Navigating the complex and evolving regulatory environment of 3D Printing
Interest in manufacturing solutions that utilize 3D printing technology is constantly growing. Recently, 3D printing has made some inroads into cell and tissue-based clinical applications. Already, there are several exciting projects in development that exploit this technology for cell therapy by printing cell-containing human organs or parts thereof, a process known as bioprinting.
The regulatory approach used for bioprinting combines general requirements of additive manufacturing with the requirements imposed by cell and tissue regulations. These requirements need to be combined thoughtfully to achieve the optimal regulatory route for product development.
To foster the regulatory knowledge of developers of 3D printed cellular therapeutics, Viscofan BioEngineering hosted a regulatory seminar on advanced additive manufacturing solutions for healthcare applications in Madrid in June 2022. The purpose was to bring together experts in the field to discuss regulatory aspects in bringing regenerative 3D printing technology developments to fruition.
Presenters came from academia, industry, the regulatory authorities and consultancies. Speakers covered different aspects related to bioprinting, including regulations for medicinal products, medical devices and combination products, clinical requirements as well as manufacturing aspects and 3D printer qualification requirements. Three Biopharma Excellence experts presented at the webinar: Zaklina Buljovcic who talked about ATMP classification, Yasser El Sherbini, who addressed the obstacles in transforming scientific inventions into marketable innovations and me, on the topic of applicable quality systems and diverse manufacturing aspects.
Addressing quality and regulatory requirements
One of the central questions in preparing the development strategy for bioprinted products is assessing the product regulatory classification. That is because the classification of 3D printed products containing cells may differ depending on the proposed mode of action of the product components. Given the novelty and complexity of the technology, the classification exercise is not always straightforward. A product component produced by bioprinting can be considered a device component or a medicinal product component depending on its function, and this influences the classification of the final product.
The classification approach also differs between major regulatory regions such as the EU and the US. The challenge here is that the product classification (non-combined versus combined ATMP in the EU and biologics versus combination product in the US) determines the proposed regulatory root and has an influence on the quality system applied during development and manufacturing. Therefore, it’s important to consider global development strategies early on.
Choosing the right 3D printer should also take regulatory expectations into account. The 3D printer is a critical piece of manufacturing equipment and should have a comprehensive qualification package. That means ensuring the requirements for additive manufacturing are taken into consideration and that the printer design is appropriate for aseptic manufacturing under GMP. Choosing the right printer from the start reduces the need for critical equipment and process changes in later clinical research and increases confidence in the product quality. This is especially important since bioprinting is a novel technology which will likely be meticulously inspected by the local GMP authority as part of the manufacturing license application in the EU.
Aside from the bioprinter qualification, another key consideration is the requirements and qualification of the bioprinting process, both in terms of regulatory submission and manufacturing license application. The printed product does not permit the classical quality control (QC) testing strategy performed on filled drug product vials, but there is still a need to conduct end product testing. Developers should define an approach to analyse the 3D printed construct with help of additional QC samples that are representative of the final product. The end goal must be to have a control strategy in place that provides reliable insight into the quality of the final product.
At the beginning I mentioned that the product classification may have influence on the quality system applied. If the 3D printed construct is considered to be a device component, ISO 13485 and ISO 10993 requirements need to be taken into account. This is particularly important for the US regulatory framework. In such cases, a smart, risk-based development program can help developers avoid the duplication of studies required by the medicinal product and device regulations.
A learning curve for everyone
Bioprinting technology is evolving very rapidly and the knowledge of regulators, developers and manufacturers is increasing as we speak. With time, the accumulated knowledge will find its way into specific regulations closing the current gaps and streamlining the current complex regulatory and development path. In the meantime, developers can take advantage of classification and scientific advice procedures to address their specific questions.
Furthermore, meetings such as the regulatory seminar on advanced additive manufacturing solutions held in Madrid are key to advancing knowledge in the field and supporting best practices for newly emerging products.
About the author:
Elena Meurer is a principal consultant at Biopharma Excellence, providing CMC and strategic advice in the field of cell and gene therapy across all clinical phases and post approval, as well as supporting preparation of manufacturing licenses and regulatory quality documentation.