Contributed Commentary by Karoline Hahn, KCR

April 22, 2022 | While most medicines are derived from chemical compound, biologics are now the fastest-growing drug class. Over the past five years, eight out of the top ten best-selling drugs were biologics, with therapeutic antibodies at the forefront (DOI: 10.1186/s12929-019-0592-z). By February 2022, the Food and Drug Administration had approved more than 90 antibody-based drugs and currently has 17 therapeutic antibodies under review, with many more are coming through the pipeline. There is unprecedented investment in these biotherapeutics, further fueled by rising gene and cell therapeutics.

To deliver these complex drugs to patients as quickly as possible, the biopharmaceutical industry is shifting away from traditional batch processing to continuous bioprocessing. It is expected that the global market for continuous bioprocessing will grow at a CAGR of 23% from 2020 to 2027 to reach 348.9 million by 2027.

Although batch processing can reliably deliver large quantities of biologics, the material must be held and tested after each manufacturing step to ensure quality. This complexity makes the manufacturing of biologics a cost-intensive and lengthy process. Instead, continuous bioprocessing aims to eliminate those intermediate hold steps.

Continuous bioprocessing involves the continuous feeding of input material, the transformation of in-process material, and the concurrent removal of the output material as integrated steps of the manufacturing system. Some or all unit operations in a manufacturing process can be directly connected:

• Batch mode unit operations are combined with continuous mode unit operations
• All unit operations of a drug substance or a drug product operates in a continuous mode
• Drug substance and drug product unit operations are integrated to form an end-to-end manufacturing process

Numerous technologies are available to support continuous bioprocessing. On the upstream side, these are employment of stable, high-efficient producer cells, optimized cell media, and utilization of perfusion bioreactors. On the downstream side, continuous filtration and chromatography with or without surge tank integration are well established. Sterility, which is critical to biologics manufacturing, is preserved by the seamless transition of the material into succeeding manufacturing steps. Utilization of single-use equipment suits the same need, but also eliminates downtimes due to cleaning and regeneration of the equipment.

Continuous bioprocessing benefits from the digital transformation currently occurring in the industry. The integration of automation to upstream and downstream processes eliminates manual testing operations saving time, but more important decreasing risk of contamination and manipulation errors. Furthermore, real-time data acquisition and analysis regulate the manufacturing processes through immediate feedback adjustments. These process analytical technologies enable an increased control of the overall production environment and, consequently, over the final drug product.

Although specific guidelines for continuous bioprocessing are pending, regulators widely support this manufacturing approach. FDA already approved about 20 biologics manufactured through continuous and integrated unit operations. The release of ICH Q13 guideline on “Continuous Manufacturing of Drug Substances and Drug Products”, anticipated for late 2022 or early 2023, will provide further clarity on regulators´ expectations (the draft guideline is currently released for public consultation).

Convergence of advanced process technology, software, automation, and analytics will push the implementation of continuous bioprocessing allowing for flexible, fast and cost-efficient manufacturing of biologics.

Dr. Karoline Hahn is a Senior Consultant for Advanced Therapies at KCR, an international clinical development solutions provider for the biotechnology and pharmaceutical industries. Dr. Hann has 20 years of experience in the biopharmaceutical industry, devising regulatory strategies and leading interactions with global health authorities. A geneticist by training, Dr. Hahn has extensive expertise in Advanced Therapies and provides top-tier strategic regulatory services in the area of ATMPs. She can be reached at karoline.hahn@kcrcro.com