At What Point in Drug Development Must a Firm Look to Process Optimization, and How Critical is this Timing to a Product’s Overall Success? A Roundtable Discussion

Moderator Dan Stanton, with Kelsey Achenbach (Roquette), Andy Davies (Prometic Bioseparations), and Eric Langer (BioPlan Associates)

Dan Stanton initiated the final roundtable of the 2019 BPI Theater at CPhI by asking panelists about process optimization. “Why has it entered the mainstream of parlance within the biopharmaceutical industry?”

Achenbach defined process optimization as anything that improves a process, typically from a cost perspective. The term interests many people in the industry now because it is at a stage where such efforts are important. “It didn’t matter in the beginning, when
MAbs were first developed in the 1980s because they were such a new thing. The cost didn’t matter. If they could save a person’s life — wow.”

Davies agreed that cost is a significant driver. “You always hear about the cost of protein A, for example, and how that’s a major contribution. It does provide the quality that you need, but the budgets for healthcare are not constantly being met, so you need to make drugs cheaper. That’s the key to getting it right: getting the right yields and quality at the right cost.”

Focus on Process Improvement
Stanton asked Langer where respondents in his company’s annual survey are focusing on their process improvements. Langer said that the focus has evolved. Over the past 10 years, his annual survey has asked participants, “What’s the single most critical trend or factor in bioprocessing?” He has found that manufacturing efficiency related to the issue of cost is at the top of the results list year after year.

“Now we know how much it should cost to manufacture a biologic per gram. We’ve done some analysis on that, and the fact is that those costs are going down. In some cases, statements coming from contract manufacturers are dramatic,” he said. “However, at the end of the day, the difference between $50 a gram and $300 a gram is on the manufacturing budget. For an innovative drug, it doesn’t even show up as a slice of the revenue pie when you’re talking about a biologic that could sell at a billion dollars a year. In that case, the cost of manufacturing doesn’t matter that much except to a manufacturer’s bottom line. The issue arises with products such as biosimilars, for which costs do matter.”

Langer also highlighted another issue he has seen recently: Manufacturing efficiencies are no longer a mere trend, but now a fact of life. He agreed that cost can create a competitive marketplace for biosimilars but pointed out that, as the cost of a biologic goes down for patients, the percentage of that manufacturing cost will go up.
Stanton asked Davies whether this is what he is seeing from a services point of view. Davies confirmed, noting that biosimilar manufacturers especially have an opportunity to improve processes while reducing cost. “It’s definitely the driver for us,” he said.
Achenbach added, “With biosimilars, you have another advantage because you don’t have to use all the same ingredients [as are used in the innovator drug]. You just have to have the same end product, indication, and therapeutic effect. We are seeing an opportunity as well for replacement of materials that could optimize the process. So this is an opportunity for innovation.”

Achenbach’s own presentation had focused on raw-materials supply. So Stanton asked whether process optimization starts with raw materials selection. “I believe so,” Achenbach replied.

Using the example of quality by design (QbD) principles that rest on critical quality assessments, she challenged the industry to study and understand what really is critical. “Consistency is critical, and consistency goes back to raw material selection. So if you don’t understand your supplier and the consistency that your supplier has, you could have problems within your process that you don’t even know are there.”

Debottling Bottlenecks
Turning the conversation toward relieving bottlenecks, Stanton remarked that upstream processes have received the majority of attention when it comes to solving problems and optimizing processes. He wondered whether the panelists have seen a disparity between upstream and downstream when it comes to process optimization efforts.
“Yes, it’s the classic ‘throw over the wall,’ isn’t it?” remarked Davies. “The yields they’re producing upstream can cause problems downstream, either from impurities or the sheer volume of what they’re producing. That causes more problems downstream that they have to cater to, so you need higher productivity.”

Langer agreed. “Over 30 years, we’ve analyzed how [expression] titers have improved, and it showed a nice upward curve. In our recent annual report, we’re now seeing that flattening out. We asked 200 bioprocessing experts what their titers are right now, and they are at about 3.2 g/L. When we started measuring, it was 0.9 g/L, then 1.5 g/L, and that was five or six years ago. Titers have dramatically improved. On the other hand, the yield after purification is stagnant. It’s just not moving year after year.” He noted that as the industry sees improvements on the upstream side, companies can scale out instead of up rather than optimize processes downstream.

Examining Plastics
Langer introduced another issue associated with raw materials: single-use technologies and the plastics associated with them. Those raw materials begin far up the supply chain. “So here you have Amgen or Saint-Gobain or Thermo coming in and saying, ‘We want you to change the way you do business with us as a buyer.’” Convincing those plastics suppliers to change management practices will never happen in an industry as massive as theirs.

Achenbach pointed to just that challenge she wishes the industry to take up. “Some suppliers do pay attention, but it’s a matter of making sure that those are the suppliers involved in your supply chain. Such long-term partnerships are only just starting in biopharmaceuticals, going back to the material manufacturers of plastics, resins, and other single-use equipment.”

When Is the Best Time to Make Process Improvements?
With the importance of having to optimize processes early on, Stanton wondered why a company in late-stage development or even with a product already on the market might wish to optimize or change its process. “Would there ever be a case for such a company to make significant changes once a product is commercial?”

“Yes,” Davies replied. “For instance, when a process was developed, maybe the company didn’t have a caustic-stable resin, which is part of an established cleaning-in-place (CIP) process. If such a resin is available now, then the cost of that change is definitely worthwhile because that will ease the flow through the regulatory bodies.”
Achenbach added that when a drug product launches, it may not be perfect. She has seen companies still needing to increase drug stability over time. “I think that there are still opportunities [for process optimization] in late stage because a drug is not perfect when it launches. It really is helping to save lives in a way that has never been done before, so it gets to market fast, and they optimize afterward.”

Stanton remarked that a difference between a perfect product and an acceptable product for a pharmaceutical company could be billions of dollars. When there’s biosimilar competition or a direct threat, then perhaps reconsidering some aspects of a bioprocess might help large companies compete after patent expiry.

Langer commented that many drug manufacturers are moving their products from the United States and Europe to China to try to capitalize on the market there. “Anytime you’re moving a process, you also have that opportunity [to optimize]. Now biopharmaceutical companies are asking, ‘Does that supply chain still make sense? Do we have to make some changes?’” He added that such companies can take advantage of different market opportunities to launch an optimization project.

Moving Toward Biomanufacturing in China
“Have you seen companies eying up the Chinese biomanufacturing space to transfer their products to that country?” Stanton inquired.

Langer said that some activity occurred strategically 15–20 years ago, when biopharmaceutical companies started to establish relationships in China with their R&D facilities. They have been training people to become experts within that environment, and that has been necessary to take biopharmaceutical manufacturing in China to the next level.

Currently, there is great interest in developing partnerships. Chinese biopharmaceutical organizations are seeking inbound investment for innovation to bring that to China with partnerships. Langer believes that “we’re going to see a lot more collaborative, innovative relationship-built opportunities in China.” Those will rely heavily on development of a domestic industry.

Stanton noted that 20–30 years ago the drug industry at large began moving to lower-cost economies such as those in China and India for drug production. He asked whether innovation beginning to come from China would change that country’s reputation as the low-cost manufacturing locale for Western companies.
“I think it’s going to be an issue of quality,” Davies replied. “You’re going to see a requirement for a quality system in place before that environment will grow into one that can meet not just the early stage raw material issues, but also expand into a global opportunity for manufacturers.”

That is not relevant only to China, he added, but everywhere around the world. “Biologics is a global industry, so for us to think of it in domestic and nondomestic terms, I think, is probably short-sighted.”

A Closer Look At Cell and Gene Therapies
The final question Stanton posed to the group was about new modalities — cell and gene therapies, specifically — and the pressure to reduce their cost of goods (CoG). “Do you think we’ll see the high CoG and high prices that occurred with monoclonal antibodies (MAbs) in the 1980s replicated with cell and gene therapies today?”
Davies doesn’t think so. Personalized medicines require technology that’s flexible enough to purify a product dependably, but cost-effective enough to to do so reproducibly when each batch is for an individual patient.

Achenbach pointed to the issue of volume as a challenge for the industry. “When MAbs first started, manufacturers weren’t really focused on the quality of their products. If you look at the ingredients that were in some of the very first MAbs, they were the kind of ingredients you can buy off the Internet now. There wasn’t even a thought given to the quality of ingredients; it was all about the process. So I think that you’ll see something similar with gene therapies as their developers ask, ‘How do we make this real? How do we deal with this volume issue?’ And then they’ll start thinking, ‘Well, now how do we make sure this is cost-effective?’”

She believes there is room for of innovation in transportation issues related to cell and gene therapies. And Langer added that surveys of contract manufacturers for cell therapies and even cell therapy innovators themselves reveal that few of them have a plan for how to commercialize. Many assume that they can prove their technology in the clinic and that, once they have done so, investors will “come crawling out of the woodwork. . . . When we see the price that Paragon just captured, that’s an example of multipliers based on what gene therapy is likely to do. And when you have that kind of money, you’re going to be able to solve things like, ‘How can we purify cells that don’t like heat?’ I suspect that anybody involved in gene therapy right now is pretty excited.”