Continuous Bioprocessing Is the Manufacturing Shift That Biologics Manufacturers Have Been Delaying for a Decade

The Manufacturing Model That Most Industries Abandoned Long Ago

Batch manufacturing, in which a defined quantity of raw material is processed through a series of steps and the entire batch is held at each step until the step is complete before the batch advances to the next, is the dominant manufacturing model for biologics production and has been since the first recombinant protein drugs were produced commercially in the 1980s. The pharmaceutical industry's adoption of batch manufacturing for biologics reflected the regulatory framework that the FDA and other agencies had developed for small molecule drug manufacturing, whose batch manufacturing model provided the traceability, quality control sampling, and batch release testing framework that pharmaceutical good manufacturing practice was built around. Each batch is defined as a discrete lot whose identity, composition, and quality can be fully characterised before it is released for use, providing the quality assurance that the pharmaceutical quality system requires and the regulatory traceability that batch-specific adverse event investigation demands. The commercial disadvantages of batch manufacturing in biologics are equally well-understood. The large stainless steel bioreactors that batch culture requires represent substantial capital investment whose utilisation is limited by the downtime between batches for cleaning, sterilisation, and media preparation. The batch process whose duration from inoculation to harvest is measured in weeks produces product quality that varies between batches as the living cells whose productivity determines the batch outcome respond to the small variations in media composition, dissolved oxygen control, and inoculation density that biological systems amplify through their growth and metabolism dynamics.

Continuous bioprocessing replaces the batch-by-batch production model with a manufacturing process whose bioreactor operates continuously for weeks or months, with fresh media continuously fed to the bioreactor and product continuously harvested from it, rather than the fill-use-empty cycle that batch manufacturing requires. The perfusion bioreactor, which continuously feeds fresh media to the cell culture while continuously retaining viable cells using a cell retention device and continuously harvesting the product-containing culture fluid, is the upstream bioprocessing technology at the heart of continuous biologics manufacturing. The downstream purification process whose chromatography, filtration, and formulation steps are traditionally performed as batch operations on the harvested bioreactor fluid must also be converted to continuous operation to realise the full benefit of continuous upstream processing, requiring the periodic counter-current chromatography systems and continuous membrane filtration technologies that have been commercially developed as the downstream complement to perfusion bioreactor upstream processing.

The Commercial Case and Its Historical Resistance

The commercial case for continuous bioprocessing is well-established in the chemical engineering literature and has been quantified in pharmaceutical industry modelling studies whose conclusions consistently show smaller facility footprint, lower capital investment per unit of product, higher volumetric productivity, and more consistent product quality compared with equivalent batch manufacturing at the same production scale. The resistance to adoption that has kept batch manufacturing dominant in biologics production despite this commercially favourable analysis reflects several factors specific to the biologics manufacturing environment. The regulatory complexity of transitioning an approved drug from a validated batch manufacturing process to a continuous process requires regulatory submissions that demonstrate product quality equivalence in the new process, and the regulatory review timelines and uncertainty whose outcome the submitting company cannot fully predict create the commercial risk aversion that delays the transition investment. The workforce skills and organisational knowledge required to operate and troubleshoot a continuous bioprocessing facility differ substantially from those that batch manufacturing requires, creating the human capital transition cost that adds to the regulatory transition cost in the total investment calculation.

The commercial momentum behind continuous bioprocessing has increased significantly as the first regulatory approvals of biologics manufactured by continuous processes have created the precedent that reduces regulatory uncertainty for subsequent submissions. Janssen's Prezista HIV medication, manufactured using a continuous flow chemical synthesis process, was the first FDA-approved pharmaceutical to use continuous manufacturing, creating the regulatory learning that subsequent biologics continuous manufacturing submissions have built on. Pfizer's and Lilly's COVID-19 vaccine and therapeutic manufacturing programmes, which used elements of continuous processing to accelerate the production ramp-up that emergency supply required, demonstrated that continuous bioprocessing could be implemented and qualified within timeframes that the traditional regulatory validation timeline would not have permitted, creating the operational evidence that continuous bioprocessing is feasible under the most commercially demanding conditions the industry has faced.

Top 10 Companies in Continuous Bioprocessing Globally

1. Cytiva (Danaher): Bioprocessing equipment leader with the ReadyToProcess WAVE bioreactor and AKTA chromatography systems adapted for continuous processing; its BioSMB periodic counter-current chromatography system is the reference continuous downstream processing technology and its end-to-end continuous bioprocessing technology portfolio creates the complete continuous manufacturing system that biologics manufacturers can source from a single equipment supplier.
2. Sartorius: German bioprocessing equipment company with BIOSTAT STR and Ambr bioreactor systems for continuous cell culture; its Stedim Biotech division's single-use bioreactor systems and its data analytics platform create the continuous bioreactor monitoring and control infrastructure that perfusion process management requires.
3. Merck KGaA (MilliporeSigma): Bioprocessing materials and equipment company with single-use bioreactors, filtration, and chromatography products for continuous processing; its Mobius single-use bioreactor and its Millistak+HC depth filtration for continuous primary recovery create the upstream-to-downstream continuous processing component supply that continuous biomanufacturing lines require.
4. Thermo Fisher Scientific: Life science tool and equipment company with HyPerforma single-use bioreactors and Thermo Scientific chromatography for continuous bioprocessing; its bioproduction division's continuous processing development programmes and its contract biomanufacturing business create both the equipment supply and the manufacturing service model for continuous bioprocessing.
5. Repligen: Bioprocessing equipment company whose ATF alternating tangential flow filtration cell retention device is the most widely used perfusion bioreactor cell retention technology; its ATF system is the enabling hardware for most commercial perfusion bioreactor operations and its position as the primary cell retention technology supplier creates the critical component supply infrastructure for the continuous bioprocessing transition.
6. Novatek International: Pharmaceutical engineering and manufacturing technology company providing continuous bioprocessing facility design and implementation; its process engineering expertise and its regulatory submission support for continuous manufacturing transitions create the advisory capability that biologics manufacturers whose own engineering resources are insufficient for the continuous manufacturing transition need.
7. FUJIFILM Diosynth Biotechnologies: Contract biologics manufacturer with continuous bioprocessing capability whose adoption of perfusion culture in its commercial manufacturing services creates the outsourcing option for biologics companies whose products could benefit from continuous manufacturing but whose own facility investment does not justify the transition to continuous processing independently.
8. Lonza: Contract biologics manufacturer with continuous bioprocessing development activities; its scale of contract manufacturing and its technology investment programmes create the commercial contract manufacturing context in which continuous bioprocessing adoption in the CDMO sector is most commercially significant for the biologics companies whose manufacturing is outsourced.
9. BioPhorum: Industry consortium for biopharmaceutical manufacturing technology development whose continuous bioprocessing working group is developing the manufacturing standards and regulatory guidance that reduce the approval uncertainty that has slowed continuous bioprocessing adoption; its member companies including major biologics manufacturers, CDMOs, and equipment suppliers create the pre-competitive collaboration infrastructure that industry-wide technology transition requires.
10. Novartis (MIT collaboration): Pharmaceutical company whose continuous manufacturing collaboration with MIT was one of the first industry-academic programmes to demonstrate continuous small molecule pharmaceutical manufacturing and whose biologics continuous manufacturing development builds on this heritage; its regulatory approval of continuous manufacturing for small molecules creates the internal organisational knowledge and regulatory relationship that biologics continuous manufacturing submissions can leverage.

The Regulatory and Facility Investment Outlook

The regulatory landscape for continuous bioprocessing is becoming clearer as the FDA’s Emerging Technology Programme, which provides early engagement between regulators and manufacturers developing novel manufacturing technologies, has been used by multiple biologics companies to discuss continuous bioprocessing submissions before filing. The FDA’s guidance on pharmaceutical continuous manufacturing, while developed primarily in the context of oral solid dosage continuous manufacturing, provides the regulatory framework principles that biologics continuous manufacturing submissions are adapting for the specific characteristics of cell culture and purification processes. The facility investment required for continuous bioprocessing is substantially lower per unit of installed capacity than equivalent batch manufacturing because the smaller bioreactor volumes that perfusion culture uses to achieve equivalent annual production reduce the physical footprint, cleanroom volume, and capital equipment cost of the manufacturing facility. Estimates from the biopharmaceutical engineering literature suggest that continuous bioprocessing facilities can achieve equivalent annual production to batch facilities at thirty to fifty percent of the capital cost, creating the investment economics that are driving the accelerating adoption of continuous bioprocessing in both greenfield facility design and brownfield facility retrofits where batch bioreactor trains are being replaced with smaller perfusion systems operating at higher cell density and continuously.