Because Scale Matters: A Flexible Approach To Demand Uncertainty

By Bruce McCafferty and Mark Santos

The pharmaceutical industry’s targeting of new therapies for niche markets has added another dimension to traditional business models. Biopharma companies contending in this fragmented and competitive market are now under pressure to find innovative ways to get ahead of their competition and reap the first-to-market benefits. Doing so, though, means making capacity decisions long before you know how your drug will perform on the market (or if it is even approved) or waiting until clinical trial data can better guide your decisions. The latter puts you at risk of not having enough capacity when you need it, risking a drug shortage, while the former could result in capacity being underutilized. Both scenarios could have costly and damaging consequences for your brand or, more importantly, patients in need of their medication.

The alternative is to work with a CDMO. With outsourcing, the onus is no longer on you, the biomanufacturer, to ensure you build the appropriate capacity for your product’s launch. Nevertheless, the partner you select must be able to respond appropriately to fluctuations in demand in order to maintain reasonable operational and capital expenditures. This requires facilities designed to ensure a reliable delivery of materials for clinical through commercial manufacturing, including a wide range of bioreactors to suit changing volume needs. Stainless steel bioreactors that can hold a wide range of volumes have historically been the go-to for drug manufacturers. Yet, the advent of single-use technology (SUT), which enables faster process changeover, lower investment costs, and smaller facility footprints, provides the opportunity to manufacture a drug at volumes of 2,000 liters or less, a significant advantage in today’s evolving landscape. However, the disparity between these bioreactor volumes leaves little room for demand flexibility between large- and small-volume needs. One solution is to use mid-volume capacity bioreactors, which offer agility in an unpredictable industry while also balancing the cost of goods as a program prepares to launch.

Meeting In The Middle

Planning capacity in the face of demand uncertainty is risky and can be costly. Even if you decide not to build your own facility, the CDMO you choose must have the capabilities to scale up appropriately as the demands of the market change based on patient population and dosage. In addition, advancements in science and technology have led to exciting new discoveries in patient treatment, with diverse molecules paving the way for multi-target drug design. Many of today’s clinical programs are exploring two or more indications for a single drug, especially in oncology, where the FDA’s urgency to meet unmet medical needs has led to accelerated approval pathways. Pursuing multiple indications also opens biomanufacturers up to a broader development strategy and can streamline the cost of development and manufacturing. A challenge with this approach is that it increases the complexity of your supply chain, especially if you have to work with multiple partners. Therefore, it is critical to find one CDMO that can accommodate a portfolio with multiple types of products/processes and support you throughout the life cycle of its development and manufacturing. This requires not only expertise and experience but also a flexible facility with a breadth of equipment options that can move wherever your demand needs take you.

Small-scale bioreactor provides many benefits in terms of the flexibility needed for modern-day manufacturing, including reduced initial capital investments and lower operational costs. The smaller scale evolution has enabled the industry to support a wider range of molecules and processes than in the past. This has been coupled with advancements in process analytical technology, multivariate analysis, and more advanced microbial control strategies. With well-developed processes, smaller scale production can now support a viable launch strategy for many programs.

There are many products whose demand will still require ether more volume at launch or soon after launch, and the industry requires more than just a small-scale or a large-scale option to support these programs. New midscale facilities offer much of the flexibility of the small-scale facilities, including the enhanced innovation and automation. This enables companies to find the right solution for their product demand. Preparing for a biologic launch is a complicated process and doing it right can mean the difference between maximizing commercial success and not having the supply to support the market. Multiple bioreactor sizes will offer the ability to be precise with your launch strategy and flexibility to scale up when needed.    

Controlling The Cost Of Scale-Up

While the services executed to launch a program, such as characterization work, stability studies, and setting process limits, are relatively agnostic to the size of bioreactor used, some components do vary as you increase in scale. For example, the cost of performance qualification batches, the amount of raw materials you need to execute those batches, and the package you use from that data to submit your regulatory filing all increase with scale.

A 2,000-liter SUB offers an efficient and streamlined approach to completing these activities, while a stainless steel bioreactor at 10,000 liters and above requires a much larger investment, especially considering the resin and membranes costs associated with scale up. These materials can be expensive, so if you overestimate demand and use a bigger bioreactor than you need, you could be subject to an overstated upfront investment and a sub-optimal supply chain strategy subject to high risks and volatility. Having access to multiple bioreactor sizes improves efficiency by always ensuring your volume is appropriate to scale.

Lonza Pharma & Biotech Portsmouth, New Hampshire, site includes mid- and large-scale assets with a new state-of-the-art midscale facility that leverages a hybrid approach with single use and stainless steel technologies. It is designed to meet customers’ needs and mitigate the unknowns inherent in drug manufacturing. For example, the midscale bioreactors are geometrically the same (in terms of dimensions) as the 20,000-liter bioreactors, including centrifugation capabilities, which can simplify scale-up when the time comes, if needed. The seed train of the 6,000-liter bioreactors uses the same 2,000-liter SUT, simplifying the jump to 6,000 liters if your product requires more supply. In addition, the real-time process control available at the Portsmouth facility allows a robust and reproducible manufacturing suite with in-line process analytical technologies to minimize the amount of offline sampling and measurements. Customers can access their data in real time through cloud-based servers in order to offer not just data transparency but also an overall stronger partnership. Using these solutions, Lonza Pharma & Biotech can minimize the variability in its manufacturing processes, optimize costs, and increase reproducibility, ultimately giving their customers a competitive advantage as they strive to meet the demands of a complex and rapidly changing industry.