I had the pleasure of attending IBC’s Flexible Facilities Conference in Berkeley, California last week. There were many interesting and informative presentations and I have summarized some of the key topics below.
Background – From Fixed to Flexible
The traditional model for manufacturing biopharmaceuticals has been to build a manufacturing facility focused on large stainless steel bioreactors usually in sizes ranging between 10,000 – 25,000 liters with extensive facility piping. These facilities require high initial capital investment and large overhead. The challenge with this type of design is that these facilities have large manufacturing capacity, but little flexibility. They usually focus on manufacturing one or two biopharmaceuticals requiring large volumes. However if demand changes, number of products run through the system changes, cell culture improvements result in higher titer, or any other alterations to volume requirements, capacity can become a problem and the facility is not flexible enough to adjust.
The development and subsequent improvements to single-use systems have offered a more flexible approach to manufacturing and have enabled the development of flexible facilities that employ the use of single-use systems over fixed in place equipment. Single-use systems offer reduced installation time, lower water for injection use, quick turnaround time, easy validation, lower start up costs, reduced cleaning and sterilization requirements, and ready out of the box options. Key benefits of flexible facilities include: easy product changeover for multiple product lines, capital investment savings, shortened time to commercial manufacturing and capacity optimization.
Are Flexible Facilities Right for Your Manufacturing?
As a result of some of the challenges experienced with traditional fixed biomanufacturing facilities there has been a desire to create more flexible spaces, but it is important for companies to decide whether flexible facilities are a good fit for their needs. Based on the presentations, there are several key questions that need to be address to determine what kind of facility is best for manufacturing. Questions around how many products will be manufactured in the facility, how many production platforms, how much capacity is needed, titer per product and whether it is variable, are just a few of the many pieces of information needed to decide the best facility strategy. I have explained a few of these key components in detail below:
It is important for companies to examine the economics behind their decision, as it is one key factor in selecting the best type of facility. Economic analysis is critical to determine what the yearly break even point will be, i.e. how many runs per year need to go through the facility to make stainless steel more cost effective based on capital investments, cleaning, validation, installation cost etc. vs. reduced to no cleaning or validation cost, minimal capital investment but higher consumable costs with single use systems.
Number of Products and Manufacturing Scale
Based on previous economic analysis, the best use for flexible facilities comes when there is smaller scale or multiple products (or both) running in a facility. The reason for this is that with flexible facilities there is easy product change over and the ease of moving equipment around a flexible facility allows for easy changes in capacity and even production systems.
In recent years, there has been increasing need to produce more products at smaller volumes. This has occurred for several reasons. Product yield increases and diversification of product portfolios has reduced the need for 10,000 – 25,000 liter batches and allowed for the opportunity to manufacture multiple products in the same facility. Traditionally turnaround time, cleaning, sterilization, and validation would have made it challenging to produce many products at the same facility. However with single use systems, cleaning, sterilization and validation are greatly reduced or eliminated. Single use bioreactors also offer many choices as to size and scale, so that scale can be perfectly matched with the current product demand. If product demand changes, than the scale of the single-use bioreactor can also be adjusted to keep pace, which greatly reduces costly capacity excess. This also enables the move toward smaller market or orphan drug products that have smaller product demand.
Another good use of a flexible facility is when there is a desire to manufacture material for different stages of clinical development. For instance in a flexible facility, you could feasibly manufacture different clinical trial material runs and then switch to commercial manufacturing for approved products. When drugs enter clinical trials it is unclear at that time how the drugs will do or if they will eventually earn approval. The attrition rate for investigational drugs is quite high, so logically companies do not want to make significant capital investments in manufacturing these products prior to approval. Flexible manufacturing is perfectly suited to address these needs. Clinical trial manufacturing campaigns can be initiated to manufacture the necessary product and then can be switched to manufacture a different drug until future need arises.
Flexible facilities are also an important component of product globalization. In some instances there is a desire to manufacture medicines closer to the populations that they will be supplied to. This also provides some safety with respect to facilities going offline. If one facility goes offline due to contamination, natural disaster, etc., the entire product supply chain will not be disrupted. With flexible manufacturing options, more single use bioreactors could come online to address any temporary shortages. Ideally model single-use system facilities could be designed with the goal of replicating these facilities in multiple countries or regions.
Multiple Production Systems
Another important point to consider is whether multiple production systems will be running in the same facility. Flexible facilities allow for production in several systems in the same facility even simultaneously in different suites. This model supports manufacturing in microbial, insect, viral, mammalian, and yeast systems all in the same facility on an as needed basis.
If there is a need to scale quickly to manufacturing scale, a flexible strategy is a good choice. There is a significant reduction in time needed to get a facility up and operational. One company stated that they were able to get to manufacturing 18 months to 2 years early by adopting single use systems and a flexible approach.
Flexible Facilities Design
While flexible facility layouts are dependent on specific manufacturing needs, the principle of flexible design integrates the ability to move equipment around as needed to provide the type of manufacturing necessary for each product. If more product is required, more single-use bioreactors or larger ones can be plugged into the manufacturing design. Because this equipment is portable it enables one size to be moved in while another is moved out or another is added. Mixers, single-use bioreactors, totes and other equipment are simply moved around to meet the manufacturing needs.
Some companies opt to employ two adjustable suites in manufacturing, each with similar equipment that can be moved in or out based on need. One company discussed their two adjacent suites; one fitted for viral vaccines the other for antibodies. They utilized a similar layout, equipment and process design for each suite which allowed employees to easily move from one manufacturing suite to the other as demand dictated with little to no training or adjustment on their part. This company used a variety of single-use bioreactors in the 50 liter to 2,000-liter scale that they could employ based on demand.
Since single-use components can be used for media and buffer prep, cell culture, finish and fill, and chromatography, it is important to understand your process and work closely with suppliers to find the best mix of components for your flexible facility. Most want to move to as many disposables as possible, but for some this might not be possible. Understanding during the planning phase what is available in single-use to meet your needs and how you will intermix some fixed components as necessary, is critical in preventing problems during implementation.
It is also important to include your supply chain in the planning of the facility. They can help to identify potential problems, possible supply bottlenecks and can work with suppliers to ensure that you have the necessary components for success. To support the flexible facility, supply must also be flexible and your team must be able to respond to changes in demand, have alternatives available and mitigation plans. As such they are an important part of the planning to ensure smooth operations.
With the many pressures facing biomanufacturing today including cost effective manufacturing and effective capacity management coupled with the many different product demands, it is not surprising that companies are looking for more flexible manufacturing options. While truly flexible facilities may not be a good fit for all biomanufacturing facilities, certainly building in some flexibility with any new facility is a good thing, particularly when you consider the ever-changing biopharmaceutical landscape.
If you have an interest in considering a flexible facility or learning more about how to make your facility more flexible, I would recommend attending this conference next year. In June, IBC is also hosting a Single-Use Applications for Biopharmaceutical Manufacturing Conference that may be of interest to those thinking about implementing flexible manufacturing.