The hidden revolution in biologics manufacturing that few saw coming

Decades ago, microchips were a luxury expensive, rare, and reserved for only the most specialised applications. The cost was high, making them inaccessible for widespread use. But as manufacturing techniques improved and economies of scale took effect, prices dropped dramatically. This shift fuelled an explosion of innovation, making computing power ubiquitous. From bulky mainframes to the smartphone in your pocket, the relentless drive to refine and optimise the microchip has transformed every aspect of modern life.

A similar transformation is now underway in biologics manufacturing. For years, biopharmaceutical production has been dominated by batch based methods, where each stage of production is completed in isolation before moving to the next. This method, while reliable, has long
been plagued by inefficiencies delays between processes, complex quality control measures, and massive facility requirements. Perfusion
technology, introduced in the 1980s, promised a more continuous approach, but the production times were too long, and yields were too low to justify widespread adoption.

But just as advances in microchip size and manufacturing unlocked new possibilities in computing, breakthroughs in cell line engineering,
process automation, and real-time monitoring have revolutionised biologics production.

Fast forward to today, and the landscape has shifted dramatically. Continuous Manufacturing (CM) enhances yields, reduces costs, and streamlines production. However, a lot of companies have different technologies that they adopt for continuous production. Some may use upstream perfusion that is then connected to the downstream processes in sequence while some may retrofit continuous components into their existing batch processes, creating a hybrid system. A few achieve a fully connected, end-to-end process. True CM integrates upstream and downstream operations without interruptions, compounding efficiency gains that go beyond perfusion alone. Enzene’s fully-connected continuous manufacturing™ (FCCM™) for biologics is one such example – an end-to-end continuous platform which can produce high volumes, around 40-50 kg of product from a 1000-liter bioreactor within approximately 30 days, depending on the molecule and titer.

A decade ago, continuous manufacturing was making waves in small-molecule drug production. In 2015, Janssen (J&J) secured regulatory approval for Prezista®, a milestone that demonstrated CM’s viability for pharmaceuticals. It was a game-changer real-time release testing, in-line monitoring, and predictive analytics became industry talking points. But biologics were a different story.

Back then, batch processing dominated biologics, producing just a few grams per liter a fraction of today’s yields. Unlike small molecules, biologics require complex cell-based production, making CM adoption much tougher. The industry faced two big hurdles: the technical challenge of linking upstream and downstream processes and regulatory uncertainty about how to oversee continuous systems.

Through the late 2010s, key innovations helped bridge the gap. The rise of single-use bioreactors lowered upfront investment costs, making it easier for manufacturers to scale biologics production. Regulatory agencies, once hesitant, gained confidence in CM, particularly as small molecule successes mounted. The complexity of large-molecule drugs meant that any deviation in production could have profound consequences. However, frameworks such as the Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8, introduced in 2008, established the principle that process design should be intrinsically linked to product performance.

Around the same time, biosimilars took off, further driving demand for cost-effective manufacturing. In 2015, the FDA approved the first U.S. biosimilar. The FDA streamlined biosimilar approvals and guidance on interchangeability requirements which made continuous manufacturing an increasingly attractive option. With biosimilar approvals growing 59 since 2015 the industry now recognises that fully connected continuous systems offer a path to not only cost reduction but also improved product consistency. International regulatory bodies such as the ICH have in fact developed specific guidelines, like ICH Q13 now, to assist drug manufacturers in implementing CM for both drug substances and products.

What has really made a significant mark towards the success of CM technology is the real-time monitoring using Near Infrared Raman (NIR)
spectroscopy and Process Analytical Technology (PAT). These enable manufacturers to observe and fine-tune production parameters in real
time, ensuring consistent quality throughout the process. Meanwhile, computational tools such as quantum computing and support vector machines have advanced chemometric modeling, boosting the reliability and accuracy of real-time testing. This combination of inline testing, predictive analytics, and cutting-edge data analysis has made real-time release testing more dependable and efficient than ever.

Currently we are seeing around 8-10g/L in batch processing a dramatic increase from 5g/L as industry standard a decade ago, and so CM for
biologics is at a turning point. Regulators have clearer guidelines, manufacturers have better tools, and market demand is higher than ever. The industry is finally poised to take full advantage of CM, making biologics production more scalable, cost-effective,
and efficient. Enzene entered the market a few years ago with an aim to make cost effective biosmilars in India.

Source : https://247biopharma.com/