Choosing the Right Technology for the Right Problems

Biopharma manufacturers may choose to use stainless steel or single-use equipment. The decision will depend on the product portfolio and the company’s own needs and resources.

With Jorg Thommes, Head of CMC, Bill & Melinda Gates Medical Research Institute. The opinions expressed in the article are Jorg’s and not those of his employer, the Bill & Melinda Gates Medical Research Institute.

What are the benefits of stainless steel?
Ultimately, stainless steel has proven to be highly reliable for the manufacture of biopharmaceutical products. Stainless steel systems are operationally robust and straightforward to maintain. The industry is familiar with the equipment and has spent a lot of effort to understand the cleaning and sterilization of stainless steel bioreactors. In addition, scale up is by now quite predictable due to excellent progress in understanding mass transport and mixing phenomena in these reactors. This predictability is a key element of why stainless steel continues to be used by biopharma manufacturers. If a manufacturer purchases a stainless steel bioreactor, they understand what they are getting. In addition, the per batch operational costs, particularly at the high productivities possible today, that are achievable with stainless steel infrastructure are also a strong benefit. Finally, a well automated stainless steel facility run 24/7, 365 days a year can provide enormous productivity for large market products.

And what about the disadvantages?
Stainless steel infrastructures are complex, requiring significant capital investment. Indeed, some companies are reluctant to build stainless steel facilities because of the required investment and the long project timelines to build and commission them. Small companies, in particular, are unlikely to have extensive cash resources at hand to build a brand new stainless steel facility.
Another downside oftentimes cited for stainless steel is that product changeover is more difficult and rigid than in a singleuse environment. It takes more time to clean and re-sterilize a stainless steel environment, whereas with single-use you simply remove the used component and install a new one. Since the connections are made aseptically, you can return to normal operations quickly. Experienced organizations that understand their stainless steel infrastructure well can minimize turnover times, but they will still likely be longer than for single-use equipment.

What is your experience with single use?
Like stainless steel, I believe that singleuse also has benefits and drawbacks. The single-use reactors are easy to use, but there is the potential of interaction of cells and media components with the single-use plastic surfaces. This is perhaps my main concern. Stainless steel is inert but plastic surfaces can interfere with the media either through absorbing of media components or leaching from the surface, which could be detrimental to growth and productivity of the biological system. To add to the uncertainty, interactions can vary between batches of single-use equipment. Single-use surfaces essentially add a new raw material to the process and raw material variability is certainly of concern in biomanufacturing. When introducing single-use systems, it is crucial for the manufacturer to thoroughly research the potential for variability of single-use surface interactions and the impact of that variability on the consistency of the manufacturing process. Similar to having to study and validate cleaning and sterilization of stainless steel equipment, the onus is on the manufacturer to understand raw material variability issues for single-use equipment.
It’s also true that single-use has advantages that may appeal to many manufacturers. As I mentioned earlier, ease of product changeover is a significant benefit. For example, a clinical manufacturing facility that only requires one or two batches of each candidate molecule can perform changeovers rapidly in succession when using single-use. Likewise, for a portfolio of diverse commercial products that all require only a few batches per year (for example, a rare disease product for a small patient population, or a highly potent compound), single-use may be the logical choice as it reduces the turnover time between products. Single-use also has other advantages; as the systems are oftentimes smaller, they are usually easier to transport. Single-use systems have recently been discussed as quite suitable for distributed manufacturing. Stainless steel equipment can, of course, be used for distributed manufacturing too, but single-use systems can be assembled with substantially reduced capital investment and be quickly deployed, ready assembled, for use in different locations.

Stainless steel or single use; ultimately, which option is superior?
It is not about which option is “superior”, it is about choosing the right solution for a specific problem. The introduction of single-use systems – and their acceptance by the industry – has given biomanufacturers more choice in how they make their products. Twenty years ago, a manufacturer would have to build a stainless steel facility because that was the only option. Today, companies can thoroughly review which technology will be best for their specific needs, or whether there is benefit in combining both in a hybrid approach.
The decision over which equipment to use can be complex, depending on the company, its strategy, pipeline and resources. For a company with products that need to serve large markets and are manufactured in a large number of batches per year, stainless steel may be considered the optimal solution, but necessitates a large cash investment. The company will also need to have the confidence that investing in a facility is the right use of their limited resources. For a smaller company, the decision can be quite different than for a large entity. Uncertainty around future pipeline and manufacturing requirements may impact the decision making. In this instance, a single-use facility will minimize the capital required and reduce building time. Stainless steel facilities need to be planned far in advance – at a time when uncertainty around the potential of a new product can be high.

How are approaches that use continuous bioprocessing further expanding manufacturing options for companies?
Continuous bioprocessing is attracting increasing interest in the biomanufacturing community. One of the most compelling advantages of continuous manufacturing is the ability to work in a steady state resulting in a continuous, consistent and reliable flow of product. Typically, biopharmaceuticals come with quality attributes where variability within a range of attributes is expected. In a continuous system in steady state, the range of quality attributes can be expected to be narrower. However, in order to run a continuous bioprocessing system, one must have an in-depth understanding of the stability of the manufacturing process and the controls necessary to get to and stay in steady state. Not all products and processes will be suitable for a continuous bioprocess and this must be something that is thoroughly investigated before choosing this approach.

Is single use essential to implement a continuous bioprocess?
Some have described single-use as an important enabler of continuous bioprocessing, but continuous manufacturing can be performed with either stainless steel or single-use. I personally believe that stainless steel complements continuous manufacturing very well because continuous manufacturing is meant to deliver a steady and consistent product output over long periods of time, which plays to the advantage of a stainless-steel infrastructure. A continuous system that produces the same product and the same quality day in, day out lends itself well to fixed infrastructure where few product changeovers are expected.
Ultimately, it is a manufacturer’s own responsibility to understand their product and to choose the most appropriate technology. The decision over whether to use stainless steel or single-use, execute batch manufacturing or adopt a continuous operation must be based on science and whether the solution is suitable for the problems at hand. Single-use is not a goal in itself, but is an excellent tool to tackle a number of issues that certain manufacturing scenarios require. The same is true for stainless steel. You should never build a single-use or stainless steel plant just because you fundamentally like or dislike it – whatever you choose should be a good fit with your product and business.

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Originally published by The Medicine Maker



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