safety.
It is also essential to have a reliable quality system in place to document and maintain established standards. This is one of critical parameters that will influence the decision of the bioprinted product developers when deciding which material to use in the process. Therefore, manufacturing under GMP is highly recommended.
Lastly, considerations about the bioburden levels should be made, since the bioprinting will likely be carried out in an aseptic environment and used for implantation in the patient, whether human or animal. For example, for bioprinting materials of biological origin, endotoxin levels should be evaluated to ensure that the material is manufactured in a way that regulatory limits can be met, no matter the product classification.
Adherence to quality and regulation, albeit necessary, does not come without significant financial impost. Manufacturers must balance their investment in meeting regulatory standards with the need to remain competitive.
However, by investing early in a regulatory strategy, both manufacturers and developers are laying the foundations for future success.
i Ear 3D-printed from a patient's own cells implanted successfully in first-in-human trial, https://www.fiercebiotech.com/medtech/ear-3d-printed-patients-own-cells-implanted-successfully-first-human-trial
iiTAU scientists print first ever 3D heart using patient’s own cells, https://english.tau.ac.il/news/printed_heart
Elena Meurer is a principal consultant at Biopharma Excellence, providing CMC and strategic advice for advanced therapies across all clinical phases and post approval.