Stretching for the Trifecta Innovative Strategies for Speeding Development, Lowering Costs, and Enhancing Quality

On Tuesday 16 June 2015, at noon on the BioProcess Theater stage at BIO 2015, Tom Ransohoff (vice president and principal consultant at BioProcess Technology Consultants, Inc.) will moderate a roundtable discussion with the following panelists:

The world of biomanufacturing is more dynamic than ever: Witness the rise of biosimilars, the return of vaccines, and the emergence of new types of products. Meanwhile, process improvements march on, producing higher upstream titers and greater downstream efficiencies. The overall goal remains the same: faster product development at lower cost with better quality. This panel will review emerging strategies for achieving that goal in a competitive global environment. Participants will focus on process intensification (e.g., continuous processing, real-time release, and integrating single-use components).

The Moderator Speaks

BPI’s online editor, Leah Rosin, spoke with Ransohoff in March 2015.

Can you tell us about the panelists you might be inviting to the BIO Theater? “We are excited to have an array of panelists who focus on technologies and approaches that will lead to more intensified processes for developing and producing biopharmaceuticals. Mark Brower is doing a lot of interesting work in the area of continuous processing and other novel process technologies. Parrish Galliher is the founder of Xcellerex, a major force in the implementation of single-use technologies. And Joanne Beck has been involved in a number of areas related to process and analytical development and is recently focusing on the topic of real-time release.”

Can you tell us more about your topic of discussion? “It’s on process intensification. We’ll focus on manufacturing strategies to produce products more quickly and more cost effectively. Anyone developing a biologic product or looking to improve manufacturing efficiencies should come to this panel. Mark, Parrish, Joanne, and Lynne are all experts in the field, so you’ll get some good insights.

Speed, low cost, and high-quality challenges the old engineer’s rule of thumb that you can have two out of three, but never all three. “You’re right. To a certain extent, that rule of thumb still applies. We are always forced to make trade-offs. But we would like to expand our thinking and our tool set so that we can move closer to the ideal of having all three. That’s the intent of the topics we’ll be discussing at the panel. How can we do high-quality work more cost effectively and more quickly to support the more rapid development and more flexible manufacturing of biopharmaceuticals demanded by our pharmaceutical and biopharmaceutical companies these days?”

What do you consider to be the most challenging aspect to each part of the trifecta? “That’s a great question. In the quality area, we are learning more and more about our molecules as we move to a quality-by-design (QbD) mind-set. So we need to bring more analytical and characterization horsepower to our processes — and do that in a more cost-effective and time-effective way.

“Bioprocess development is moving more and more toward platform approaches, particularly for monoclonal antibodies (MAbs). Yet there are still unique challenges for each molecule. How we manage those and how we manage the manufacturing processes around them is also a challenge.”

What recent technological developments have made it possible for companies to speed things up, to lower costs, and to improve biotherapeutic quality? “A number of technology developments have been helping companies in these areas over the past decade, and we see that continuing through the next decade. These include the advent and increased use of single-use technologies across the process flow stream and emerging interest in continuous processing and other technologies to intensify manufacturing processes. Process intensification means doing more with less capital and in a shorter time. Finally, some incredible advancements in analytical methodology allow us to more completely and rapidly characterize our products. At the end of the day, that may lead to enough confidence in our products and processes to move toward the ideal of real-time release, which would provide a huge time savings for the industry.

What developments have shown promise that didn’t pan out? “There are many, and we tend not to focus on those too much. I think the industry has a very good way of evaluating technologies and implementing them. It’s a staged approach that allows those that are both good ideas and have potential to make a meaningful impact to be implemented in a way that doesn’t compromise the safety and effectiveness of our products. Although it is a little frustrating and takes time, the industry has improved in identifying, evaluating, and eventually selecting new technologies to use in biomanufacturing processes. •

Managing the Contract Relationship

On Wednesday 17 June 2015, at noon on the BioProcess Theater stage at BIO 2015, Patti Seymour (senior consultant at BioProcess Technology Consultants, Inc.) will moderate a roundtable discussion with the following panelists:

Seymour will lead them in discussing the contracting process for developing and manufacturing biopharmaceuticals and how both sides need to come to mutual agreement. The panel will address expectations of both clients and contract manufacturing organizations (CMOs). How does each party manage risk, e.g., related to intellectual property (IP), failed batches, time lines, cost, and scope creep? Some case studies in contract negotiations will illustrate approaches and outcomes.

The Moderator Speaks

BPI’s online editor, Leah Rosin, spoke with Seymour in March 2015.

Can you tell me a little bit more about your panelists? ”We’ve put together a really top-notch group of people. First will be Steve Taylor from Fujifilm Diosynth Biotechnologies. He’s been part of that commercial group for a very long time. He’s an extremely experienced executive in contract manufacturing. So he’ll represent the contract manufacturing perspective of the panel.

“Next we’ll have Justin Skobel with Aduro Biotech in Berkeley, CA. He’s also very knowledgeable about outsourcing. Aduro is developing some pretty exciting, cutting-edge technology in cell therapy. Finding the appropriate contract manufacturers to work with has been quite a challenge for that company over the past several years. Identifying cell-therapy–competent CMOs and working with them continues to be quite an effort because of the novelty of the technology. Aduro has disclosed exciting clinical data publicly and is trying to move as quickly as possible into phase 3.

“Tom Douville is with Kolltan Pharmaceuticals, another exciting company. It’s based in New Haven, CT, having emerged with a technology that was developed at Yale. Kolltan focuses on a pipeline of monoclonal antibodies (MAbs) targeting oncology indications. It is outsourcing many different aspects of the supply chain and dealing with its own challenges.

“Antibodies are fairly straightforward compared with cell therapies. So I thought it would be a nice contrast to present those different types of technologies and talk about the different challenges that they face when it comes to outsourcing.

“And Lily Vakili will provide a legal perspective of negotiations. She has a wealth of experience negotiating supply chain contracts across multiple product platforms and stages of development.”

How important is a quality agreement to setting expectations in an outsourcing relationship? What other documents are helpful? “Well, before you get to the quality agreements, you have to put together a reasonable master services agreement or some kind of contract that represents the appropriate interests of both parties. You can begin with a miniature version of that document, the equivalent of a letter of intent. That would not cover most good manufacturing practice (GMP) activities, but it would allow both parties to get started sooner rather than later. Speed is always a big concern for small companies and others that want to move quickly. So getting those in place first is important.

“Then the quality agreement has to follow and be in place before any GMP activities happen. This is pretty much a global requirement now. Regardless whether you are going into Europe or not, almost all US and companies based outside Europe use quality agreements. They need to be in place especially if you are starting at the very beginning and making master or working cell banks because those are going to be done under GMP. Even though you may have a few months of process development to do before you get into GMP activities, you need to have quality agreements in place to start cell banking.

“That absolutely helps set expectations: simple things such as describing what documentation will be provided as part of batch release. Sometimes it can be a surprise when a team is reluctant to provide certain pieces of information or certain documentation that was never explicitly called out for in the beginning of a relationship. Typically I put those types of requirements in a quality agreement to prevent misunderstandings. ‘The customer will receive full batch records. The customer will receive copies of raw data,’ and so on.

“We also need to set expectations around who is doing what. For example, how will specifications be set? Generally that has to be a mutual process. It can’t just be customers dictating what the specs should be. The process has to be capable of meeting those specs, and if a CMO is developing the process, then it will need to have some input into how those specs are set.

“Also, you want to make sure that the methodology is sensitive enough and appropriate to measure down to the levels at which a specification is set. It is important to have mutual input into things like that. Such information is generally (or can be and should be) captured in a quality agreement.”

What are some common IP risks involved in contract manufacturing on both sides? “That’s a great question, and it’s often very heavily negotiated. I’m happy to say that over the years, I’ve seen this area move to a point of mutual understanding regarding what is important to both sides. Many years ago, CMOs used to fight tooth and nail to control or own intellectual property (IP) developed as part of the services that they provided. Of course, customers would fight to own anything that came out of the work they paid CMOs to do. It seemed like they were diametrically opposed about who should own it.

“In fact, what I’ve seen happen is that people finally started asking, ‘Well, what is important here?’ It’s not important for a CMO to own IP and prevent customers from using it, but it is important for CMOs to build on experience and knowledge that they gain in doing the work. For example, they learn how to run a certain chromatography step or something similar that could be applied fairly generically to other clients’ work. That helps them improve the way they do business, and it doesn’t necessarily do any damage to the first customer. But that client also wants the flexibility and freedom to take a process and move it if necessary. I’ve seen that kind of language really evolve to be reasonable and fair.

“Many times when I’ve read contracts — certainly in the past year — I haven’t had to make too many strongly worded edits in those sections because I think that CMOs have finally gotten the message. Customers (at least the ones we work with) are accepting that approach as well because it doesn’t bind them or prevent them from developing their product further.

“As for areas where IP comes into play, certainly expression technologies are probably one of the biggest. They are covered a lot more extensively with true licensing terms and milestones and royalties. That’s very significant to IP negotiations. Then you get into things like media development and feeding strategies, some types of processes that are unique adaptations. Those things don’t necessarily rise to the level of requiring milestone payments or royalties, but they do require some framework to make sure that, for one thing, a CMO can apply the same tool kit to future projects. But also, the customer needs the flexibility of using that technology elsewhere with no or minimal strings attached (e.g., if it chooses to bring a process in-house, go to another CMO, or work with a partner).”

Could you define scope creep in this context? “In some cases, if you haven’t thought out ahead of time what you need to do, then you will end up constantly creating change orders. You’ll say, ‘Let’s go after this interesting phenomenon and explore it more,’ and then it expands your scope and adds time and cost. That’s not necessarily what a customer or even a CMO wants. The latter will have some predicted time lines describing how quickly a project needs to move through both process development and manufacturing areas to meet overall client project needs.

“One of the things I strongly recommend to prevent scope creep is to have a well-defined request-for-proposal in the beginning. That means really thinking through what a project needs at its current stage of clinical and process development. Sponsors should work closely with their CMOs to ensure that such a proposal is sufficiently detailed so that it makes very clear what is included in the project — down to (for example) the number of small-scale bioreactor repetitions in early development.

“For example, here are some questions that come up with chromatography processes: How many different types of media will be screened if you’re scouting for resins? With each resin, how many variations will be evaluated? The CMO doesn’t necessarily have to be finely detailed at the proposal stage, but it should include enough information to help the client to make informed decisions about a CMO’s value proposition. Once you get into process development, all of those things need to be very clearly defined. Both parties need to understand what level of effort will be needed and what amount of data can be expected from that experimental plan.

“Those are the types of things for which, if you plan ahead, you can reduce the potential for scope creep later on.”

What is the most often misaligned expectation on each side of a biopharmaceutical outsourcing arrangement? “Everybody wants to have products that are usable for their intended purpose, whether that’s preclinical R&D material or clinical material. And you also need the data package that goes with it.

“One expectation that isn’t always met is the amount of data or information that is provided. I’m very sensitive now when I see in a proposal or other document that ‘a summary will be provided.’ I immediately strike that and say, ‘No, a detailed report will be provided,’ or something like that. It must be very clear that the deliverable will include raw data, a complete analysis of what was done, and interpretation.

“Most customers don’t just engage CMOs as a pair of hands; they engage these companies to bring their brains to work, as well. We want CMOs to help interpret or at least give their expert opinion on our results because, in many cases, that is development. We often encounter results that are unexpected or difficult to interpret, so we really appreciate a CMO’s input. It’s very frustrating when the people doing the work come back with a data dump and don’t provide any interpretation or even their opinions. It doesn’t necessarily mean that the customer has to agree with those opinions, but they do provide greater perspective. Ultimately, it is the customer’s responsibility to explore results and make sure to understand them. Receiving as many inputs as possible certainly will help along those lines.

“It goes back to setting expectations, defining deliverables and how much information should be included — and also making sure that when a customer receives a deliverable that the project team will actually review it carefully upon receipt. If several weeks go by before they come back with a page full of questions, it can be difficult for the CMO to reengage that part of the process quickly and provide all the necessary information. It is working quickly and have already moved on to the next phase. We need to keep things moving quickly in real time so that people don’t have to spend a lot of effort digging through things or trying to reconstruct them. It is very important for both sides to ensure that they get the highest quality information and deliverables in the end. •