An introduction to modern monoclonal antibody manufacturing

Now, forty years after the first monoclonal antibody therapy emerged, new indications and therapy types such as antibody drug conjugates (ADCs), bispecific antibodies, and multispecific antibodies are revolutionizing treatment options. New process and facility designs are redefining what it means to move fast and deliver these treatments to the patients who need them.

In 1986, patients suffering the effects of a rejected transplant found hope from a novel source: the FDA had approved the world’s first monoclonal antibody, Muromonab-CD3, an immunosuppressant indicated for organ rejection in humans. In 2021, the FDA approved the 100th antibody therapy on the market.

During the 35 years separating those milestone events, monoclonal antibodies were established as the majority contributor to the global biologics market. In fact, they represented about 70% of total biopharma sales in 2019—a 50% increase in just four years.  Meanwhile, as approvals of antibody therapies accelerate and new combination therapies continue to emerge, one thing is certain: monoclonal antibodies are here to stay.

Today’s innovators and established manufacturers are moving the mAb industry toward an all-new frontier, where high-throughput screening and AI-powered protein design will de-risk the developmental pipeline and increase the overall value proposition of mAb products.

For startups, mature pharma companies, and contract development and manufacturing organizations (CDMOs) alike, the key to riding this wave of innovation into an exciting and sustainable future lies in asking the right questions early, and in planning your future manufacturing network strategy around the answers.

Questions for building a strong monoclonal antibody strategy:

• At what point in the development timeline should you invest in manufacturing capacity?
• What are the risks and advantages of flexible, highly scalable single-use technologies versus fixed stainless steel installations?
• How can you better standardize and intensify your process while staying flexible enough to rapidly adapt as your development pipeline evolves?
• How can you efficiently produce a variety of therapy types in your pipeline?

This article will explore the latest insights related to these and other important questions. Although we’ll focus on monoclonal antibodies in particular, the approaches and ideas explored below apply directly to other types of molecules including bispecific antibodies, multispecific antibodies, antibody fragments (fAbs), and some therapeutic proteins.

First, the basics: how do monoclonal antibodies work?

What are monoclonal antibodies and how do they work? Monoclonal antibodies, sometimes referred to as mAbs, are lab-made antibodies that are cloned from a single parent cell (hence their prefix, ‘mono-’), and they’re engineered to bind to a single foreign antigen.

The human body typically takes several weeks to naturally manufacture a collection of antibodies in response to a specific antigen. Monoclonal antibody manufacturers have learned to recreate and accelerate that process in the lab, effectively giving patients’ immune systems an enhanced weapon against many diseases, including oncological and non-oncological indications.

Beyond monoclonal antibodies are bispecific antibodies (BsAbs) and multispecific antibodies. These proteins are made up of two (‘bi-’) or more (‘multi-’) monoclonal antibodies, making them capable of recognizing and binding to two or more different antigens. This capability enhances their potential immune function and makes them an especially versatile immunotherapeutic tool.

Terms to know 

What are the benefits of monoclonal antibodies?

How are monoclonal antibodies produced?

Monoclonal antibody manufacturing generally involves culturing a genetically modified organism to express the target protein, followed by downstream chromatography and filtration steps.

Although this process is relatively standard across the industry, a key difference from one manufacturer to the next has to do with the technologies behind their manufacturing approach.

Stainless steel technologies are the traditional choice for large-scale manufacturing, while single-use technologies have gained popularity because of their agility. For some manufacturers, a hybrid manufacturing technology approach designed to amplify the benefits of both stainless steel and single-use technologies (while minimizing their drawbacks) is the best way forward.

Flexible fixed stainless steel manufacturing technology for mAbs

When designed around a range of potential processes, a facility featuring fixed technologies can support a number of different products while holding its value, even as product pipelines or products change.

Single-use manufacturing technology for mAbs

A reputation for supporting fast and flexible processes has popularized single-use technologies among antibody manufacturers, particularly those working with lower volumes.

Hybrid stainless steel and single-use strategy for mAbs

The choice between a fixed technology system and a single-use strategy is not necessarily binary. Many manufacturers generate value by combining these approaches in a hybrid system that optimizes cost, robustness, and speed to market.

Who is manufacturing monoclonal antibodies?

The monoclonal antibody industry is a meeting ground for mature pharma companies seeking to diversify their drug product portfolio, research labs with promising molecules in development, and CDMOs with the capability to support some of this production capacity.

To succeed in such a crowded marketplace, each of these manufacturers needs a strategy that’s right-sized for their unique business case, drug product portfolio, process requirements, and other needs.

In the second half of this article, we’ll look into what goes into designing that forward-thinking plan, from choosing the right manufacturing technology approach to overcoming the challenges of a fast-moving and competitive marketplace.

What are the challenges of producing monoclonal antibodies?

Manufacturing challenge #1:

Manufacturers are under pressure to increase speed to market.

Like building an airplane while in the air, mAb manufacturers have to juggle many complex factors as they race their competitors to the marketplace: regulatory approval, market demand, competitive positioning, available manufacturing capacity–the list goes on.

Success depends on getting each of those factors right, and on doing it all under tight scheduling constraints. That’s especially true in the wake of the COVID-19 pandemic, which introduced expedited regulatory pathways and redefined what it means to move fast in the life sciences industry. In fact, speed to market has significantly increased as a business driver across all manufacturing types, according to research from the 2021 Horizons: Life Sciences report which leverages survey responses of more than 500 industry leaders.

One of the more reliable and important ways to increase speed to market while readying for future growth is by prioritizing flexibility in multiple ways:

• Strategic facility planning: Do you need multi-product launch facilities designed for rapid scale-out or a larger-scale facility optimized for higher throughput–or some combination of the two? How will you leverage strategic partnerships? Strategic facility planning will uncover the answer to these questions, ensuring that your business objectives align with your overall manufacturing network strategy.
• Integrated project delivery (IPD): This approach, an alternative to traditional design-bid-build project delivery, relies on collaboration, respect for people, and shared accountability to deliver projects faster and with greater flexibility. At CRB, we call this integrated approach ONEsolution.
• Modular manufacturing: By designing for rapid repurposability at the facility level, manufacturers can campaign between products and support multiple processes with minimal downtime.

Manufacturing challenge #2:

Platform manufacturing can improve speed and lower costs, but manufacturers don’t always have time to standardize from the start.

Under pressure to move fast, R&D teams may feel the need to quickly develop a process that will work for a single product of interest. This approach might save time in the lab, but it will cause major bottlenecks in downstream production when manufacturers have to develop bespoke capabilities for each successful product in their pipeline.

Standardization is the solution. The key is to think in terms of ranges, not point values. These ranges become guardrails for R&D teams, who can then align their process development efforts with the capabilities of their company’s existing or planned commercial manufacturing network. Unless driven by a compelling financial or quality-related reason, deviations are discouraged. This sets up manufacturers to mix and match processes and facilities according to the needs of a multi-product portfolio while maximizing the economies of common cell lines, media formulations, resins, buffer systems, analytical tests, and other resources.

When planned well and established early, this standardized approach lays the groundwork for a fast-moving, high-throughput mAb development pipeline, which in turn feeds a manufacturing operation that’s capable of rapidly integrating new products. This approach also allows an early and comprehensive cost of goods analysis to improve the competitiveness of therapies in the market.

The trouble is that not every team has the bandwidth or resources to plan for standardization from the start. That’s where an expert partner can help. With the right know-how and experience working for them, mAb manufacturers who missed out on early opportunities to standardize their process can still develop an effective commercial manufacturing approach. The key is in expertly assessing the many options available—from bespoke solutions to platformed, off-the-shelf equipment technologies—and designing a facility that can ultimately accommodate any number of non-standard processes as efficiently and cost-effectively as possible.

Manufacturing challenge #3:

Manufacturers must balance the intensification process.

Over the last fifteen years, cell line engineering and medium development have enabled monoclonal antibody manufacturers to more than double their average upstream titers—that is, the amount of protein expressed relative to bioreactor volume.

High-titer processes offer many advantages in upstream manufacturing. They help squeeze more productivity from your bioreactors, which means you can use smaller, single-use equipment and less space to achieve the same throughput as a lower-titer process. Higher titers can also improve your flexibility, making it possible to rapidly campaign between products or to adopt a different process with minimal renovation.

Manufacturers can also intensify their upstream process through bioreactor pooling, N-1 perfusion, N perfusion, standard fed-batch or concentrated fed-batch production. Some manufacturers might further intensify their upstream process by relying on multiple seed labs or concentrated cell banks to increase campaign cadence and reduce scale-up time. These approaches can help to intensify production in existing facilities or improve the commercial viability of a low-titer process.

Process intensification isn’t a magic bullet, though. The more productive your upstream process, the more pressure you’re shifting to your downstream and support operations. In-process hold volumes, unit operation cycles or sizing, cleaning and sanitizing operations, waste processing—these can all become rate-limiting without an expert plan in place.

A more productive upstream process also introduces the challenge of acquiring, paying for, and storing more media and buffer—a challenge which multiplies as your productivity grows. Buffer and media concentrates with in-line dilution or in-line conditioning may help relieve this pressure. Multi-column chromatography, which reduces buffer consumption by maximizing your resin capacity, as well as in-line concentration are other ways to preserve the process density you worked so hard to gain upstream. These approaches can further impact your utility systems and facility infrastructure.

The future of antibody manufacturing is all about flexibility

Since that first approval in 1986, mAb manufacturers have learned so much about what it takes to efficiently and consistently produce these life-changing molecules for a global market. But, on multiple levels, there are many more advances to come.

New approaches to discovery, such as emerging AI systems capable of predicting protein structures quickly and accurately, are paving the way for new products to emerge. At the same time, techniques such as targeted gene integration and medium optimization are accelerating the process of making highly productive, high-quality cell lines. Continuous technologies, designed for faster campaigning and a more compact facility footprint, are also emerging as a potentially viable strategy in the near future.

What does all of this mean for monoclonal antibody manufacturers? It means that success will depend on your ability to leverage existing knowledge while staying flexible enough to adapt as future technologies and processes cross the starting line, changing the antibody manufacturing landscape yet again.

Finding your partner

It takes expertise to maintain a high level of flexibility and ensure that you’re minimizing your risks while accelerating your speed to market. At CRB, we’ve developed that expertise over hundreds of projects, helping our clients align their manufacturing strategy to their projected product portfolio by integrating modular designs, hybrid process technologies, and scale-out approaches that offer the potential to support multiple therapy types. These techniques are the key to delivering complex product portfolios faster and more reliably.

If your pipeline includes monoclonal, bispecific, or multispecific antibodies and you’re ready to establish a commercialization strategy that fits your unique situation, let’s talk.