What types of economic analysis should one conduct before adopting single-use equipment?
Dr. Jenkins: We determined that we would incur lower infrastructure costs—for example the use of less steam and water, lower capital expenses since we would not require clean-in-place, lower risk of cross contamination, and improved safety. However, the higher consumable cost of bags and assemblies partially offsets the positives gained by the reduction of fixed costs.
Matthews: The major advantage of adopting disposables is facility cost reduction. One simply needs to compare the cost of a traditional stainless steel facility to the disposable facility and the answer becomes clear. Expenses of disposable equipment are far outweighed by reduced capital depreciation.
Munk: We conduct a thorough economic evaluation of all single-use projects, including risk analysis and opportunity costs during reconstruction of our facilities to better take advantage of single-use technologies. We only engage in projects where the ROI is double-digit percent.
Dr. Runser: Integrating any new disposable solution requires a successful and thorough evaluation. If the available disposable solution meets internal and external technical and regulatory criteria, it usually has a superior outcome compared to standard stainless steel equipment. However, large-scale GMP biomanufacturing still has a lot of technical limitations that slow down wider use of disposable solutions.
Dr. Schlatter: Whatever analyses are done, one should consider factoring in flexibility and customer attractiveness. Disposable technologies are becoming more and more economically attractive, especially for facilities producing multiple products and with many changeovers.
VonEsch: A simple cost vs. benefit analysis based on the cost of traditional CIP/SIP systems against fully disposable technologies showed that the up-front costs of disposables would be slightly greater, simply because of order quantities to take up gaps in lead times. However, a true savings in time and money, especially with regard to use with multiple products, quickly became evident.
In our situation we currently fill three different products with volume ranges of 10x from one another using a single disposable assembly configuration. The flexibility these systems provide gave us the ability to conserve continuous costs by the elimination of cleaning validation, development work, while reducing changeover times from each production batch.
Dr. Witcher: For small-scale clinical and commercial manufacturing, the cost savings are relatively obvious and little economic justification is required. For manufacturing a large number of lots, an economic analysis is useful to justify the higher variable costs associated with disposables versus amortizing the cost of fixed stainless steel CIP/SIP systems and validation costs.
Economic considerations tend to start the disposable discussion, but when decision time comes, reliability of the components and the ability to reliably get the necessary components tend to become important factors.
What are the limits for adopting disposables?
Dr. Jenkins: I think there will always be scale issues. The handling of large units becomes difficult, for example a 20,000 L bag. I am not sure how much that will actually limit the use of single-use systems given the drive toward higher titers and smaller batches.
But the higher titer does cause downstream bottlenecks. Today this will be one of the more limiting factors in terms of speed and cost of goods. There has been substantial improvement in upstream processing but the development activities will need to improve in purification to exploit all these improvements fully.
Matthews: If the same product is being produced frequently at scales greater than 2,000 liters, the economics for disposables start to lose their advantage. If 2,000 liters isn’t enough capacity for commercial production, one could consider perfusion cell culture. But this decision needs to be made early on because the switch from fed batch to perfusion is substantial, affecting many areas such as process development, regulatory filings, and with the risk of changing product characteristics, the potential need for new clinical trials.
Munk: The major limitations for single use are technical, mostly with processes that represent extreme conditions from the perspective of the disposable equipment.
Some related factors include volumes over 3,000 L, high temperatures, high pressure, high flow, aggressive chemicals, or high physical power input. Plus vendors still have difficulties offering cost-effective solutions for chromatography.
Dr. Runser: Today, the appropriate use of bags without stirring systems is still limited to maximal volume of approximately 2,500 L. Additionally, stirred bag systems are still cost-intensive and relatively cumbersome to operate in an industrial GMP environment, even below 2,000 L.
To be more precise, stirred systems frequently need the use of online pH and conductivity probes. However, the available probing systems are currently not robust enough for routine usage.
Also, disposable filtration systems partially still have pressure limitations. And nonsterile filters cannot always be sterilized in place by steam or a caustic solution, which prevents their use in a fully closed manufacturing environment.
Dr. Schlatter: One limit is the scale of bioreactors, currently around 2,000 liters, and the economic appeal of stainless steel for supplying larger volumes of a single product.
VonEsch: The major limitation I see with disposables with regard to sterile filling will remain tubing compatibility and pump life.
Another will be the prices vendors may look to charge for such systems. “Frontier” users will incur expenses greater than might be expected before these systems become more widely adopted. But unfortunately, it appears that baseline pricing only increases over time, without correlation to widespread adoption. Vendors could possibly out-price themselves before the industry recognizes the true benefits.
Dr. Witcher: The obvious limit is the scale. About 1,000 liters seems to be the practical limit, although larger volumes may be possible. The major advantage of disposables comes from their use in portable, skid-mounted systems that can facilitate the change-out of process equipment that can be used to bring new processes into an operating area quickly and efficiently.
As processes become lower volume and more efficient, for example at higher yields, disposables will become more attractive. Another obvious limitation is fermentation, where heat transfer and mixing are major issues.