In a world where life-saving biologics are in increasing demand, a quiet revolution in how these therapies are manufactured is unlocking new possibilities for efficiency, cost, and quality.
For decades, the production of biopharmaceuticals has relied on batch processing—a familiar but cumbersome approach where each production step is completed separately before moving to the next. This method, while established, is often time-consuming, requires large equipment footprints, and can lead to variable product quality.
Spurred by growing pressure to lower drug costs and the rising competition from biosimilars, the biopharmaceutical industry is undergoing a significant transformation. It is increasingly turning towards continuous bioprocessing, an integrated method where product flows steadily from one unit operation to the next.
This isn't just an incremental improvement; it's a fundamental redesign of manufacturing that promises to make biologics production more efficient, consistent, and accessible. This article explores the key concepts and groundbreaking approaches that marked the evolution of integrated bioprocess engineering.
Achieving a continuous process requires seamlessly linking individual unit operations. Research has crystallized three distinct strategies for this integration 1 .
Picture a child's building blocks. In this approach, each unit operation is an independently optimized module. These modules are then connected using "enabler" technologies, like surge vessels, which act as buffers to manage flow between steps.
Advantage: Flexibility; modules can be developed and improved independently and swapped in or out as needed 1 .
Sometimes, a seamless fit requires a little modification. In this strategy, one or more unit operations are adapted to handle the output of the preceding step directly.
Example: Modifying anion exchange chromatography resins to accept feed material at higher salt concentrations, enabling its direct connection to a preceding cation exchange step without needing intermediate processing 1 .
The most radical of the three, this approach combines what were multiple, distinct unit operations into a single, unified step.
Example: Expanded bed adsorption, which merges clarification, initial purification, and concentration into one streamlined process. This merger significantly reduces equipment needs, residence time, and overall cost 1 .
To understand the real-world challenges and potential of continuous processing, let's examine a representative area of intense research: the development of scaled-down models for continuous perfusion culture.
A central challenge in bioprocess development is that laboratory equipment often behaves very differently from large-scale production bioreactors. In the mid-2010s, a key experimental focus was creating microbioreactors that could accurately mimic the conditions of their industrial-scale counterparts to enable reliable process development .
Researchers used miniaturized stirred-tank bioreactors with working volumes as low as 15-250 mL. These systems, like the Sartorius Stedim's ambr systems, were equipped with disposable bags and placed within automated biosafety cabinets to maintain sterility .
A critical step was integrating non-invasive optical sensors to monitor key parameters like dissolved oxygen (DO) and pH in real-time, just as in production tanks. These sensors were validated against traditional electrochemical probes to ensure accuracy .
The systems used automated pipetting robots and miniature pumps for feeding nutrients and making pH adjustments. The core of the experiment was to carefully control and match scale-dependent parameters—notably oxygen mass transfer (kLa) and power dissipation per unit volume—to the values measured in large-scale perfusion bioreactors .
The ultimate goal was to establish a stable, high-density perfusion culture. This required maintaining a continuous inflow of fresh media and outflow of spent media while retaining cells in the bioreactor, a significant technical challenge at such a small scale due to the need for long-term sterility and efficient cell retention devices .
Experiments with these advanced microbioreactors demonstrated that it was possible to achieve reasonable correlation with bench-scale stirred tanks for both microbial and mammalian cell cultures . However, a key finding was that certain parameters, like agitation speed, do not scale linearly with bioreactor size. This underscored the importance of matching the environment the cells experience (e.g., energy dissipation) rather than just the geometric shape of the reactor .
The successful development of these scaled-down models is a crucial enabler for the entire industry. It allows scientists to conduct high-throughput process optimization and troubleshooting in the lab with a high degree of confidence that the results will translate to manufacturing scale, thereby de-risking the adoption of continuous processing technologies .
The following tables summarize key experimental data and components relevant to advancing continuous bioprocessing, based on research from the 2014 era.
This table outlines the critical parameters that must be controlled when translating a process from a large production bioreactor to a small lab-scale model .
| Parameter | Importance in Scale-Down | Challenge at Microscale |
|---|---|---|
| Oxygen Mass Transfer (kLa) | Must be high enough to meet cellular oxygen demand and remove CO₂. | Achieving sufficient gas transfer in small volumes without excessive shear. |
| Maximum Shear Rate | Must remain below a critical value to avoid damaging sensitive cells (e.g., CHO cells). | Agitation and sparging can create locally high shear zones. |
| Circulation Time | Affects how often cells pass through high-shear zones near the impeller. | Smaller vessels have inherently different fluid dynamics and shorter circulation times. |
| Energy Dissipation Rate | Influences the transfer of internal energy to the cells, affecting physiology. | Difficult to measure and control directly; often maintained via power per unit volume. |
This table contrasts the dominant processing modes, highlighting the driving factors behind the shift to continuous and hybrid models 6 .
| Processing Mode | Description | Key Drivers & Industry Status (c. 2014) |
|---|---|---|
| Batch | All process steps are completed discretely with hold times in between. | Established, well-understood, but less efficient and more variable. |
| Hybrid | Some unit operations (typically upstream perfusion) are continuous, while others (downstream) remain in batch mode. | A pragmatic first step; perfusion bioreactors had been used commercially for decades. |
| Fully Continuous | All unit operations are linked in a single, continuous flow stream. | The emerging goal; offered the highest efficiency but faced significant technical and regulatory hurdles. |
This list details key technologies that became vital for the development and control of integrated bioprocesses .
Enable non-invasive, real-time monitoring of critical culture parameters in small-scale reactors.
Provide high-throughput, miniature cultivation systems (e.g., ambr, Micro-24) with automated feeding and sampling.
Essential for perfusion processes, allowing cells to be kept in the bioreactor while spent media is removed.
A framework for designing, analyzing, and controlling manufacturing through timely measurement of critical quality attributes.
Despite its promise, the full adoption of continuous bioprocessing in 2014 was still facing headwinds. The industry identified several areas requiring sustained innovation 6 .
Moving from a batch-defined to a continuous-validation mindset required new approaches to quality control and defining a "batch" for release.
Persistent difficulties in integrating continuous downstream operations like chromatography and developing robust process analytical technology (PAT) for real-time monitoring.
The 2014 White Paper on Continuous Bioprocessing strongly recommended joint efforts between industry, academia, and regulatory authorities to address these challenges. The collective goal was clear: to harness the power of integrated, continuous manufacturing to produce biological drugs that are more affordable, consistently high-quality, and available to patients faster than ever before 6 .
The journey from discrete batch steps to a seamlessly integrated continuous flow represents one of the most significant leaps in bioprocess engineering. It's a testament to the power of reimagining established systems, proving that how we make a product can be just as innovative as the product itself.