Hybrid Facilities for Flexible Biologics Scalability

We’ve compared advantages for single‑use plastic and multi‑use stainless steel bioreactors over a series of blogs. Here, we’ll look at use cases for both single‑use and multi‑use skids in biologics manufacturing and discuss how they can be used cooperatively in hybrid facilities.

A hybrid facility uses a combination of single- and multi‑use skids to produce drugs, whether large‑molecule biologics or small‑molecule APIs. While nearly every facility uses at least some disposable components, not even state‑of‑the‑art manufacturing technology can use 100% disposables (especially when operating at scale). In reality, almost every manufacturing site is a hybrid facility, whether scale‑up, clinical, or commercial.

• Single‑use skids have much lower startup costs and much higher availability than stainless steel skids.
• They are generally considered to be more environmentally friendly.
• While still highly customizable, they are more standardized than stainless steel, and can be qualified and validated very quickly. Standardization comes with a broader array of use cases and shorter lead times on new equipment.

Multi‑use advantages

• Stainless steel skids bring higher capacities and the opportunity for full customization.
• They are generally cheaper over the full cost of the lifecycle.
• Multi‑use reactors are difficult to mishandle, offering superior product integrity and higher confidence in the safety of operators.

Single‑use skids achieve higher yields than multi‑use skids in equivalent volumes, but they are primarily available for small bioreactor volumes and have capacity limitations. Stainless steel bioreactors can often be used in cases where single‑use skids are limited, such as for large batch sizes.

The optimal mix of stainless steel and single‑use skids and components will depend on whether the facility is used for scaling, clinical, or commercial production. Both the batch size and the lifecycle costs will vary based on the setting.

The considerations of an engineer at a contract manufacturer are entirely different than those of an in‑house manufacturer at a pharma company — regardless of the scale of operation.

The key reason is that contract manufacturers require a higher level of flexibility at their facilities than traditional pharmaceutical setups. Whereas pharma companies tend to be dedicated to a single drug, a contract manufacturer must be ready for rapid changeovers between campaigns. (As a side note, it will be interesting to watch if this changes over the next several years for pharma companies moving from solely focusing on blockbuster drugs to developing orphan drugs, genetic therapies, and other treatments requiring only small batch sizes).

This is likely why CMOs were early adopters of single‑use bioprocessing technologies: they were able to increase batch success and minimize contamination risk, while also achieving savings to the bottom line from reduced cleaning requirements. Further, this meant fewer processes to be validated.

Optimal facility layout and automation strategies are specific to the types of equipment used. A roundtable published in American Pharmaceutical Review strongly recommends first choosing the production volumes necessary for each manufacturing step, and then moving on to determine the optimal solution for each skid or piece of equipment. Footprint constraints, connectivity, and specific skid preferences all play a role in determining the best solution.

Example considerations for a hybrid approach

• Upstream stainless‑steel skids are totally customizable. Reusable bioreactors and fermenters can be much bigger than single‑use reactors, which are limited by oxygen transfer.
• Single‑use reactors can achieve higher cell densities than multi‑use reactors in the same volume.
• Stainless steel requires a fair amount of fixed infrastructure for the delivery of cleaned steam, while single‑use equipment is more mobile, often on wheels, for easy reconfiguration of manufacturing areas.
• Centrifuges are available with fully disposable contact surfaces, and can handle up to about 700 L/hr.
• Alternating and tangential flow filtration equipment is available fully disposable, to handle up to 1000 L/day.
• Single‑use chromatography and filtration equipment is widespread — only 1% of large‑scale chromatography columns were single‑use in 2010, a number which jumped to 37% by 2015.
• Raw materials and buffers mixed in single‑use bags are often added into stainless steel production vessels.
• Samples may be transferred from stainless steel vessels into single‑use testing equipment.
• Some stainless steel skids require only chemical cleaning, not steam sterilization. As sterile steam generation presents a challenge and large cost, the lifecycle cost of stainless steel drops dramatically when it is not required.
• Single‑use facilities can generally get validated for clinical trials in a faster and more cost‑effective manner.
• Single‑use facilities require more confidence in your suppliers — who need to confirm that they are supplying clean, sterile equipment and will be able to deliver inventory as necessary.
• Single‑use consumables necessitate holding inventory, which requires physical space (or prompt vendors) and impacts the P&L.

There is no standardized method for integrating single‑use and stainless steel into the same facility. That being said, if moving toward a hybrid solution seems advantageous, there are certain skids which may be easier to transition away from stainless steel.

Media mixing and buffer prep equipment is generally simple to transition from stainless steel to plastic, single use. The single‑use equipment mirrors the reusable equipment fairly closely and can therefore drop into existing setups relatively easily. The frequent changeovers required by these skids also mean that switching to single use increases uptime and availability by eliminating cleaning steps.

Bioreactors are also fairly simple to transition between stainless steel and plastic. Most early challenges with single‑use control systems have been overcome, and single‑use systems provide flexibility to move toward perfusion setups and continuous manufacturing that steel cannot achieve. And, as discussed earlier, it is not uncommon for a single‑use seed reactor to feed a stainless steel production reactor.

As the biologics and overall pharmaceutical industry has begun operating by the principles of quality by design and are thinking about validation early on, hybrid facilities are proving to be quite advantageous. Hybrid setups allow for a mix of customization, flexibility, and off‑the‑shelf validation, while balancing lifetime costs, quality, and availability to your biologics manufacturing process.