Friday, July 31, 2009

Stronger, Smarter, and not Quite so Big

Pharmaceutical Solid Dose Manufacturing

By Neil Canavan

The current state of solid dose manufacturing is like a coming of age story — it’s all about growing up and learning how to let go. Big pharma is learning to let go of in- house manufacturing; single-owner development programs are learning to make room for partners; business models in place for years are being redefined to include new core competencies; and finally, when it comes to the manufacturing facilities, smaller is the new large.

“After having made a lot of noise about it over the last five years, you are finally starting to see large pharma getting rid of their manufacturing sites and outsource more,” said Terry Novak, Patheon’s president of North America, and global chief marketing officer. The change has taken this long to implement because, naturally enough, moving anything large takes time. In the case of big, entrenched pharmaceutical companies, there’s also the time needed to cautiously pare the part of one’s identity that just isn’t working out. “Large pharma has always had this thing about manufacturing being one of their core competencies. You know: R & D, sales, and manufacturing,” Mr. Novak added.

They always loved the idea of the one-stop shop. Coming to grips with the fact that the way you’ve defined yourself is now self-limiting is a fact slow to be realized, and it’s painful. Picture this: at some point the head of manufacturing of Blockbuster Pill, Inc. has to stand before the executive roundtable and willingly fall on his corporate sword, or, at the very least, try to defend a business proposition, and his part in it, that is increasingly untenable.

A big part of the problem is a pipeline dripping dry. “They’re not running their plants at the right utilization rates,” said Mr. Novak. Consider their master site plan say, five years out: Blockbuster Pill, Inc. is looking to replace assets that were going to be tail products, or go generic, with the next miracle innovation. That was the plan. “But now, they’re just not seeing what’s going in to that plant as the next generation product,” Mr. Novak remarked.

Mr. Novak, who was tenured at DSM Pharmaceuticals before moving to Patheon, has noticed that not only is more solid-dose outsourcing being sought by pharma, but that his current company has become part of the most recent pharmaceutical wave: the high-potency compound: “What I’ve seen particularly in the last year is an increase in requests for proposals for Category 3 compounds. These are products coming through the pipeline from the specialty pharma companies — the Shires, the Cephalons, Sepracors — the ones that have little if any manufacturing capacity. It’s an advantage for us because we have significant expertise in manufacturing high potent compounds.”

Also benefitting from this trend — and literal witness to the growing pains — is Don Potter, senior architect at Integrated Project Services (IPS). IPS is a full-service engineering, design, and construction company dedicated to the pharmaceutical industry; Mr. Potter does front-end design for these facilities. “A lot of the medications are moving to band four and five (highly toxic compounds),” he remarked. As you go up the bands there’s more possibility of bad things happening, like cross contamination to other products, or toxic exposure for employees. “So, cleanliness in general, and things like gowning in and gowning out of the facility into a specific processing suite becomes more stringent,” said Mr. Potter.

The pain in doing this comes from the squeeze. “A lot of people now are trying to put all the equipment in a single room, and the challenge is retrofitting that in an existing facility,” Mr. Potter explained. To begin with, non-high potency facilities are usually multistoried buildings. A typical process might have excipients and actives weighed out, put in bins and taken from one floor to the next, then charged through a chute down to a fluid bed dryer, or a granulator, and then perhaps to another level and charged down to a mill or another mixer. Going through floors like this is an open system, and it’s leaky. For toxic compounds you can’t afford to take that risk. “What people have started doing is moving things around in the IPC bins using lifts. So, if I have that bin of active and excipient, they can be charged in that bin, brought into another room and another hoist would charge the granulator, or the fluid bed dryer, and then after that process it comes out the bottom and then maybe is shot over to a mill — all in that same room,” said Mr. Potter. You’ve now eliminated all those transfer points where you can have cross-contamination.

Isolating the compound is one set of costs, and isolating the potential contaminator is another. In what Mr. Potter sees as a way to stay ahead of the industry regulators, new high-potency facilities are also including elaborate decontamination showers: “These showers run from $30,000 to $50,000. Some of them are using mist showers, and you come out of that an into a deluge.” It’s expensive and it all takes up more space, he pointed out, adding, “That’s the big challenge of it in an existing facility, and even in new facilities being planned. We’re still getting pressure from clients, like, ‘Why does it have to be so large?’”

Yet, there is some size differential with high-band facilities. The advent of very potent drugs means a small amount of API is used in the pill or capsule, whereas before, APIs were much larger volumes. “Volumes per batch is going down to some degree,” said Mr. Potter, “and that helps reduce the size of the footprint of a facility.” And surprisingly, now might be a good time to refit; costs for materials have come down drastically. “All commodities have come down — copper, dry wall, cement — it’s a great time to build if you have the money!”

Whether the facility is new or a retrofit, the powders passing through it may well have come from International Specialty Products (ISP), an excipient supplier to the pharmaceutical industry for more than 50 years. “The trend we’re seeing,” said Tim Bee, senior director of Pharmaceuticals at ISP, “is the big push in pharma to reduce costs. They are looking to improve production efficiency and one of the things that means is they’re doing a lot of off-shore manufacturing.” From this, the impact on ISP has been minimal, as they have 70 locations worldwide. However, the push to change — as well as the effort to better the odds of running a successful business — has encouraged Mr. Bee to keep improving the cards in his hand.

“We’re primarily known for supplying tablet binders and disintegrants, but three years ago we started supplying tablet coatings, and getting our coatings program established and off the ground is now our biggest concern.” ISP started by first offering immediate release coatings, and then enteric coatings — the basics. Then last fall at the industry meetings of CPhI, and AAPS, the company introduced a high solids, high heating system for high throughput, and continuous coatings. “We’re trying to improve the overall efficiency of the coating process. That’s a new development in the industry, and it’s something that’s being very well received by customers who’ve sampled it so far,” Mr. Bee contended.

The new product, the Advantia coating system, facilitates weight gain in the coating process. “A typical coatings solution might be 12-15% solid level,” Mr. Bee said, “but this new product is rated at 25%, so we can cut the coating time in half.“ Advantia can also be applied in high heat, allowing for the application of a sturdier coat on standard preparations, and overcoming adhesion issues often seen with more exotic formulations. The result is less peeling and chipping of the tablet surface, and thus, fewer quality defects and a faster throughput.

The remaining challenge for Mr. Bee is to get the industry to see ISP in a new light: “Providing coatings is both a product and a service-oriented business. Almost every coating formulation that goes on a tablet is custom formulated, so there’s a lot of back and forth.” It’s a different sort of business relationship than just selling ingredients, but Mr. Bee says he’s ready: “A number of companies have tried to get into coating systems and have not been successful, so we’re trying to do everything we can.”

For competition, he need look no further than Coating Place, Inc., which has been providing Wurster process, fluid bed coating services for 35 years. And for encouragement, he may want to talk to Coating Place’s vice president of sales and marketing, Fred Schulze. “There’s always been a lot of business to go around. Big operations are outsourcing more, and that means what we’re bringing in-house now is of higher quality than it used to be,” said Mr. Schulze. This, he says, is not to belittle the startups, which are the hope of the pharmaceutical future, but for now the older, branded companies have the will, and the money to pony up.

Which begs the question: if pharma has the money, why not purchase some of the highly available Wurster units for themselves? “Actually, installing the Wurster coating equipment is very expensive, on a square footage basis, and with big pharma trying to avoid capital expenditures it behooves them to come to people like us who are experts in the field. I mean, we have operators of the equipment that have been around 30 years.”

That sort of record may sound static, but one of the best features of the technology is its ability to adapt and evolve. “We’re constantly doing more work on controlling the parameters,” said Mr. Schulze. “The air temperature, the humidity of the air, solvent abatement. . . .” And an environmentally green component has even been added, an RTO system that’s clean burning, and recaptures most of the heat generated. “A lot of that heat we capture is used for makeup air, and when it’s 15 below — our operations are in Wisconsin, remember — you need to be able to prewarm the air coming into the unit so that you can actually hit your temperature targets.” And Coating Place is now pushing those temperatures to the extremes, using its recently FDA approved electronic data capturing system to track its progress.

Whereas Coating Place is content to play a role with powders, granules, and beads, Monosol RX is looking to break into film. Spun off from its parent company, Monosol, five years ago, Monosol Rx, is exclusively dedicated to the development and manufacture of thin film. “We operate in a couple different ways,” said John McCracken, senior vice president of business development. “We consider contract manufacturing opportunities, but really, we prefer to create value by developing a drug in film.” Mr. McCracken wants to leverage what he considers an underserved market by drawing off clients that might have gone the route of oral dissolving tablets (ODT).

The drawbacks of ODTs are many: “There’s chalking; when you push it through the foil it crumbles; particles stick in your teeth and in many cases you still have to take water…” With film, he noted, there’s no particulate, no problematic packaging, and, as Mr. McCracken put it, “it’s a much more elegant form.”

What distinguishes Monosol’s efforts is the “RX” part. There are companies enough that can manufacture thin film, but a scant few have FDA approval to incorporate prescription products. In fact, Monosol’s first prescription product, a thin film version of the antiemetic, ondansetron, is due to file in 1Q09. “We’ve seen a lot of interest in the approach,” said Mr. McCracken. “Generally, companies want to know more about it — they understand melts, and they understand delayed or controlled release, but many don’t realize the capabilities of thin film, quick dissolving, buccal, or sublingual delivery.”

The limitation here is the dose load: 100mg or less. “It’s unlikely anyone would be able to put more that 100mg on a thin film and have it be small enough where it will dissolve in your mouth.” The other issue is taste masking, a component that also takes up space.

As already stated, Mr. McCracken’s goal is to have a stake in product. While this is not a standard position for contract manufacturers, but those interviewed for this piece all acknowledge that the times they are a-changin’.

As cash dries up, negotiations may include a piece of the pie in place of the flat fee. In other words, to survive in today’s world of solid dose manufacture, it may be wise to remain fluid.

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