The biotechnology industry has from the start been characterized by its dependence on innovation. New therapeutics, new indications, new technologies — and the continual drive toward new approaches for optimizing processes — all contribute to getting novel products to the market (and to patients) efficiently and cost-effectively.

Most of the technical literature reports on development processes for the therapeutic products themselves. But one element largely ignored forms an essential foundation to the work of the biotechnology industry: How are products developed for use by those manufacturers? Beyond a company’s proprietary product/molecule are the various equipment types and “ingredients” — columns, resins, and other raw materials, single-use bags and fittings, and commercially available platform technologies. Such products do not come about by chance but from various suppliers’ responses to market needs and their own decisions to develop, manufacture, and commercialize them. How do those companies decide what projects to pursue?

This topic was brought to our attention by Al Jackewitz, biopurification market manager for Tosoh Bioscience LLC, who offered to share with us how new product development is done at his company. Beyond general interest in learning about yet another part of the biotechnology industry puzzle and without venturing into the company’s proprietary activities and plans, general knowledge of how suppliers have chosen to develop familiar products and materials may also give readers some tips for making similar needs known.

The approaches described here are specific to Tosoh Corporation of Japan. The hope is that following this article, other companies might be interested in sharing with us their perspectives and philosophies behind methods for new product development.

Identifying a Need

I began by asking Jackewitz how new product development is performed at Tosoh Bioscience in Japan. He explained that “basically, the whole process starts with identification of a need, which can be one of two types. It can be either a market-driven need or it can be a customer-driven need.”

A market-driven development product is determined by members of Tosoh’s global sales and marketing groups as they attend various industry meetings and conferences. Every so often they see an emerging theme that helps them focus on a type of new product to develop for the market. “For example,” Jackewitz explains, “I might go to a conference and hear a speaker at a roundtable discussion say, ‘We really need to reduce our pool volumes because our plant footprint is cast in stone now. And although using higher capacity resins can improve throughput, they can also increase the elution pool volume and any process improvement must be made within the givens and the confines of our existing structure or tankage.’ So if Tosoh develops such a product for that particular industry need, it becomes a market-driven product available eventually to all customers.”

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By contrast, there may be a specific customer need. “There are many different target proteins, and other types of molecules being expressed or synthesized that in some cases don’t have an adequate method of purification available to them. And a customer may find when he goes to do his purification that he’s got something that kind of works but it doesn’t really work efficiently for him.”

The outcome of a customer-driven request is a product available just to that customer. In general both types of requests are channeled into what Jackewitz describes as the “fuzzy front end” of Tosoh’s new product development through a form called the experimental product inquiry form (EPIF).

Beginning a TRIP

The program Jackewitz describes is referred to as TRIP, the “Tosoh Resin Innovation Program.” It begins with the EPIF. The form is the first part of a system to get a market- or product-driven request to the product development group. “One of the precursors of all of this is that the customer has tried our existing commercial resin product offering, and that there are data from those experiments that they can share at the start of TRIP, so that in addition to telling us, ‘It kind of worked, but it isn’t exactly what we want’ or that ‘it didn’t work at all,’ and so on, we can actually see what they are talking about from the traces.”

The form itself is a fairly simple way to get started, but it does need some qualifying information entered for Tosoh — given that few companies have open-ended pocketbooks for research and development. Tosoh wants to focus its efforts on products that its customers will take to the clinic, and for which their marketing groups and companies have decided to put on a fast track.

Jackewitz adds, “We understand that going to the clinic doesn’t necessarily mean that a product is going to be commercial because we know that only one out of every five products gets through clinical trials. So 80% don’t make it. But realistically we know that if a customer’s business group has made a decision to go to the clinical trials with a now-highly prioritized product as one of X number that they do on an annual basis, and that they may need a resin that’s a little bit different from what is commercially available, we’re willing to work with them to try to help”

Through the form and conversations with Tosoh, a potential customer defines the level of manufacturing volume of the final resin it will need if the therapeutic survives clinical trials and also the general type of feedstock used to express the system. Is it improving on a monoclonal application, for example? Is it improving another therapeutic protein that’s E. coli expressed? Is it a yeast-expressed protein? What types of concentrations are expected? Is the customer looking for a capture step?

From this are developed inputs that help Tosoh to understand what sort of resin a customer needs and, more important, whether it is of a type that fits Tosoh’s existing technology. For market-driven products, this is a stage at which potential products are discussed for the company to schedule into its plans, whether now or in coming years.

Assessing the Potential

A regionally approved completed experimental product inquiry form is then submitted by the market manager to the Tosoh office in Japan. Jackewitz explains the next steps: “If Tosoh has questions they get back to us and we clarify things. And eventually they consider whether this would be a product that we can make with our existing platforms. Tosoh offers seven different pore diameters, and eight different particle sizes based on the same base bead polymerization chemistry. We have existing functionalization chemistries already on file with the FDA for these beads. Is it going to be something that’s just a modification of what we already do but with a different physical nature based on pore diameter and particle size? Or is it going to be something that we may need to make a new chemistry for? Do we need to create a new bead (which is an unusual request), or do we need to come up with new ligand attachment chemistry to get the performance that the customer or marketplace has requested? So it can be fascinating following the thought progressions of these types of opportunities.”

Then Tosoh looks at the request and at the provided multiyear volume estimates and approves or rejects the request.

He emphasized, however, that the company’s focus is on projects with solid commercial potential. “We try to discourage requests for basic research — we don’t normally make resins in 30-mL or 500-mL volumes because that’s just not something that’s a good payback for Tosoh’s time and effort. But if we have an industrial customer with a prioritized therapeutic entering the clinic, or a marketplace-driven product needed, typically the form is accepted. At this point it becomes necessary to talk about what kind of specs we want for this first sample set so that the development path can commence. So following this kind of fuzzy front end, Tosoh will prepare samples incorporating different physical parameters, maybe different levels of existing attachment chemistries, to come up with —maybe four or five different product variations or types for the end user(s) to evaluate.”

For a customer-driven product (which requires a confidentiality agreement), only the customer is sent the requested samples. It is then up to that customer to tell Tosoh which samples work best. If on the other hand it’s a market-driven product, Tosoh has confidentiality agreements in place with many major companies, which are offered the chance to evaluate the developing product.

Hurry Up and Wait

I asked about customer response times. Jackewitz explained that customers are “normally fairly anxious to get samples into their hands. But because of the customer’s corporate time imperatives and the clinical trial timeline path itself, in a number of cases by the time a customer receives the sample, the initial evaluation window may have passed. So there may be a delay before they get to a second resin screening window. So from our perspective we kind of run, run, run sometimes to make the samples and then we wait, wait, wait to find out what the people think.”

I asked whether Tosoh assigns one of its people to work with the client, who would then know why the delay was occurring. He replied that “For the TRIP process, I’m the window to a contact at Tosoh in Tokyo. So we talk very frequently about these things or at least exchange emails about these different opportunities. But where the rubber meets the road, where the sample interchanges are happening with the customers, typically our business development managers are all clued in to what’s going on. They have probably initiated the request for the particular account and individual customer and received the requisite okay from the National Sales Manager to pursue it. They interact collaboratively with the customer by, making sure the samples get there, getting the customer feedback, logging any updated information into our contact management system (CMS) so that we can then feed it back to Tosoh as the evaluation progresses.”

The process then becomes quite structured. Business development managers meet with process development people at the major accounts, with many of whom they have built long-standing business relationships.

Round Two

When the evaluations are returned, Tosoh evaluates customer input data. Did Tosoh hit the nail on the head the first time (“probably not,” says Jackewitz)? “If not,” he continues, “Why not? What happened? What worked best? What didn’t work? And so on. We take what was learned, and if certain samples showed promise then the second iteration of samples is produced by Tosoh.”

Although there are platform technologies for monoclonal antibodies, for other molecules there are still individual purification steps for which no such platforms exist. In many cases, people are working on unique molecules, so another issue faced by the Tosoh developers is finding a suitable surrogate with which to do its resin development

That prompted me to ask whether proprietary obstacles or conflict of interest issues arise during these initial assessments — particularly when working one-on-one with a customer. Jackewitz said normally a simple two-way agreement between Tosoh and the client is all that is needed.

However other specific situations involving streamlining communication lines or intellectual property rights can become somewhat more complex. For instance, if a customer is working with a contract manufacturer, Tosoh may initially end up with separate two-way agreements with the contract manufacturer and with their client.

“But, Jackewitz adds, “we’re not allowed to talk to either of them about what we know about the other. So a lot of the times you have to navigate through the initial separate agreements and arrive at a point where a three-way agreement is in place that then allows the discussion to occur with all parties.

“Also if somebody has a unique application for us — let’s say they need a new type of polymer bead and they want to make an affinity resin that has a particular epitope or a particular ligand on it for their target’s purification — then that obviously becomes something that is treated more rigorously.”

Global Integration

As vendors develop products for the industry, their approaches naturally are defined by their corporate philosophies and overall operating structures. One main difference between Tosoh’s approach to new product development and that of some other companies may be the degree of integration fostered from plant to plant, division to division — and from country to country. Each division is charged with watching the market needs in its region, and communication is actively fostered to ensure that priorities are clear across the whole company.

Jackewitz explains: “We’re a global organization, but we act regionally. Here at Tosoh Bioscience LLC we manage the needs of customers in the Americas. We have our European colleagues at Tosoh Bioscience GmbH in Stuttgart, Germany. And we have our Japanese Bioscience Division of Tosoh Corporation in Tokyo, our R&D and manufacturing in Nanyo, and our newly opened business unit, Tosoh (Shanghai) Co. Ltd., in China. We need to talk to each other frequently because our markets do differ. The North American market may be monoclonal antibody-centric. In Europe you may find that it’s blood fractionation centric, and in Asia you may find it’s now moving toward fermentation products, small molecules.”

Recognizing that there are needs for different new-product opportunities, all Tosoh locations are set up with video conferencing equipment. The groups get together electronically a few times a year. “During these meetings we exchange ideas and sometimes have very pleasant and surprising ‘AHA!’ moments like, ‘You know, I have a need for what you’re working on in Europe here in the United States,’ or ‘Do you see the applications we’re working on in your region?’ And at least once a year we get together as an international group, normally in Japan, to review business issues and go through and help prioritize Tosoh’s development pipeline for the next year.”

Jackewitz mentions that “sometimes we start these conversations and another group has a resin under development that we were just being made aware of. It’s been under development for maybe two months or three months for their application for it, but we’ll look at it and realize that it might work for some of things we’re seeing here. So the synergy that occurs and the expanding of the marketplace opportunities for a particular product comes out of that. It’s pretty slick.”

Fostering Communications: With his emphasis on corporate communication strategies, I asked Al how those habits and philosophies had evolved in his company. I wondered whether there had been a need to work through particular cultural difference in operations or whether things had been pretty well set up historically. The answer was that with retention rates being fairly high in the company, many of its employees have worked together for years and have therefore developed a comfortable sort of “universal language” for communications. Also, he says, “Tosoh pretty much sends people out on three- to five-year stints and they get rotated through a lot of different positions — primarily on the management and maybe senior technology level positions. They develop a perspective of what’s going on in the United States and Europe, and it’s been really interesting to see how that has developed with time.”

Commercializing the Product

Regardless whether a product is market driven or customer driven, at some point the vendor has enough information and enough iteration and feedback to know it wants to make that product. It thinks that all the parameters are identified, so the next step is to set lot-release criteria.

In the process that Jackewitz describes, this launches the Tosoh ISO commercialization process. “That means now we go back to the clients we have been working with and say, ‘Look, these are the specs we’re going to shoot for, and they seem reasonable.’ And if everyone is in agreement, then Tosoh starts making the resin in larger scale. Tosoh makes three manufacturing runs. The runs usually determine the lot release criteria and the resins produced come out of the ISO procedure as commercial material ready for sale. Once we meet the release criteria and create the C of A [certificate of analysis], then the product is officially commercialized.”

He reiterated that market decisions are pretty much made up front, from the information contained in the original EPIF. These include volume estimates, the application, and how many customers (if market-driven). “So once it gets into the system it’s already decided that if we can come up with the right product, we’re going to commercialize it.”

I asked him to explain what constitutes the rate-determining step in the TRIP and EPIF process. He referred back to the need for a customer to evaluate the samples and the inevitable delay when confronting customer timelines and staffing limitations. “We send the samples, and then they sometimes just sit there for a period of time before the actual evaluations are made. So while that’s happening, Tosoh moves on to other projects. The rate-determining element for us is getting the information — getting the evaluation information back from the customers, so we know what happened.”

Although customer-driven products are confidential, I asked whether he could give me some examples of market-driven products developed using this TRIP system. He said that “the Toyopearl GigaCap resin products were requested five to seven years ago and are a direct outcome of the TRIP process. The resins were initially requested on an EPIF as market-driven products for MAb purification and were subsequently reviewed at the annual global business meeting in Japan. Tosoh had up until then been known more for its hydrophobic interaction resins than for its ion-exchangers. The materials required a new ligand attachment chemistry to be innovated by Tosoh. So intensive development was required. And in the chemistries that they developed, not only did they develop the high capacity resin, but also a resin that has better mass transfer for larger proteins like monoclonals.”

Jackewitz explained that “typically, Tosoh will do this in the R&D group first before it goes to the development group for manufacturing. So the R&D lab worked on the chemistries and presented things at conferences and with different posters and got a feel for whether they were on the right track or not. And probably about three years ago, the request was formally put into the ISO commercialization procedure for not just one product, but three different resins. Starting in mid 2007 we’ve been introducing these resins, one every four months or so. So you could say that they were in development about three or four years.”

Due Diligence

I commented on the importance of due diligence, and Al agreed. “With the Toyopearl GigaCap resins we had to identify what the market was, make estimates, really drill down into some of the annual reports from other companies to find out what volumes were. So we could then look at the business side of this and determine which products to devote major resources towards — to ensure we did it right the first time. And we have to understand the customer information requirements for these new materials to satisfy their regulatory needs, particularly if they’re based on a different chemistry where the customers look at them and ask for the regulatory support package. Where’s the information on base stability for CIP? What are the extractables and methods of analysis? How about shelf life? Neither we nor our customers want surprises!”