Continuous Manufacturing of Biologics Is Ready to Scale

Scaled continuous manufacturing of biologics and recombinant drugs is now a commercial reality.

Bringing together the cost, regulatory, and technical evidence, it shows that for manufacturing teams batch-only thinking is getting harder to defend.

Image

Why Is Batch Manufacturing Losing Its Footing?

Pharmaceutical production has run on batches since the apothecary era.

The chemical and petrochemical industries adopted continuous flow decades ago.

But biologics lagged for good reasons. Living cells introduce variability, and regulators long preferred lot-release testing over real-time control.

However, economic pressure has changing any manufacturing calculation. U.S. biologics spending reached about U.S. $500 million and U.S. $2 billion to build. Biosimilar makers must also price 20% to 30% below reference products to win share.

Facility decisions lock in capital for decades. A traditional plant relies on bioreactors of 15,000 to 25,000 litres, large tank farms for intermediate storage, and several dedicated production suites.

Continuous designs replace much of that bulk with smaller equipment that runs without pause. That shift changes both the capital plan and the floor plan.

What do the headline numbers say about continuous biologics production?

Compared with batch processing, the following gains have been reported for continuous operation:

• Up to 70% smaller equipment footprint
• Three- to five-fold higher volumetric productivity
• 30% to 50% lower facility costs
• More consistent product quality

Manufacturing teams can treat these figures as planning ranges. Pharmatica’s earlier Insights into continuous pharmaceutical manufacturing explains why the shift matters beyond biologics.

Regional momentum varies.

The Asia-Pacific as the fastest-growing region for adoption, helped by government support. For example, Samsung BioLogics in South Korea has made major continuous bioprocessing investments and market growth of 15.9% a year through 2030 is projected.

Read Maximise Pharma Innovation With Quality-by-Design

Maximise Pharma Innovation With Quality-by-Design

Find out how Quality-by-Design improves reliability and compliance in pharma and how you can maximise innovation through quality-based pharma development systems.

ICH Q13 Gives Industry a Shared Rulebook

ICH Q13 is the first globally harmonised framework for continuous manufacturing.

The guidance runs to 39 pages. A 15-page main text covers development, implementation, and lifecycle management. Five ICH Q13 annexes then address specific scenarios. Annex III covers therapeutic proteins, including monoclonal antibodies.

The guidance describes continuous manufacturing as a steady feed of inputs, ongoing transformation of in-process material, and constant removal of output. It covers fully integrated lines and hybrids that blend continuous and batch steps.

Adoption has moved quickly. The U.S. Food and Drug Administration (FDA) adopted Q13 in March 2023, and the European Medicines Agency (EMA) followed in July 2023. Japan’s PMDA, China’s NMPA, and Brazil’s ANVISA have built their own pathways, according to the review.

Harmonisation also reaches beyond text, including coordinated training, shared review standards, and specialist assessor teams at the FDA and EMA.

ICH Q13 demands deeper process understanding than batch work.

Manufacturers and sponsors must show how critical process parameters affect quality attributes, including during startup and shutdown.

They also need a control strategy that detects drift in real time and diverts off-specification material. Inspectors will test those controls. You can read Pharmatica’s guide to the GMP inspection process.

Regulators also invite early dialogue. The FDA Emerging Technology Program has held more than 27 meetings on continuous manufacturing, and the EMA runs dedicated scientific advice routes.

Early regulatory engagement lowers submission risk.

Image

The Technology Stack Behind the Shift to Continuous Manufacturing

Three technology layers make continuous manufacturing of biologics work in practice.

Upstream, perfusion bioreactors keep cell lines productive for weeks. Downstream, connected chromatography purifies products without pauses. Across the whole line, real-time analytics confirm quality as it forms.

Each layer depends on the others, so leaders should assess them as one integrated system. 

Perfusion and single-use bioreactors

Fed-batch cultures run in discrete cycles. Perfusion keeps cells in a steady state, feeding fresh medium while removing product continuously.

Cell densities can exceed 100 million cells per millilitre, against roughly one million to 20 million in fed-batch and stable perfusion usually runs beyond 60 days.

Cell retention is the key design choice. Tangential flow filtration offers high retention and scalability but can stress cells and foul membranes. Alternating tangential flow reduces that stress through optimised flow patterns.

Single-use bioreactors strengthen the case. By removing clean-in-place and steam-in-place steps, they cut facility qualification costs by 30% to 40% and shrink facilities by 25% to 35%. The trade-off is price. Perfusion systems may cost 50% to 100% more than fed-batch equivalents.

Continuous chromatography

Downstream processing is the hardest step to make continuous.

Periodic counter-current chromatography links several columns in a synchronised cycle. When one column nears breakthrough, feed shifts to the next. Resin use approaches full capacity, compared with 60% to 80% in batch.

There is about 50% less buffer use, equal to 7,400 litres saved in a 20 kg monoclonal antibody campaign.

Integration remains tricky. Perfusion bioreactors run at steady flow, while chromatography often needs variable flow. Advanced process control must reconcile the two.

Real-time quality control

Continuous plants cannot wait for offline lab results. Near-infrared and Raman spectroscopy monitor protein concentration, cell density, and aggregation in real time.

Online size exclusion chromatography and, increasingly, mass spectrometry add further checks. Machine learning layers then flag deviations early.

A four-phase digital roadmap over about eight years has been outlined. It moves from basic integration to full Industry 4.0 links to supply chains.

Regulators expect validated methods, maintained calibration, and strong data integrity throughout.

Read The Looming Threat of Geopolitical Risk in Clinical Supply Chains

The Looming Threat of Geopolitical Risk in Clinical Supply Chains

Geopolitical risk is reshaping how clinical supply chains are managed, demanding resilience and foresight. Learn why building supply chain resilience is the key for clinical trial success.

Image

Hurdles to Clear and Moves to Make for Successful Continuous Manufacturing

The financial case for continuous manufacturing looks strong on paper.

Models payback in three to five years for greenfield plants and four to seven years for retrofits.

Net present value is estimated to be 15% to 25% higher than batch over 10 years, with internal rates of return of 18% to 28%.

Real examples add weight. Genentech’s South San Francisco site reportedly cut manufacturing costs by 35% with multiple sustainability and environmental footprint benefits demonstrated.

Biosimilar uptake shows why cost matters: Bevacizumab, trastuzumab, and rituximab biosimilars reached shares of 82%, 80%, and 67% within three years.

Supply chains change too. Implementation of continuous manufacturing demonstrates inventory reductions of 60% to 80%, which frees working capital.

Lower buffers demand more reliable suppliers and stronger quality programmes, as Pharmatica’s Insights into pharmaceutical cold chain risk shows.

Access is the wider prize. IQVIA projections show that biosimilars could save U.S. 125 to 237 billion between 2023 and 2027.

Smaller continuous plants may also make biologics viable for smaller patient populations and emerging markets.

Validation changes too. Process performance qualification needs extended campaigns, validated real-time release methods, and tested systems for diverting faulty material.

Sustainability adds a further argument in favour of continuous manufacturing. Continuous operations are linked to lower water, energy, waste, and chemical use, and some regulators reward greener manufacturing with faster reviews or reduced fees.

People matter as much as equipment. Continuous plants need talent in process engineering, analytics, automation, and regulatory science.

Teams must also work across traditional functional boundaries, which may require structural change.

Read continuous manufacturing evidence with care

Many industry figures are modelled ranges drawn from secondary sources, including market reports.

There are also workforce gaps, scale-up differences, and cybersecurity exposure where operational and information technology networks meet.

Hybrid approaches deserve consideration. Q13 allows combinations of continuous and batch steps. A company need not convert an entire process at once.

Cost Reduction Strategies, Regulatory Pathways, and Global Implementation

Continuous manufacturing of biologics and recombinant drugs now have a harmonised rulebook, proven equipment technology, and credible economic gains demonstrated.

The remaining task is implementation, starting with a well-characterised product, building process-control and analytics talent early, and engaging regulators before filing. Pair that with a realistic pilot to test the modelled gains on your own data.

At Pharmatica, we analyse the Manufacturing and Supply Chain shifts that decide who delivers biologics faster, cheaper, and at scale. Our Insights connect regulation, technology, and market dynamics so leaders can act with confidence.

Pharmatica: Insight. Connection. Impact.

Image