Novel and Advanced Therapies have made great strides over the past decade but that means that manufacturing process consistency, GMP standards and so on must now meet more formal requirements. This involves challenges because the products and their development processes differ from traditional models, explains Elena Meurer, Principal Consultant and CMC expert at Biopharma Excellence.
Novel and advanced therapies are coming on in leaps and bounds. A decade ago, most of these products were only just entering early clinical research. But as the market evolves there is a shift towards later clinical trials as a number of cell and gene therapies enter the later stages of development.
We’re now seeing several examples of approved CAT-T therapies. Meanwhile CRISPR technologies, and induced pluripotent stem cell therapies, have also made substantial progress. New players are entering the market and new types of products are emerging, including 3D printing, organs and products for ‘bedside manufacturing’.
These developments are, of course, enormously positive, but they also mean that the bar is being lifted now in terms of the formal requirements for manufacturing process consistency, GMP standards and so on. This is the natural course of things as the knowledge base grows. Yet it also presents some challenges.
Lagging behind
In advanced therapies, Chemistry, Manufacturing and Controls (CMC) provision often lags behind clinical development. Reasons include the need early on for a clinical proof-of-concept, and accelerated programmes that promote clinical development. But it also leads to time pressures at the CMC development stage, presenting challenges in later development.
Other practical factors include the small batch sizes associated with advanced therapies, which make it harder to reach product consistency. The use of biological materials and autologous manufacturing approaches add to the variability, too.
The challenges of bedside manufacturing
Take the example of manufacturing at the patient bedside. This won’t usually involve a facility separate from the hospital, or even a dedicated hospital room where the product is manufactured. Instead, the product will be generated with the help of a particular device beside the patient’s bed.
This presents challenges. To start with, this is not a controlled environment. Additionally, cell-based therapeutics and gene therapies currently require a very long product release time: at least several days, more typically even several weeks. Those protracted timeframes are not viable if the goal is to establish highly efficient manufacturing at the patient bedside. This means we need to find another approach to quickly deliver the product for the patient while still ensuring its safety and efficacy.
Addressing these kinds of issues means much earlier consideration of all of the moving parts. It also requires a multi-pronged strategy that combines Regulatory, Manufacturing, Quality, and Development perspectives so that nothing is missed in the planning.
Global considerations
Global clinical development needs to be considered from the beginning. This is not just because of regulatory differences across and between regions, but also because it could influence the choice of materials used in manufacture, including the starting materials of biological origin.
There are differing standards for facility qualification between regions such as the US and the EU, for instance, as well as viral safety requirements. Take the establishment of standards for iPS cell lines for manufacture: viral and transmissible spongiform encephalopathy (TSE) safety has to be very carefully considered from the beginning if the cell line is going to serve product manufacture across the globe.
Also, we often see that research-level materials are used or relevant quality information is provided by the material manufacturer in the Drug Master File in the US, so that the manufacturer of advanced therapies often lacks sufficient insight into the quality of critical materials. Such issues need to be carefully considered, otherwise these omissions could trigger change later.
Manufacturing changes are inevitable, but by being prepared – by understanding the critical quality attributes of the product and working out comprehensive comparability plans – manufacturers can have control over the fallout.
An interdisciplinary approach
More product approvals are coming on stream and the competition is undoubtedly growing. That means that an interdisciplinary approach to planning is becoming more essential in order to ensure from the outset that nothing is missed.
What is so exciting about cell and gene therapy is the genuine potential to cure disease, not just alleviate the symptoms. We’ve seen the example of CAT T-cell therapy, and the potential which gene therapies have, in fighting disease very efficiently and we can be confident of more ground-breaking examples coming to market in the upcoming years.
Biopharma companies need to devise strategies and approaches that foster and support innovation, to facilitate the efficient development, manufacture and marketing of products. But fortunately, it should be relatively easy to obtain the help that you need because stakeholders from scientists and regulatory authorities to biotech companies and experienced consultants, are collaborating to develop suitable strategies that cover all requirements.
About the author:
Elena Meurer is Principal Consultant and CMC expert at Biopharma Excellence, which helps dynamic biopharma companies bring innovative new therapies to market by providing strategic, proactive practical support across their product journey. The Biopharma Excellence team is a fusion of three scientific powerhouses that came together under the PharmaLex brand. It combines more than 35 years of empirical experience and respected regulator relationships. Elena’s background is in quality, manufacturing and regulatory, with cell and gene therapies as core areas of expertise.
