The advantages of hybrid equipment in biologics manufacturing

What is bioprocessing?

Bioprocessing is a technique by which we use biological resources such as living cells or microbes, and their machineries such as enzymes or metabolites, to obtain desired products. Bioreactors and fermenters are optimized to provide the best environment for these reactions to take place and yield the greatest amount of product. In medicine, mammalian cells are cultured in bioreactors to produce biologic drugs – often proteins, antibodies, or DNA fragments.

Once optimized, a bioreactor may produce millions or even billions of cells that can be cultured during upstream processing. These cells and their products are then moved further downstream via filtration, separation, purification, and fill and finish. Within these steps, the relevant proteins are purified out of the cell mass and processed to meet purity and quality requirements.

Equipment types for biologics manufacturing

Bioprocessing equipment may be either multi-use stainless steel or glass (requiring cleaning and sterilization between batches) or single-use plastic.

Multi-use equipment: stainless steel bioreactors

While glass equipment may also be used, particularly in lab settings, we’ll focus here on stainless steel as representative of all multi-use equipment. Stainless steel bioreactors have a long history in the biomedical production field as they are corrosion resistant, easy to clean, and can easily reach batch sizes of 10,000-20,000 liters.

Single-use equipment: disposable plastic bioreactors

Single-use bioreactors (SUBs) have become increasingly popular in the bioprocessing industry since their introduction in the late 1990s, primarily due to their flexibility in comparison to stainless steel reactors. SUBs require lower capital expenditures, and eliminating CIP/SIP skids both reduces operational costs and mitigates risk of cross-batch contamination. While these advantages can decrease manufacturing timelines by several months, this really only works for small batch drugs (those with small addressable markets or small-scale runs for clinical trials) as SUBs currently max out at batch sizes of about 2,000 liters.

Hybrid bioprocessing

Hybrid bioprocessing uses a combination of single-use and reusable components and skids in the production line, to simultaneously reap the benefits of both technologies. Manufacturers most often opt for hybrid setups while slowly testing and transitioning to single-use equipment.

Hybrid setups are able to achieve lower costs, smaller environmental footprints, and less supporting infrastructure by using single-use skids where able. They are also able to maintain larger batches for various critical processing steps by using stainless steel skids in those areas. The specific mix of single-use and stainless steel skids will depend on the various production needs of the manufacturer.

Advantages of hybrid facilities over fully stainless steel setups

Reduced environmental footprint

Hybrid systems provide a practical and environmentally-conscious design, offering an opportunity to reduce a plant’s environmental footprint without requiring a total overhaul of the manufacturing process. Hybrid facilities allow system designers to take advantage of single-use skids where appropriate, while recognizing their limitations in other areas and continuing to use stainless steel where necessary.

Lower production and operation costs

The capital and operating costs for single-use equipment are much lower than for the comparable stainless steel equipment. The savings in operating cost are attributable to single-use equipment being disposable and therefore not requiring cleaning or sterilization by the manufacturer. Overall savings, however, will depend on the scale of the production run. For example, in campaigns requiring a high number of batches, the cost of single-use consumables may ultimately exceed the startup costs for stainless steel.

Given the different batch size limitations for various stainless steel and single-use skids, it is fairly straightforward to determine the optimal skids to transition to single-use for a hybrid setup. The capital costs of stainless steel equipment for large batches must simply be compared to the consumable cost of single-use equipment for smaller batches.

Custom designs

Stainless steel bioreactors are often fully customized to a single product line. For facilities dedicated solely to that product, this is an advantage. For facilities requiring more versatility, SUBs can be better as they are configurable and easier to adjust based on changes to process condition or drug type. The appropriate bioreactor for a hybrid facility will depend on the overall development and market landscape for the drug in addition to various batch size considerations. This holds true for other skids as well.

Shorter turnover between campaigns

Switching between batches of drugs in facilities using stainless steel equipment can take up to three weeks due to the various processing steps required to fully decontaminate and sterilize the equipment. Hybrid facilities can shorten this process significantly, by introducing fast-changeover, single-use equipment wherever possible.

Overall increased flexibility

Using equipment that can be easily switched between the manufacture of different biologics has become increasingly advantageous in recent years due to a rapidly increasing demand for biologics and a shift toward orphan drug treatments, genetic therapies, etc.

Hybrid facilities are also particularly advantageous to contract manufacturing organizations (CMOs), which serve the needs of clients developing diverse biologic drugs and must be able to pivot manufacturing strategies as necessary to meet the specific needs of each client.


Choosing between single-use and stainless steel is often challenging for biologics manufacturers, and depends on the market demand for the drug as well as its commercial maturity. A hybrid plant is good way to combine the benefits of both systems and to maintain high production capacity while taking advantage of single-use equipment.

When using hybrid facilities for biologics, it is most common to use stainless steel bioreactors in upstream processing, and single-use skids in downstream processing for separation and purification. Due to size limitations, SUBs are perfect for research and pilot studies. Whereas manufacturers focused on commercially available biologic drugs with large markets will often still require stainless steel reactors to meet their production demand.

It is clear that a hybrid approach to bioprocessing is quite advantageous, enabling processes to benefit from single-use wherever appropriate. As manufacturers advance in biologics manufacturing, they will need to carefully weigh initial speed and flexibility with long-term cost advantages and processing of large volumes.

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