Top choice — What works best when developing a biomanufacturing strategy?
In this article Steve Lam, senior vice president and head of biologics, Patheon, looks at which choice is best when developing a biomanufacturing strategy.
Global pharmaceutical companies are expanding their biologics pipeline, and biologics represent an increasingly large share of new drug approvals, accounting for 32% of total new molecular entities (NMEs) in 2016, up significantly from only 10% in 2005. There are currently 12,382 biologic projects in clinical development, 1,600 of them underway in neurology alone.
The maturing biologics pipelines at major pharma companies has created a dynamic in which smaller biotech companies need to keep their assets for longer. This means they need funding during the later stages of development and need to continue manufacturing products for late stage clinical trials. This is changing the already-challenging funding dynamics for biotech companies and increasing their reliance on external capacity.
Bulk product requirements are increasing, but at a lower rate than the size of the biologics pipeline. Changes in capacity requirements are due to advances in cell lines and processing technologies; the increasing focus on rare disease therapies, which target small patient populations; and competition for market share. This creates an interesting opportunity for biopharmaceutical companies and contract development and manufacturing organisations (CDMOs) alike, demanding new investment strategies and increasing demand for flexible, mid-scale capacity.
Commercial production of approximately half of the biologics currently in development could be met with reactors of 5,000 litres or less (figure 1), due to higher titres and product yields. Demand for 70% of new monoclonal antibody products approved between 2016 and 2020 is expected to be less than 100 kg per year per product.
The number and complexity of therapeutic classes for biologics is rising, and these products are increasingly targeted, with more competition for the first-to-market position (figure 2).
The total manufacturing capacity available to the biopharma industry is greater than demand, with overall biologics capacity utilisation currently estimated at 62%, and forecast to rise to 72% by 2020 (figure 3). However, capacity may not be aligned with demand. Many large-scale bioreactors are available, but these may not be the best solution to meet current expectations for titres. Mid-scale expertise may instead be needed. A recent study by ORC shows that the number one challenge faced is access to biologics capacity within the timelines requested.1 This is a consequence of the very large existing capacity and inflexibility, due to historical industry efforts to drive down costs.
Manufacturing advances
Advances in biologics manufacturing over the past two decades have included:
As a result, biopharma companies have access to a wide range of manufacturing choices, and need strategies to take account of this flexibility (figure 4).
The challenges of forecasting
When a biologics company is preparing to launch a new product, it must forecast the required manufacturing capacity, but this remains a major challenge (figure 5). Key drivers of forecast inaccuracy are market size (based on approved indications, reimbursement and competition), launch timing, dosage (it is not unusual for forecast and actual dosage to vary by a factor of three), titre and price. Variations in these factors can lead to sharply differing demand scenarios, opening the firm to the risks of investing in too much capacity, paying more per unit of product, or not being able to satisfy demand. Inaccurate forecasting can lead to delays in the clinic, tied-up capital and foregone profit, which, for a small, early-stage company, can be catastrophic.
To address these often inaccurate predictions, biopharma manufacturing executives have many options for meeting capacity, including in-sourcing vs outsourcing, one-step development vs two-step development, large-scale vs small-scale, single-use vs stainless steel, and existing capacity vs new capacity (figure 6).
Planning should take account of both volume and scale, with target product cost calculated from likely dosing and pricing (figure 7).
Biologics executives may believe they do not need to think about manufacturing early in development, as their limited resources are focused on securing funding and establishing proof-of-concept for their molecules. It may also seem too early to consider the likely final dose range, delivery mechanism or manufacturing plans. Yet, the earlier the manufacturing strategy is developed, the more options a company has at launch and beyond (figure 8).
Responsive manufacturing strategy
The key is to develop a manufacturing strategy that balances responsiveness and cost while enabling the company to meet its forecasted demand. This can be done by mixing and matching the options for outsourcing, single-use, scale, and existing or new capacity through the duration of the commercialization process. An effective strategy will have key decision points from Tox studies through launch and beyond when changes in the strategy can be made to react to any new available data.
Flexible biologics manufacturing models
In addition to the traditional capacity approach, several flexible biologics manufacturing models exist:
- Dedicated capacity: Companies with two or more products with similar bioprocessing requirements, launching within 18 months, need a dedicated facility or manufacturing line to enable them to modify their manufacturing schedule until they fully understand the market demand for each product. Within the dedicated facility, the company can determine how much is used for each product and can transfer technology in and out of the line.
- Fractional ownership: Fractional ownership is an option for companies that lack the budget (or volume) for a dedicated facility or line. This is where the CDMO partner builds a single manufacturing facility or line for two or three clients, providing flexible capacity for each. This model is less expensive than the dedicated line, but still provides flexibility and scalability.
- Flexible network access: For regulatory purposes, global companies may need manufacturing capabilities in multiple regions, or may require on-demand access to capacity without preference for location. Flexible network access provides biopharma companies with access (within a specified period) to a specific type of capacity within the CDMO’s global network. Companies can adjust the product mix with the assurance they will have the right type of capacity when they need it.
- Condominium capacity: This is a fully customised solution for a company introducing a new product with unique characteristics (e.g., novel product types or platforms) that cannot be manufactured on a conventional line. Here, the CDMO partner provides design services, works with equipment suppliers, validates the process, builds the line and manages operations on behalf of the client. Overheads are shared and the line can operate as needed to meet demand.
- Enterprise: This is a solution for companies that own facilities that are in need of operational improvements. Some facilities may need to repurpose existing equipment, while others may need to be closed. The CDMO partner manages the facilities to accomplish these goals, allowing biopharma companies to focus on their core competencies.
Ultimately, a flexible biomanufacturing strategy is essential in addressing the inevitable inaccuracies of forecasting. While there is no single, right manufacturing strategy, companies should consider manufacturing at the earliest possible stage of product development. Having a biomanufacturing strategy and revisiting it regularly enables biopharma companies to build in the necessary flexibility, and preserve as many options as possible. Working with an experienced CDMO partner in this space will allows them to optimize their planning — and their chance of success — in the face of an uncertain environment.
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