The Business Case For Continuous Manufacturing In Biologics

By Richard Steiner, Pharmatech Associates

In the late 1970s, Eddie Van Halen built the Frankenstrat guitar, piecing together parts from different instruments to achieve his now-iconic “brown sound.” He didn’t invent a new instrument from scratch — he combined what already worked, modified it, and made it greater than the sum of its parts. The result was so influential that manufacturers soon began producing their own “superstrats,” transforming the market for performance guitars.

Pharmaceutical continuous manufacturing (PCM) follows a similar principle. Few companies leap straight into fully end-to-end continuous processes. Instead, they pursue hybrid approaches — blending batch and continuous steps to unlock new levels of productivity, quality, and efficiency. The aim isn’t perfection in continuity. The aim is smarter, leaner, and more resilient manufacturing that meets business needs.

For biologics — complex therapeutic proteins that represent the fastest-growing segment of the pharma pipeline — PCM represents the next frontier. The question for leadership is not if continuous manufacturing will transform biologics, but when and how quickly to invest.

From Batch To Flow: Defining Continuous Manufacturing In Pharma

Pharmaceutical continuous manufacturing links multiple unit operations into a steady-state flow regime, borrowing from Six Sigma and lean principles. In practice, this can take several forms:

• Hybrid models, where upstream or downstream steps are continuous but fill/finish or viral clearance remain batch.
• Mini-batch strategies, which produce smaller lots in rapid succession to mimic continuity.
• End-to-end continuous, where all steps are fully integrated.

Over the past decade, adoption has grown steadily in oral solid dosage (OSD) and active pharmaceutical ingredient (API) manufacturing. By 2023, regulators had approved more than a dozen OSD products produced continuously and several APIs made via flow chemistry. Industry consensus has formed: for OSD and APIs, the case for continuous is proven.

Biologics are at an earlier stage. While pilot-scale continuous platforms are advancing — with perfusion bioreactors, multi-column chromatography, and viral clearance technologies — there are no fully commercialized biologics yet produced by end-to-end PCM. That gap represents both a technical challenge and a business opportunity.

A Turning Point: Regulatory Guidance And Validation Pathways

Historically, regulatory uncertainty slowed PCM adoption. That barrier has now shifted. In March 2023, the FDA finalized ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products, explicitly covering therapeutic proteins. The guidance lays out expectations for continuous upstream culture, downstream purification, and integrated quality management.

The signal is clear: regulators want to see biologics move into continuous regimes. Agencies are not only open to dialogue but actively encouraging sponsors to explore hybrid and continuous pathways. For executives, this marks a watershed moment. With the regulatory road map in place, delaying investment risks ceding competitive advantage to faster-moving peers.

Why Biologics Are Different

Biologics present unique technical and economic complexity. Unlike small molecules, they require living systems, aseptic operations, and long culture times. Every lot represents a high-value, high-risk endeavor. Manufacturing economics are also different: many biologics treat rare diseases or highly targeted patient populations, which means each dose carries exceptional cost.

This creates what might be called batch bias: industry infrastructure — from quality systems to workforce training — has been built around batch paradigms. Changing to continuous requires not just new equipment but new skills, regulatory strategies, and cultural alignment.

Yet the potential upside is far greater than in OSD. When a therapy’s cost of goods sold (COGS) accounts for a disproportionate share of margin, and where shortages carry both patient and financial risk, the productivity and agility of PCM can be transformative.

Key Benefits And Drivers Of PCM for Biologics

The benefits of PCM are well documented in OSD and APIs. For biologics, they are amplified by product value and market dynamics.

• Increased productivity: Continuous perfusion bioreactors have demonstrated five to 20 times higher volumetric productivity (grams per liter per day) compared to fed-batch. This means more drug product from smaller facilities.
• Lower cost of goods: PCM reduces raw material consumption, energy use, and facility footprint. Smaller plants mean lower capital intensity and faster payback periods.
• Supply chain resilience: Modular, flexible facilities support reshoring strategies, redundancy, and responsiveness to geopolitical or pandemic-driven disruptions.
• Improved quality and consistency: Steady-state continuous systems reduce variability, enable real-time release testing (RTRT), and improve compliance confidence.
• Speed to market: Integrated PCM accelerates tech transfer and scale-up, critical for both innovators racing to launch and biosimilars racing to compete.
• Sustainability: With smaller footprints and greener processes, PCM aligns with environmental, social, and governance (ESG) commitments increasingly scrutinized by investors.

For leadership, these factors translate into financial outcomes. Executives can model net present value (NPV) improvements and use NPV-at-risk (NPVaR) frameworks to compare PCM adoption against the costs of supply chain disruption, quality failures, or lost market share.

Professor Clifford Rossi, Ph.D., and I presented a strategic framework study for assessing, comparing, and justifying continuous bioprocessing investments at the October 2025 ECI-VII-Bio Conference in Croatia, in which the nominal NPV of a batch versus continuous process was calculated over different batch sizes (refer to Figure 1 below). Productivity was calculated based on exemplary data collected through implementation episodes in literature data, such as, for example, 18.28 [gr/h] for the batch process and 325 [gr/h] for the continuous perfusion process. The higher the batch sizes, the closer the NPV is between the two alternatives (batch and PCM), which shows that productivity can only be increased by a bigger process volume, which consequently means scale-up. As one of the core principles for PCM is scale-out, the only other alternative is an increased total overall equipment effectiveness (OEE) toward the highest performing unit operation.

Figure 1: Nominal NPV of a batch versus continuous was calculated over different batch sizes – Source: ECI-VII-Bio-CM Conference October 2025, Prof. C. Rossi (Univ. Maryland) & R. Steiner (PAI)

Main cost factors such as raw materials and consumables, labor/personnel, utilities and energy, QC/QA, and maintenance were considered as OPEX. The risk modeling framework graph below shows the distribution of simulated NPV as outcome.

Figure 2: The probability density function (PDF) graph depicts the distribution of net NPV (PCM - batch) given an assumed throughput volatility (standard deviation) of 25% (a figure drawn from academic research) – Source: ECI-VII-Bio-CM Conference October 2025, Prof. C. Rossi (Univ. Maryland) & R. Steiner (PAI)

The cumulative density function (CDF) for net NPV provides insight into the concept of NPV-at-Risk. Applying a single path net NPV of 147% implies that the PCM project would generate a net NPV at or above that percentage, while the CDF also shows that a project manager could be 95% confident that such a project would generate a net NPV of at least 225%, making them more confident in the decision to implement a PCM solution.

Figure 3: The cumulative density function (CDF) for net NPV provides insight into the concept of NPV-at-Risk – Source: ECI-VII-Bio-CM Conference October 2025, Prof. C. Rossi (Univ. Maryland) & R. Steiner (PAI)

The conclusion and recommendation of this study support the transition from traditional fed-batch to continuous manufacturing (CM in biologics. It is no longer a question of if, but when. With the technology proven at commercial scale, regulators publishing supportive guidance (ICH Q13, FDA Emerging Technology Team, EMA pilot programs), and equipment vendors offering robust perfusion and multi-column chromatography platforms, the strategic window for adoption is clearly opening.

Bottlenecks And Challenges Of PCM In Biologics

If the business case is compelling, why hasn’t PCM for biologics reached commercial scale? The path forward is not without obstacles.

• Downstream integration: Integrating continuous downstream purification remains a formidable technical challenge. While continuous chromatography and filtration are proven, scaling them reliably with viral safety, sterility, and regulatory assurance remains difficult. Protein A capture and viral inactivation are persistent bottlenecks.
• Aseptic fill/finish constraints: Even when upstream and downstream processes are continuous, final product filling is often still performed in batch mode. Continuous aseptic fill/finish under GMP conditions is still more concept than commercial reality. Developing reliable continuous solutions here will be essential to achieving true end-to-end manufacturing.
• Process stability: Long-duration runs require robust process analytical technology (PAT) to monitor critical quality attributes and prevent drift or contamination. Sensor failures in a continuous system can cascade quickly.
• Validation burden: Even with ICH Q13, proving comparability and control over long-run processes is complex. Global regulatory harmonization is incomplete, creating risk for multiregional filings.
• Economic trade-offs: Up-front investments in new infrastructure and analytics can be significant, and once a biologic process is validated, changes are expensive. Executives must weigh the long-term savings against short-term disruption.

Pathways To Adoption: A Road Map For Biologics Manufacturers

For most biologics manufacturers, the shift to continuous will not happen overnight. Instead, adoption is best understood as a staged transformation — one that balances technical feasibility with business value, regulatory confidence, and organizational readiness. Executives evaluating PCM should think less in terms of a single “switch” and more in terms of a progressive journey with multiple entry points.

1. Start with a Business-First Assessment

The foundation of any adoption plan is clarity on where continuous can add the greatest value. Leadership teams should map their end-to-end process, identifying bottlenecks, cost drivers, and points of highest variability. For some, productivity gains in upstream cell culture will present the strongest case; for others, reducing downstream constraints or accelerating release timelines may drive ROI. This “value mapping” ensures investments align not only with technical feasibility but also with financial and resource priorities.

2. Pilot Hybrid Models in Upstream and Downstream

While end-to-end continuous remains aspirational, hybrid systems offer a pragmatic starting point. Continuous perfusion bioreactors, for example, already deliver more consistent quality and higher yields. Downstream, advances in chromatography, filtration, and viral clearance are enabling unit operations to move toward continuous or semi-continuous flow. Transitional strategies — such as pairing continuous perfusion upstream with batch purification downstream, or introducing mini-batch steps — allow organizations to capture many of the benefits without wholesale change.

3. Invest in Analytical and Digital Readiness

No continuous system can succeed without a robust monitoring and control infrastructure. PAT integration provides the real-time insights needed to maintain product quality and regulatory compliance. Complementary tools such as residence time distribution (RTD) modeling and digital genealogy systems ensure traceability and enable predictive control. Leadership teams should prioritize building this analytical backbone early, as it not only supports PCM but also strengthens traditional batch operations.

4. Align Early and Often with Regulators

Both FDA and EMA have signaled support for continuous manufacturing, but regulators expect a clear demonstration of comparability, control, and quality by design. Companies pursuing PCM should engage early to align on study design, data requirements, and validation strategies. By treating regulators as partners in innovation, manufacturers can reduce uncertainty and build confidence in novel process approaches.

5. Prepare the Organization for Change

The technical shift to PCM requires an equally deliberate organizational shift. SOPs must be adapted, operators and engineers retrained, and quality teams prepared for a real-time monitoring paradigm. Just as importantly, leadership must foster a culture that embraces continuous improvement and looks beyond batch-era assumptions. Without cultural readiness, even the most sophisticated technical solutions may stall.

6. Scale Through Stage-Gated Expansion

Adoption is rarely an all-or-nothing proposition. The most successful companies will scale incrementally — starting with pilot runs or single-unit operations, expanding to hybrid systems, and eventually progressing toward end-to-end continuous where the business case is strongest. This stage-gated model not only manages risk but also creates opportunities to build organizational confidence and demonstrate measurable value at each step.

PCM In Biologics: The Frankenstrat-egy

Like Eddie Van Halen’s Frankenstrat, PCM in biologics is not about building something entirely new for novelty’s sake. Continuous manufacturing is not a binary decision but a journey of staged adoption. Success requires a blend of technical readiness, regulatory alignment, and cultural change, anchored by a clear business case. By taking a stepwise approach — starting small, investing in analytics, engaging regulators, and preparing teams — executives can unlock the productivity, resilience, and speed advantages of PCM without overextending resources or jeopardizing quality.

The companies that will win in this new era are those that recognize the opportunity early, balance technical feasibility with business strategy, and embrace PCM not as a risky experiment but as a competitive necessity.

About The Author:

Richard Steiner leads Pharmatech Associates’ Pharmaceutical Continuous Manufacturing practice. He has more than 30 years of experience. Over the course of his career, he has held senior roles across the pharmaceutical process technology landscape, including leading the Leistritz Pharma Extrusion business unit and later serving as global sales director for continuous processing technologies at GEA Pharma Systems. Steiner is a frequent speaker at international conferences and a contributor to trade journals and scientific textbooks. His career has been defined by a passion for advancing PCM as a transformative approach to pharmaceutical production, helping organizations unlock new levels of efficiency, quality, and scalability. He studied mechanical engineering at the University of Applied Sciences in Nuernberg, earning a degree in mechanical engineering (Dipl. Ing.) and an MBA, and earned his MBM at the FU University of Berlin.