Continuous bioprocessing set to revolutionize cGMP manufacturing of biologics
The biopharmaceutical industry has grown enormously in recent decades, yet the high cost of biologics and their global accessibility continues to be a major challenge.
Moreover, the emergence of precision medicine, pandemic threats and bioterrorism require different strategies to those which established today's hugely successful monoclonal antibody (mAb) therapies such as Humira®, Herceptin® and Avastin®, including the need for shorter development timelines, different manufacturing strategies and flexible facilities where appropriate.
The composition of biopharmaceutical drug pipelines is changing
Innovations in molecular design have resulted in the emergence of newer modalities such as bi/multispecific antibodies (bs/msAb) and antibody drug conjugates (ADCs). These next-generation therapeutics have complex molecular architectures which may present challenges during their development and overall productivities from the manufacturing processes can be lower. However, these molecules are usually highly potent and may be intended for smaller patient populations. Consequently commercial demands of many of these next generation therapeutics are lower, ranging from tens to a few hundred kilograms per year compared to a blockbuster mAb where demands can reach metric tons per year. These diverse needs continue to present challenges to established manufacturing strategies which now encompass the use of single-use bioreactors or stainless steel bioreactors.
Global health threats require more agile strategies
The current COVID-19 pandemic demonstrated that it was possible to reduce the overall timeline to approval by adopting risk-based clinical development models supported by pragmatic, proactive regulatory strategies and more agile, platform-based development and manufacturing approaches.
In addition, the pandemic highlighted the fragility of global supply chains for pharmaceuticals; this has fostered new national biomanufacturing strategies in many countries, such as the US National Biotechnology and Biomanufacturing Initiative, including plans for building more localized development and manufacturing facilities to more effectively address future global health threats, as evidenced by Just–Evotec Biologics' collaboration with the US Department of Defense under their Accelerated Antibodies Program. Being in a position to respond quickly to health threats by rapidly manufacture and deploy therapeutics that cannot be stock-piled due to short shelf-lives, is increasingly important amidst the potential threat of biological weapons and bioterrorism.
Innovative approaches can address current industry challenges
The trend towards precision medicines has resulted in many established biotech and pharma companies expanding their therapeutic pipelines instead of relying on the development of a few blockbuster products to generate revenue and sustain growth. This shift, however, can stretch the internal resources of development and manufacturing teams and the finite capacity of manufacturing assets.
There is also a need for more diversity and flexibility in manufacturing strategies as well as more efficient, agile approaches which also take into consideration the present global environmental challenges, the need for sustainability, and rising energy costs.
In view of these multiple challenges and finite resources, there is an increasing trend among pharmaceutical companies to outsource not only their drug manufacturing needs but also many traditionally in-house activities, such as drug discovery and development, choosing instead to focus on overall strategy, in licensing activities and pipeline management. This approach places greater emphasis on establishing trusting, long term partnerships with specialist providers who are focused on addressing their clients' needs through a combination of innovation and operational excellence.
Just - Evotec Biologics is leading the way in supporting its clients to address these industry challenges through the provision of a highly integrated suite of services for the discovery, development and manufacturing of biologics; J.DESIGN combines the use of artificial intelligence (AI)/machine learning (ML)-driven molecular discovery tools, high-throughput process development, state-of-the-art analytical tools with hybrid/fully continuous cGMP manufacturing platforms, housed in modern, flexible and rapidly constructed facilities called J.PODs.
J.DESIGN services incorporate the following features:
- Molecular optimization to decrease the risk associated with product and process development using high-throughput tools for assessing developability and manufacturability.
- Streamlined, risk-based approaches to bioprocessing and product development leveraging platforms, automation and standardization, where appropriate.
- Scalable and flexible manufacturing processes which can cater for a larger dynamic range of needs, from production of the more specialized, next-generation therapeutics such as bispecific Abs, to the multi-ton requirements of blockbuster mAb therapeutics.
- Efficient processes to achieve a lower COG and consequently more affordable and accessible treatments.
J.POD®– an agile, small manufacturing footprint, rapidly deployable cGMP manufacturing facility
J.POD is a small footprint cGMP manufacturing facility for the manufacturing of bulk drug substance (BDS) that can be rapidly constructed virtually anywhere in the world. J.POD is based on a flexible facility design whereby Grade B and C clean room modules (PODS) are located within a Grade D ballroom.
J.POD’s intensified, continuous manufacturing process connects high-performance, perfusion cell culture with intensified downstream processing. In contrast to more traditional fed-batch processes, product degradation can be minimized by maintaining a viable cell population at high cell density and through continuous removal of the product from the bioreactor. This minimizes the bioreactor residence time which could affect the stability and purity of the product. In addition, both the facility design and manufacturing processes are fully optimized for high efficiency and flexibility, thus reducing the plant’s footprint and environmental impact as well as construction time and cost.
J.DESIGN processes can be run using highly automated equipment with single-use flow paths at 500 L or 1000 L bioreactor scales. Instead of scaling up, a process can be scaled by bioreactor culture duration to deliver anywhere from a few kilograms of drug substance to metric tons. Moreover, intensified processes can be operated in hybrid or fully continuous processing modes to produce the desired quantity of BDS in a compact space, without the need for Cleaning-in-Place and Steam-in-Place strategies.
These intensified perfusion-based bioreactors typically generate 2–4 g of product/L/day for well-behaved mAbs. Taking into account the collection window and downstream process yield, this roughly translates into drug substance batches of 4-8 kg for a 15 day-500 L bioreactor scale process or 25-45 kg for a 25 day-1000 L scale process.
Just - Evotec Biologics opened its first J.POD facility, which was built in 16 months during the COVID-19 pandemic, in Redmond, WA (US) in August 2021. The first cGMP batch of mAbs for the United States Department of Defense was completed in J.POD by March 2022. Just-Evotec Biologics has been undertaking process development and cGMP clinical batch manufacturing of mAbs and newer modalities such as bi-specifics, Fc fusion proteins and exosomes for several clients at its J.PLANT and J.POD facilities.
Just - Evotec Biologics' first European J.POD facility, located in Toulouse, France, is expected to be operational by H2 2024, with construction having started in September 2022. Just - Evotec Biologics’ strategy is to build a global network of J.POD manufacturing facilities to enable regional manufacturing to support the clinical and commercial supply needs of its partners, from large biopharma/biotech to virtual/start-up biotech companies and government agencies.
J.DESIGN and J.POD respond to evolving industry needs by providing agile, flexible solutions for faster and more productive discovery, development and cGMP manufacturing of biologics.
*The construction of J.POD Toulouse, France (EU) benefits from French government funding as part of the Investments for the future Programme
(programme d’investissements d’avenir in French) and is also supported economically by the Occitanie Region and Toulouse Métropole.
Content written by Nigel Shipston, PhD, a Senior Director Business Development at Just - Evotec Biologics
J.POD is a registered trademark of Just - Evotec Biologics
Humira is a registered trademark of AbbVie, Inc.
Herceptin and Avastin are registered trademarks of Genentech, Inc.