6 considerations for scaling up an industrial biotechnology process

6 considerations for scaling up an industrial biotechnology process

Industrial biotechnology processes face a unique set of challenges when it comes to scale-up.

Biotechnology, specifically medicinal-focused biotechnology, receives a lot of recognition and media coverage for significant technological strides in advancing human and animal health—especially recently with the rise of COVID-19 novel therapies. But biotechnology is also pushing innovations for bio-based materials, consumer goods, and chemicals. This subset, called industrial biotechnology, is creating fuel from plant-derived sugars, developing bio-based plastic and synthetic fabrics, and reimagining new uses for formerly unused biomass waste. Industrial biotechnologists are leading an impressive charge to create eco-friendly and cost-effective alternatives for manufactured goods.

One of the early innovations in industrial biotech still provides a great example of its capabilities. In the 1970s, the use of phosphates in laundry detergents to remove stains created a water pollution problem. Using biotech processes, scientists were able to create an enzyme that could remove stains from clothing and replace the phosphate. Not only did this non-polluting alternative solve the pollution problem that phosphate caused, but it ultimately performed better than the phosphate.

This illustrates the immense potential for industrial biotech. The market is expected to reach $576.89 billion by 2026 while promising to reduce pollution, resource consumption, and cost. However, producing a commercially available bio-based product does not come without challenges.

The hurdles to scaling up industrial bio processes

Taking a promising technology from benchtop to commercial scale is a significant challenge to growing the industrial biotech market. While it’s true that every new process faces the scale-up challenge, this market faces very unique obstacles that separate it from food, dairy, or pharmaceutical manufacturing.

  1. Product margins are small in comparison to other biotech markets, and often the cost of goods sold (COGS) dictates that these industrial bio products be made in massive batch sizes. The capital investment to build a large-scale production facility for industrial bio is disproportionately high due to the extremely large scale required.
  2. As a bio-based process, there is an inherent level of unpredictability when scaling, especially to such large sizes. This is arguably the most significant risk when investing in the commercialization of a new industrial bio product.

Take large scale fermentation for example—the mixing effectiveness (i.e. homogeneity), heat removal, and hydrostatic pressure are all specific parameters that are difficult to mimic at small scale that may have unknown effects on the biological process until the process runs at scale. Therefore, decisions made during the design process are crucial. Performing a risk assessment early in design identifies the critical concerns and allows for the opportunity to find creative ways of designing around risk areas in your specific process. Reach out to experts in the industry that have taken similar processes scale and can help you avoid some of the major pitfalls that cause some to fail.

Secure funding early

Success in commercial industrial biotechnology is striking the balance of producing appropriately priced consumer goods with a relatively high capital expenditure price tag. The moments leading up to funding approval on your long-awaited scale-up is both exciting and nerve-wracking. Understanding factors that are commonly overlooked during early design phases, while using the best tools available can help you anticipate issues earlier in design. This allows you to better control overall plant costs and minimize risk.

A quality feasibility study justifies the capital investment, but not without including a thorough “look behind the curtain”. This pre-funding study should uncover risk areas to eliminate unwelcome surprises (more money!) in later design, construction, or start-up. Seek the advice of trusted contacts in your network, from process and design to construction consultants during this time. Asking the right questions early can guide you toward a successful project and healthy long-term operation. These are some key stagegate questions for scaling processes moving towards commercialization.

6 considerations to scale up your industrial bio process

1. Adjust your formula for larger scale

The most obvious step is often the most often overlooked. Increasing your output is not a matter of simply doubling the component parts to get double the final product. Ingredients may not behave in the same way as you add more to the mix. As such, start by figuring out how much is required or adjust your formula to achieve your desired result. Identify the ingredients that are difficult to handle and mix, or are hazardous/corrosive. These “annoying to deal with” materials at lab-scale will manifest as serious project issues when handled in bulk, exacerbating capital and operating costs.

Another aspect of adjusting your formula is the cost and quality of ingredients. As you scale up, an ingredient may become too expensive to meet your price target, or you may run into difficulty sourcing a larger amount of equal quality ingredient from a different supplier. Again, this might mean you have to adjust your formulation or develop a new sourcing strategy.

2. Identify relevant building codes

Ultimately, your scaled-up process needs an appropriate facility. Building that shell means understanding applicable building codes, which can also dictate where it can be located. Early on, investigate and classify your materials and process based on hazards. Are you dealing with volatile organic compounds or hazardous air pollutants? Limits dictated by building codes, regulatory bodies, and local authorities having jurisdiction (AHJ) may mean significant project costs to add measures like containment dikes and off-gas scrubbing equipment. Additionally, electrical classification due to combustibles and flammables or H-class building construction can also drive up project costs. Get to know your local AHJ and, where necessary, consult architectural & electrical expertise when selecting and storing raw materials.

3. Select the right equipment

Scaling will not only affect the formula; you will have to adapt to new or modified equipment to handle the larger batches. First, it’s important to understand how large-scale equipment will enable or change your process. Take mixing design for instance. Approach to agitation can change drastically from benchtop to large scale because scaling the mixing process is complex. The addition of a low density powdered media or additive that was added via manual carboys in pilot scale may now require specialized powder handling or high-shear powder incorporating equipment to make the large-scale approach timely and effective (i.e. free of clumping or powder bridging). Instead of carboys, consider the use of bulk bags, drums, or conveyors, which also require custom handling & delivery equipment.

Downstream equipment selection will also be critically important for the overall success of the project. Perform a thorough analysis of all facets: capital and operating cost, size and footprint, operability, processing duration, cleanability, etc. From mixing and powder handling, fermentation and purification, all the way to filling and packaging, we’ve seen that no two applications are the same.

4. Anticipate changes to instrumentation and diagnostics

Monitoring the performance of your process is much easier at smaller scales. When that process grows, you may need to collect more data on your process at additional points to determine improvements and troubleshoot problems. Identify the critical process parameters (CPPs), as well as where you are measuring these parameters, to determine what is important for you to monitor at scale. Will intermittent sampling analyzed by an offline, manual method be sufficient? Or do you need continuous monitoring to pull data that the process can automatically react to? Considering this difference will help you determine what additional instrumentation you need. Also, because your process has grown, you may want to consider redundancy, multiple sampling locations (i.e. various probe belt locations), and historian tracking. By bringing on automation expertise early on in concept design, you can prepare for facility scaling and process control for years to come. They will help you navigate how integrated you want your facility to be and how robust your IT and building systems will be.

5. Determine cleaning and sterilization needs

Cleaning and sterilization can also look much different at large scale. These aspects must be considered as part of early design/feasibility, as they can significantly impact the project cost. In our experience, if cleaning or steam sterilizing are inadequate, it won’t become obvious until the plant is constructed and the first batches being made with poor yield or frequent contaminations. At this point, it becomes a debilitating fix. But it’s something that can be caught early in the project.

One risk is that your cleaning process may not be robust enough to handle your new manufacturing process. Additionally, guessing at your cleaning needs may create unnecessary chemical, water, and energy costs. Instead, you can work with a lab-based service like Steris’ PACE study during development to identify the ideal cleaning makeup for your scaled-up process. However, if time and cost won’t allow for this, plan for flexibility in your operations to adjust your cleaning temperature, action, time, and chemical type and concentrations. Cleaning downtime and equipment redundancy can also be included in your process simulation to help you understand how these changes will impact your throughput.

As for sterility requirements, in the industrial bio world, it’s process dependent. Some bio-based processes can handle adversity, or foreign organisms, and still produce better than other processes. How bulletproof is your process? This will lead you to the appropriate steaming cycles on the spectrum between sanitized and sterilized. Decisions around sterile design will directly affect equipment/piping design and automation complexity. These decisions also carry non-trivial impact on your process schedule. Ultimately, your focus is optimizing yield and minimizing contaminated batches going down the drain. It’s where scientists, engineers, and project management collide; work together to nail down the design philosophy early on, so your facility is catered to exactly the needs of the project, without over- or under-designing.

6. Optimize your process

As you advance your process to large scale, the processing time for heating, cooling, additions, and fermentation; cleaning, sanitization (steam or chemical) and planned shutdowns; and personnel and material flows will all change. You need to be able to accurately predict how modifying each component will impact your throughput. You also want to determine the right adjustment for each part to optimize your overall process. Don’t rely on trial and error to do this.

Modeling and process simulation are the best tools to help you make these determinations early on in feasibility and conceptual design. CRB has helped many different manufacturers with customized simulation modeling to help de-bottleneck, improve efficiency and lower operating costs. Using your current process data, simulations allow you to make changes to each potential variable and see how it will change the outcome. This way you can dial into the right adjustment for each part of your process and build an accurate schedule for your large-scale process. Right-sizing your facility is particularly important in industrial bio to ensure you make an appropriate capital expenditure for a predictable process output that yields predictable payback.

Whether you are developing a new technology or you are already an established manufacturer, thinking through these considerations allows you to plan for the future and constantly improve your process. There are many points to factor in when scaling up, but there are also many things to celebrate. Industrial biotechnology is a field that is constantly stirring up creative new ideas and the level of collaboration and partnership in this field is second to none. Be sure to leverage a partner who’s traveled this road before.

How can CRB help you scale up your process? Let’s talk.

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