Scaling up biotechnology processes involves transitioning from laboratory-scale operations to larger production scales. This process is crucial for the commercialization of biotechnological products. Ultimately, the specification for the final end-product is the most important driver for the choice of process, quality of product and the costs involved in generating. The end goal is to produce products that is commercially viable and satisfies a larger number of customers.
A scale-up process involves taking a system that has been developed at laboratory-scale to pilot-plant scale so as to understand how realistic it might be as a larger version in terms of whether a product can be manufactured and whether it is commercially viable.
A design team with good understanding of large-scale processing generates a concept manufacturing process. In that process is an idea of the equipment and attendant plant needed for scale-up.
Using knowledge of biochemistry, microbiology and chemical engineering, a biotechnology process is developed into a design study based on flow diagrams, energy and material balances operating around particular unit operations and various economic models that dovetail with the technology.
The object then is to understand what is required for project viability and all the parameters that influence economics and large-scale production. Considerations in the scale-up of biotechnology processes include the following aspects which we discuss here.
Process Optimization
The process in its early stages is not fully developed or even integrated. The batch operations at a laboratory scale are usually run in such a way that product is lost at each step. A number of steps are examined at laboratory scale to understand whether improvements can be made and whether the losses can be stemmed on scaling-up.
- Ensure that the laboratory-scale process is optimized for efficiency, yield, and product quality before scaling up.
- Identify critical parameters and optimize them to achieve the desired results.
Equipment Selection
- Choose suitable equipment that can handle larger volumes while maintaining the required conditions for the bioprocess.
- Consider factors such as mixing, aeration, and temperature control in selecting equipment.
Bioreactor Design
The bioreactor is one of the central points in a biotechnology process and the focus around which many designs are based. It deserves it’s own assessment as we have discussed elsewhere. As a unit operation it is a priority because it is still the most expensive part of an biotechnology process both in terms of the capital cost, raw materials and utilities needed. The type of fermentation dictates the downstream processing element as well as waste products which must be dealt with.
Fermentation and bioreactors are also extremely complex, even brewing requires considerable experience to get right. many of the processes are scale dependent – they change as scaling up increases. This is partly due to equipment design and available scale, cost constraints and economics. The elements to consider are:-
- Optimize the design and configuration of bioreactors to maintain optimal conditions for cell growth, fermentation, or other bioprocesses.
- Consider factors such as oxygen transfer, nutrient supply, and waste removal.
- Designs can also feature tests on a range of alternative pieces of equipment as well as investigating a number of suppliers to ensure continuation in supply chain.
Scale-Up Criteria
Establish clear criteria for successful scale-up, considering parameters like cell density, product yield, and overall process efficiency.
Having developed the early phases to understand costs, feasibility of running scaled-down equipment, a pilot-plant scale is developed. The pilot-scale is designed to validate the process for a larger-scale operation, to minimise the risk of investing in capital equipment and in both energy and maintenance costs, investigate the supply chain and produce sample for marketing and even early commercialization purposes.
Many pilot plant operations are tested to see if they can run continuously and whether waste and other environmental factors can be accommodated. We can see that without substantial investigation, taking a process to industrial scale is not possible if investors are not convinced of the viability of such an operation.
Scale-Up Factor
Determine the appropriate scale-up factor based on the specific characteristics of the bioprocess. This involves calculating the ratios of parameters such as volume, surface area, and mass transfer rates. A scaled-down process is somewhere between 1% and 10% the size of a full-scale operation.
Quality Control
Implement robust quality control measures to ensure the consistency and purity of the final product at larger scales.
Monitor critical quality attributes throughout the scale-up process.
Sterilization and Sanitization
Develop effective sterilization and sanitization protocols for larger equipment and systems to prevent contamination.
Ensure that cleaning processes are scalable and maintain product integrity.
Supply Chain Management
- Evaluate and secure a reliable supply chain for raw materials, including media components, cell culture nutrients, and other inputs.
- Ensure that the supply chain can support the increased demand at larger scales.
- Substantial amounts of product are needed for sales and marketing campaigns as well as developing customer relationships, offering confidence in the supply chain and understanding the economics of supply and demand when larger operation of the plant is required.
Regulatory Compliance
- Understand and comply with regulatory requirements for the scaled-up process, including Good Manufacturing Practice (GMP) guidelines.
- Prepare for regulatory submissions and inspections.
- Be aware of any regulations relating to the product, whether it is subject to tax when manufactured at scale.
Cost Analysis
- Conduct a comprehensive cost analysis to identify potential cost drivers at larger scales.
- Optimize the process to reduce production costs while maintaining product quality.
- Remember that a pilot-scale process will be between 5 and 20% of the total project cost.
Environmental Impact
- Assess the environmental impact of the scaled-up process and implement sustainable practices where possible.
- Consider factors such as energy consumption, waste generation, and resource usage.
Personnel Training
- Provide training for personnel involved in the scaled-up process to ensure that they understand the challenges and requirements at larger scales.
- Develop experience in design and process monitoring and use the knowledge gained when translating to full-scale operation.
- Establish a competent team capable of managing the complexities of the scaled-up operation.
Process Monitoring and Control
- Implement robust monitoring and control systems to continuously assess and adjust process parameters in real-time.
- Use advanced analytics and automation to optimize process performance.
Technology Transfer
- Ensure smooth technology transfer from the laboratory to production, involving clear documentation and communication between teams.
Management
Skilled project management and business management in its entirety is critical. If the management of the project is unfocussed or loses track of the project then success is never achieved. Business owners with technology and business experience are invaluable in this environment because they understand what aspects of the project need focus and how to make decisions when there are failures at the intermediate scale. When a process moves to full-scale production than the macroeconomics of production take over.
Intellectual Property
There should always be continued exploration of the intellectual property to make sure that technology developed in the scaled-down process is not lost through careless security of the knowledge. Trade secrecy is an important feature in protecting early stage knowledge. Freedom to operate, patenting and trade marking come to the fore when designs need to be protected. It also means revealing a certain degree of detail however many competitors already have similar understanding and wisdom around a process if they are working on similar systems. It’s also useful to check the patent literature (as well as new academic literature) to see if new light can be shed on an existing process and to iron out wrinkles.
Financing Considerations
Transitioning from one phase to another takes time. Most producers developing a process ready to attract investment will spend somewhere between 3 and 10 years in taking a laboratory scale process to pilot plant level. Unless the investor is particularly knowledgeable about the risks in the scale-up process, it is unlikely that a manufacturer will generate enough confidence without showing some progress in scale-up.
The scale-up phase of a project is probably its most risky phase. It is the phase which is commonly the most expensive but requires funding to take it over the threshold into industrial manufacture. If lucky, the pilot-scale operation takes a minimum of 6 months but experience shows that at least 3 years is needed. Many producers are highly unrealistic with investors when they say 2 years because we know that at least 75% of all new start-ups underestimate the time it takes to achieve enough knowledge to move to the next phase. Very often, a pilot-scale operation will fail because it does produce product to the desired specification or reveals issues which are insurmountable. There are under-performance issues and even delays that might hold the project back as well as competitors developing processes which are shown to have better viability.
Common Mistakes and Errors Made In Scale-Up
Invariably, errors and mistakes occur during scale-up. It is one of the facts of life in a pilot-plant that catastrophic failures occur simply because not enough ‘homework’ was conducted early on or there were simply unforeseen unknowns about the process. One of the reasons for testing at a scale-down or intermediate stage is to identify what the potential issues are and whether they can be alleviated or mitigated for. In our experience, a number if mistakes occur which a pilot-scale operation is designed to allow for.
There are times when the pilot plant operation simply does not deliver what was observed at laboratory scale. Deviations should be expected so it is important to revisit laboratory systems to check whether something has been missed or a particular part of the design needs checking or even rechecking.
A good design team may well have built a similar plant or at least taken advice. It may be about other aspects such as the use of utilities or handling waste which need to be consulted on.
The raw materials available may not be of the same quality as those used in the pilot plant. One of the issues of scale-up is keeping costs down. Using cheaper raw materials comes with caveats if they cannot be used in a process or handled properly further downstream. The same can be said for using equipment which is not to standard. In some cases monitoring the process too is poor and the process not controllable.
Routine and preventive maintenance is weak which produces product losses. Part of the pilot-scale operation is building in a maintenance programme and testing to see whether the process can be controlled at scale.
Deviations to the process are not considered properly such that there is a loss of rigour in the investigation. Clearly that needs addressing because it may be a lack of experience in the operators.
By addressing these considerations, organizations can increase the likelihood of a successful and efficient scale-up of biotechnology processes. Each bioprocess is unique, so these considerations should be adapted to the specific characteristics of the technology being scaled.
Leave a Reply