Single Use Versus Stainless: Let's Talk Titer
By Trisha Gladd, Editor, Life Science Connect
At last month’s BioProcess International Conference and Exhibition, five representatives from companies across the industry sat down to discuss today’s biopharma trends as well as look ahead to the future of biopharmaceutical development and manufacturing. The first of several topics covered during the hour-long panel discussion was what factors a company should consider before implementing single-use technology (SUT). To no one’s surprise, this was not a simple answer. However, the entire group did agree there was one question that needs to be answered before considering any others – is a 2,000-liter bioreactor enough? The panel, much like the rest of the industry, agreed that titer plays a key role in determining this answer.
The Future Of Titer
Earlier this year, Ronald Rader, a senior research director at BioPlan Associates and president of Biotechnology Information Institute, and Eric Langer, president and managing director of BioPlan Associates, released a report about the historical and future trends of titer, yields, and efficiency in commercial-scale bioprocessing. Using titer and yield data for nearly 40 biopharmaceuticals (all recombinant proteins with a concentration on major monoclonal antibodies) and going back as far as the 1980s, they were able to determine that the average titers at commercial scale 25 years ago were less than .5 grams per liter (g/L). In the industry today, technological trends, such as improved expression systems and use of process analytical technologies (PAT), have increased this average to 2.5 g/L. The authors expect this to increase to 3.25 g/L in the next five years. Nonetheless, they did find that “many products entering the market in coming years will have titers at or approaching 7 grams per liter.”
If a company must meet a high demand for a product but is not producing high titers, a larger bioreactor will need to be utilized. Nonetheless, as titers increase, companies have the option of moving to a smaller bioreactor, giving them a choice between stainless or single use. Once this happens, why wouldn’t they move to the less expensive, more flexible option of single use?
How Do You Know When To Use Single Use?
In an article I wrote last year with Jeff Johnson, new technology lead at Merck, he reviewed the findings of a study completed by his Technology Encouragement Collaborators (TEC) team, in order to answer that very question. TEC is a group of teams Merck put together to assess new technologies and determine whether or not to implement them. What they discovered was that, when comparing the capital costs of a facility with six 2,000-liter single-use bioreactors and a stainless-steel facility with six 2,000-liter stainless-steel bioreactors, single use was, as expected, the winner ($70 million for the SUT facility compared to $200 million for the stainless). However, during an analysis that also included titer and cost per gram, it became clear that titer is really the deciding factor when it came to what type of facility a company should build. He says, “At higher titers, these single-use factories start to make a lot of sense, especially for moderate volume products. You could certainly launch a facility and service a lot of smaller products in single use if the products have a titer above three grams/liter. If you have a big blockbuster drug and you need more than a thousand kilograms, go to a CMO that has a big stainless-steel factory.” Ultimately, he and his team determined that the best solution was to implement a hybrid approach with both single-use and stainless-steel technologies. This allows a company to take advantage of the benefits of single use at the lower operating costs of stainless.
Panel member Rahul Singvhi, chief operating officer at Takeda Vaccines and panel member at the BPI fireside chat, says for a low-volume business, such as vaccines, the answer is obvious. “From a vaccine perspective, 2,000 liters is not a limitation,” he explains. “That is actually very large for vaccines, which makes it sufficient for producing drug substances.” He adds that when combining that factor with the additional well-known benefits of SUT, such as the shortened timeline of constructing an SUT facility, the flexibility of being able to use multiple products in the same facility, and what he calls a reasonable cost of goods, single-use is a very obvious approach for Takeda.
Look To The Market For Your Answer
While higher titers will certainly give manufacturers the ability to move to single-use, that doesn’t mean that increased titers will move manufacturers to single use. “It’s not a matter of either/or,” says Hanne Bak, senior director of preclinical manufacturing and process development at Regeneron Pharmaceuticals. "I think it’s fair to say that many of the antibody-based drugs that we have, either in clinical development or on the markets, they have very high doses. The dose that we’re giving is a lot higher now for some indications than it is for some of the existing drugs on the market. What that means is that, if the market uptake is good, you may be looking at producing tens of metric tons of protein. If you just do a simple analysis, even if you have very, very high titers in a fed batch system, that’s an enormous amount of 2,000-liter single-use bioreactors that you need to turn over every single year.” She continues by adding that, if fed batch is your production method of choice and you’re looking at a drug with a very high dose and a potential for a large patient population, there’s certainly an argument to be made for stainless steel. This is in regard to your cost of goods as well as your ability to churn out the number of batches that you need.
Victor Vinci, chief scientific officer and vice president at Cook Pharmica, pointed out a major benefit that a single-use facility offers over a stainless steel facility, which Kimball Hall of Amgen had discussed during her conference keynote. When reviewing the benefits of the next generation facility Amgen built in Singapore, Dr. Hall pointed out that single-use facilities do not take a long time to build. The one in Singapore took 15 months, but she says three of these months were due to the need to pile. Without that, it could’ve been built in a year. This gives any company that chooses single use the ability to wait the market out to determine how much capacity will actually be needed at the time the drug is ready for commercial manufacturing.
“It’s not disposable versus stainless. It’s not profusion versus fed batch. It’s what is the product driving in terms of product quality? What does the market look like?,” explains Vinci. “If you’ve seen market projections in larger companies, they range all over the place. We’re trying to guess, and most companies are guessing at the high end of that market penetration.” This is a dilemma for many companies. Someone has to make the multi-million dollar decision and no one wants to be wrong. Vinci says this is a major advantage, particularly for growing companies. “If you’re a mid-sized or evolving biotech company, I think you have the most compelling decision to make. You have the freedom of not having a billion dollars sunk into stainless steel, which is difficult to get rid of. You could make a decision that is more informed than many companies have been able to make for a long time.”