Emerging biotechnology companies often are at the forefront of pharmaceutical innovation. Small companies develop novel molecules and complex biologics that advance global healthcare and improve patient outcomes. However, the complexity of such molecules hinders their production, increasing the cost of manufacturing and the final-product price. Unfortunately, this means that life-changing therapies are often inaccessible to patients — a problem that is amplified on a global scale because of discrepancies in healthcare systems. There are many other challenges in biologics production, but some continuous manufacturing strategies can provide solutions that improve access equity across global healthcare systems.

Biologics are often large and complex molecules, requiring a multistep process with several interconnected stages. First, cell-line engineering is used to express a gene of interest (GoI). That is followed by upstream and downstream processing, formulation, and fill–finish, with each step requiring optimization. Refining each process ensures productive and high-quality biomanufacturing. For emerging biotechnology companies with limited experience, it can be difficult to optimize biologics production steps and ensure that processes are interconnected. Biomanufacturing challenges continue after the optimization of production steps.

Quality control (QC) processes are required to ensure that production meets standards for biologics safety and efficacy. Analytical testing and stability studies are used during QC. Personnel also must monitor critical quality attributes (CQAs) and critical process parameters (CPPs) to control factors such as identity, purity, and potency. Clinical-phase manufacturing is subject to stringent regulatory requirements that can be difficult for emerging biotechnology companies to navigate.

Ultimately, organizations must invest significant resources to optimize their processes and overcome practical challenges in biomanufacturing. The financial burden can be prohibitive for emerging companies, leaving them unable to fund their own clinical trials. That problem is compounded further by tight deadlines and a lack of access to the infrastructure and specialized equipment required.

Continuous Clinical-Phase Biologics Manufacturing

Continuous manufacturing is an innovative approach that can be used to overcome the challenges faced in clinical-phase biologics manufacturing. Unlike traditional fed-batch techniques commonly used in biologics production, fully connected continuous manufacturing (FCCM) constantly loads and processes materials to produce a final product.

Using perfusion processes in upstream processing and multicolumn chromatography in downstream processing enables uninterrupted unit operations, which can be integrated for an FCCM approach. Processes run from upstream to downstream continuously, after which the bulk is filtered to obtain the final drug substance. Operations can be combined with on-line process analytical technologies (PATs) to monitor CQAs and CPPs in real time. That aspect of FCCM simplifies optimization steps for emerging biotechnology companies, improving efficiency and cost-effectiveness.

FCCM approaches provide advantages in biologics production when compared with fed-batch processes. By running both upstream and downstream processes constantly, companies can improve their productivity and drive down costs dramatically. Perfusion processes reduce a product’s contact with cell-culture fluids, thus increasing product quality and reducing the risk of degradation. That aspect of continuous manufacturing is particularly useful for complex proteins that are unstable and prone to degradation. Moreover, the equipment used in FCCM is significantly smaller than that used for fed-batch processes. That relative footprint in turn enables organizations to save money by optimizing facility and resource use.

FCCM during clinical phases also improves flexibility beyond what is possible with traditional processes. Often, companies need only small amounts of biologics to support their clinical trials, but demands can change quickly as those trials progress. Continuous processes use large bioreactors that operate based on the “scale-up and scale-on” concept, which reduces the facility footprint and introduces greater flexibility compared with fed-batch processes. The process is ideal for producing small quantities of product, ensuring an efficient and cost-effective supply when demand is low. When demand increases, the flexibility to scale-up or scale-on enables scientists to meet the higher production needs effectively.

Continuous manufacturing also facilitates clinical-phase manufacturing for emerging biotechnology companies. Ultimately, continuous manufacturing will help biotechnology companies address equity issues across global healthcare systems.

Himanshu Gadgil is chief executive officer of Enzene Biosciences Limited, Plot No. A 22, A/1/2 Chakan Industrial Area, Phase 2, Khalumbre, Chakan, Pune, Maharashtra, India 410501; https://www.enzene.com. For inquiries, please contact Royston Pinto at [email protected].