Manufacturing at the Edge: Smaller, Localized, and Agile Factories will be Key to Biopharma Drug Production

Pharmaceutical manufacturing has had to navigate transformational changes during the pandemic, just like many other industrial sectors. Demand for manufacturing capacity reached levels that would have been unthinkable a few short years ago.

Yet although the situation was unprecedented, and the measures taken extraordinary, the pandemic did not actually change the direction of travel for how biopharma companies manufacture drugs.

As biotherapeutics rapidly evolve and diversify, manufacturing needs to do the same, particularly regarding how and where drugs are produced.

The traditional monoliths of large, centralized facilities need to be augmented with a constellation of smaller, more flexible ones to support the exciting new modalities made mainstream by the pandemic.

Just as “edge computing” is emerging in the technology space, biopharma production facilities must become smaller and more numerous, moving closer to the “edge,” meaning closer to the patient.

I have spent my career working at the cutting edge of advanced therapeutics, first as the head of Pfizer’s biotherapeutics research and development group, then at AbbVie as head of drug discovery. In the midst of the pandemic, I moved to Danaher Corporation, a global science and technology innovator whose companies solve complex challenges for biopharma and biomedical customers, to become the company’s chief science officer because I believe this manufacturing shift is fundamental to the future success of the biopharma industry and, most importantly, to its ability to treat some of the most debilitating and life-threatening conditions humans face.

At the heart of the manufacturing challenge are questions of technology and scalability. Historically, drugs prescribed to large populations of individuals for common diseases — metformin for diabetes and ACE inhibitors for high blood pressure, for instance — are made in large facilities at large scales, which typically gives rise to cost advantages and economies of scale. Small-scale manufacturing, on the other hand, has traditionally been extremely costly, with no guarantee of recovering costs through sales and few incentives for biopharma companies to pursue their commercial development.

Recent shifts are changing this. The rapid rise of genomic medicines and the increasing focus on orphan drugs for treating rare diseases — with highly individualized or one-and- done precision medicines — have made it crystal clear that a new balance is needed. To support new therapeutic modalities, from mRNA vaccines to modified cell and personalized therapies, antibodies, and other large-molecule drugs, there will need to be a proliferation of small-scale facilities to produce them.

To give a recent and familiar example, RNA-based therapies can be rapidly designed and developed as either population-based or personalized medicines, which makes them incredibly agile. It’s no coincidence that two of the most widely used Covid-19 vaccines are based on mRNA. Technologies and manufacturing solutions that easily translate from bench to bedside are facilitating the expansion of RNA and related medicines and will allow a more diverse range of companies, even small ones, to become genomic medicine developers.

Distributed and localized manufacturing solutions for cell and gene therapy — including gene editing approaches like CRISPR — will play a key role in enabling these medicines to live up to their potential to treat a wide range of diseases, be it vaccines against a global pandemic or modified CAR-T cells for cancer.

Shifting manufacturing to smaller, more localized facilities doesn’t just make manufacturing more feasible. It also speeds development and reduces the cost of producing genomic medicines, orphan drugs, and other large-molecule products, making them more accessible to more people. More efficient drug manufacturing processes, along with rapid, precise analytical techniques, will support biopharma companies in reducing costs and enhancing availability across patient populations.

Manufacturing genomic medicines, particularly viral vectors, is challenging. There are diverse methods by which genomic medicines are produced but most, if not all, of them involve a critical step in which a key component is grown in cultured cells. This involvement of living organisms in the production process presents complex challenges, namely in producing sufficiently high amounts (yields) of the key component, at concentrations that are not too dilute (low titer) and in such a way that high yields and titers are reproducibly achieved every time.

Gaining access to more rapid and precise analytical methods that allow scientists to experiment with manipulating and engineering cells to become more productive and to optimize manufacturing cycles using less-complex surrogates instead of actual cells in so- called cell-free systems will provide developers with near-real-time data on which to base reproducible, high-yield and high-titer processes.

These processes can then be designed to incorporate standardization, which makes them easier to implement reliably and in compliance with regulatory standards. Standardization also allows for the development of staff training programs using both experimental and computer-simulated data, which facilitates faster learning.

However, as the diversity of manufacturing needs grows, these standardized platform processes also need to build in flexibility so they can be adapted to fit a broader range of production methods. This flexibility is achieved by breaking up processes into modules, some of which are then developed into multiple interchangeable versions that can be used to tailor a process. Such adaptable modular platform processes are better implemented in small agile facilities.

Greater dependence on local facilities also relieves pressure on the complicated supply and operational chains that come along with personalized cell and gene therapies. For example, extracting cells from a patient, shipping them to a location to be modified and cultured, and then returning them to the patient at the original or another location can be challenging.

Shortening this chain by localizing and automating processes via decentralized, small-batch manufacturing facilities will go a long way in reducing the complexity and risk involved in seamlessly executing this chain.

Regulatory challenges introduced in the model can be addressed through the application of more standardized platform elements into the process. These often include standardized plug-and-play equipment for single-use only and automated solutions that come with regulatory validation. Processes that have already been successfully implemented at another facility and approved by regulators can be duplicated in the current model.

The reality is that the two strategies — regional, large-scale, versatile manufacturing hubs to produce the larger-volume batches needed for treatment in large populations and smaller, localized manufacturing to produce more personalized biotherapeutics — must exist in tandem. To enable true flexibility, the biopharma industry must embrace modular, single- use technologies and standardized manufacturing platforms that can support both large- and small-scale bioproduction. In practice, this could involve rapidly setting up manufacturing plants using prefabricated building blocks and smart automation, significantly reducing construction time and costs, and decreasing consumption of water and energy — for example through the elimination of costly cleaning and sterilization of multiple-use equipment — compared with traditional facilities. The coming years will likely see a significant increase in diversification and geographical expansion, with major manufacturing hubs supplemented by smaller and more localized facilities.

The Covid-19 pandemic laid bare a reality that should have been better appreciated for years: Secure and resilient supply chains are essential for the biopharma and other industries. Diversification of facilities will go a long way toward ensuring not only security of supply, but the ability to handle the spikes in demand that are occurring during the pandemic and will likely emerge again in the future.

Forward-thinking companies like PfizerLonza, and BeiGeneare already investing in building “edge” facilities to support the new directions of therapeutics and optimize agility. Biopharma companies and their partners need to continue developing creative ways to bake that flexibility into the supply chain by accurately forecasting needs, holding greater repositories of single-use components, and gaining more visibility and control over their network of suppliers.

Biopharma companies, like most others, must confront the certainty of risk and the constancy of change. If they don’t master new ways to conduct small-scale drug development and manufacturing with the cost efficiencies of industrialized biopharma, the risks they face will continue to increase and adapting to constant change will become ever more challenging. Most important, patients will not have access to the treatments they need when they need them. And if the pandemic has taught us anything, that is the only goal that should really matter to anyone in the biopharma industry.

This article by one of our Danaher Life Sciences thought leaders was originally published in Statnews. Shared here by permission.