Gil Y. Roth
Oral delivery is still the Holy Grail for drug products, but plenty of new drugs (and many more in development) require injection. With so many large molecules like oligonucleotides and PEGylated versions of drugs in the pipeline, and so many smaller and virtual firms developing them, the market for parenteral outsourcing remains robust.
We spoke to a number of providers and sponsors about the market for contract production of parenteral drugs, and found a very healthy outlook. ?There?s rapid growth going on,? said Craig Mastenbaum, director for business development at HollisterStier Contract Manufacturing, a Spokane-WA based CMO. ?There are a lot of companies?both classic pharma and newer biotechs?that are doing a lot of research. Plenty of drugs are coming out of this research, and many will reach the clinic.?
We all know the stats out there on how many are discovered, how many hit the clinic, and how many end up commercialized; it?s a diminishing number as you climb the pyramid, but the sheer volume of new entities has been a boon for manufacturers. ?Demand is still extremely high, even with our (and the industry?s) higher capacity,? said Peter Hansbury, general manager, contract manufacturing services, for Bedford, OH-based Ben Venue Laboratories. ?We?re noticing a higher proportion of commercial contracts to clinicals; that?s definitely a change in the field. It looks like some of the early-stage work we?ve been doing is paying off with commercial approvals.? He added that the two key drivers for growth in the parenteral CMO market are demographics (?More people are getting older?) and getting access to drugs for Third World populations.
Another provider contended that Big Pharma has established itself as a serious client-base for parenteral CMOs, right alongside virtual Biopharmas. With the virtual companies, the impetus to outsource parenteral manufacturing is obvious: their capital is finite, their burn rates tend to be spectacular, and there?s no way they can commit the time and money to physical production facilities. But what about Big Pharma, with its access to massive amounts of capital, and its historic predilection for keeping this work in house? ?It?s only speculation, but I think that, as these companies get even larger, they?re finding it difficult to justify the investment for the sheer volume of clinical projects in development,? said one source. ?It?s a multi-million-dollar (and sometimes multi-hundred-million) investment, and some of the bigger companies are now finding it more judicious to outsource this part of production.?
?There?s definitely a mix,? said another. ?But more of the big guns are partnering with CMOs during the clinical phases, rather than going through the capital expenditure. I?m not sure how it carries through the rest of the outsourcing landscape, but there are particular aspects of aseptic processing that can be very expensive. Cleanroom space is very difficult to build, and it?s very costly.?
So, in a sense, risk-mitigation is a driver, even for Big Pharma. As a sponsor put it, ?In the early- to mid-?90s, I think companies were much more open to building, purchasing and/or expanding capacity. But with the number of clinical trials that fail, they were taking a big risk in doing that. Clinical-stage, virtual companies quickly realized that they had to look to CMOs rather than building out. In fact, even when they began to reach commercialization, some choose to stay with CMOs rather than go through the process of site transfer to bring something in house.?
One development for parenteral manufacturers has been the rollout of automated loading and unloading systems for lyophilizers. Lyo remains a major part of the parenteral manufacturing process, and some companies have found that these new loading systems offer a process advantage that they can pass on to customers.
DSM Pharmaceuticals has undertaken a major lyophilization expansion in its Greenville, NC site. The facility includes 3,700 sq. ft. of lyo capacity. Engineering manager Danny Rouse recently discussed the expansion with us, explaining the importance of the auto-load/unload features. ?When you?re talking about lyophilization, one of the most important things is getting the product in and out of the dryer with as little human intervention as possible,? said Mr. Rouse. ?To that end, the automatic system can provide an advantage.?
Traditionally, loading was a manual process: open the door, get materials in quickly, close it up so that frost doesn?t build up. One client we spoke to remarked the she?s seen manufacturers scraping frost from shelves, prior to loading. She welcomes the new automatic processes.
HollisterStier Contract Manufacturing has also deployed auto-load/unload with its new 200 sq. ft. commercial lyophilizer. Jeff Milligan, HS? vice president of technical operations, discussed the new technology: ?In our site, we implemented an internally designed method for cold shelf loading. We developed a special HVAC/HEPA system that reduces humidity and temperature, removing the frost buildup that can cause loading problems. This helps with products that are temperature-sensitive, of course. With suspensions, for example, it?s really important to keep material from settling. If you can get the product on the shelf and freeze it quickly, you don?t get that separation.?
Making a Difference
As with any business, differentiation from competitors is key to survival. For Burlington, MA-based Hyaluron, it has a built-in differentiator. ?When we started out in 2000,? said president Shawn D. Kinney, Ph.D., ?we were a manufacturer of hyaluronic acid, which is a very viscous biopolymer. We built our reputation on that, but then we started to get interest from customers who had other viscous polymers that they needed to get into syringes.?
From there, the company began branching out its contract manufacturing services. In 2003, Hyaluron was able to fill out 6,000 sq. ft. of cleanroom space with a pair of aseptic processing suites. Last year, the company moved into vial-filling, since the aseptic infrastructure was already in place, and it recently deployed an H3-5V vacuum syringe-filler from Inova that works completely air-free and is the first of its kind in the U.S. Hyaluron?s also at work on a commercial facility that will include lyophilization capacity.
?We?re capable of filling thinner solutions, but we?ll always have a specialty in high-viscosity products,? said Dr. Kinney. IIn fact, he contended, more viscous products are entering the market of late. ?One trend is in bioerodable systems that deliver drug molecules, as carriers for bone fragments and other suspended materials for injection. We see that as a marketplace that?s growing significantly, and there aren?t any other CMOs that are in this segment,? he remarked.
Other providers have less specialized niches, and have to develop other methods of differentiation. Mr. Milligan at HollisterStier said, ?It?s a clich?, but customer service and project management skills are really important in this field. Being receptive to the customer is critical.?
Mr. Hansbury commented that the CMO sometimes must help guide the client, or at least figure out exactly what the client?s need is. ?Occasionally, we all get customers who have a nebulous idea of what they want from a CMO. It?s our job to get them to understand what they?re asking for, which sometimes only becomes apparent over the course of the work. That?s why it?s critical for a good CMO to sell its experience,? he re-marked, adding, ?For that reason, one of our key rules is: never commit to a fixed price unless you know what it is.?
Ben Venue (a division of Boehringer-Ingelheim) recently received corporate approval for the fourth phase of its facility expansion, adding two high-speed tunnel fill lines and more lyo-capacity. The fifth phase will add two more lines, plus six dryers. In the longer term, the company is developing plans for a dedicated cytotoxin-handling facility. ?Cytotoxics are definitely a growing market, and a very underserved one,? said Mr. Hansbury.
Expand for Contracts
DSM Pharmaceuticals? Greenville site has seen a number of owners since its construction: BurroughsWellcome, GlaxoSmithKline, Catalytica, and now DSM Pharmaceuticals. Mr. Rouse contends that the prescience of the original design is paying dividends today, with competitive advantages. ?Construction was done in the early 1990s, before automatic loading and unloading systems became popular. This site was on the cutting edge when it was first designed, integrating clean-in-place and sterilize-in-place technology.? By de-signing and constructing in this manner, he contended, the site offered a complete product path, where CIP and SIP would be implemented from manufacturing through filling, including the dryers.
How different is a CMO facility compared to an in-house one? Mr. Rouse discussed the engineering of a DSM?s site. ?The engineering itself is the same as you?d find at a Big Pharma facility. You?ll see the same specifications and the same technology,? he remarked. ?It?s in the practical aspects that contract manufacturing sites have their biggest challenge.?
He continued, ?There are unique challenges that you likely won?t find in a dedicated, in-house facility. Sometimes, at a CMO, multiple clients want to own the product delivery system (PDS), the hard-pipe system that moves their product. In our case, that hard-pipe runs through two floors, so we set it up to install multiple PDSs, all of which are CIP/SIP.? He mentioned that the Green-ville site includes one area that features six PDSs on a single filling line, each keeping their product secure and within specifications. ?When you?re an aseptic CMO, you have to be flexible with processes,? he said. ?You have to be able to handle a wide range of products, and