Производство твердых дозировок

Solid dosage may not be as sexy as some of the novel drug delivery forms of recent years, but they remain far and away the prevalent dosage form on the market. The contract manufacturing market for them continues to grow, spurred on partly by new, smaller entrants into the marketplace, product line extensions, and large Pharma companies' need to rethink their manufacturing platforms. We spoke with a number of solid dosage CMOs to find how they view the industry, the regulations, the technologies, and their plans for the future.

Steve Meeker, director of Bayer Pharmaceutical Manufac-turing Services, remarked, “I think there is a huge future for solid dose third-party manufacturers, particularly with ethical products. The trend in the 1980s and 1990s was toward huge solid dose manufacturing capabilities with many of the Big Pharma groups. The capability to make hundreds of thousands of solid dose tablets was everywhere because it met the needs of the market, ie, the market was using dosing theories that usually required the patient to take two or three tablets per day for a specific period or, in some cases, for a long period.

“Today, with more solid dose products being based on high active compounds, the typical dosing regimen for a patient is BID, or one tablet per day. Large Pharma companies are still tooled to make the huge batches, but with high active-based solid dose product, the manufacturing need is for smaller batches, based on flexible capabilities and flexible processes. This is where the third-party producers are aligning their processes.”

Bayer's outsourcing program, conducted out of the Bayer Healthcare facility in Shawnee, KS, has been handling third party manufacturing for approximately four years, and has decided to expand the operation and pursue marketing initiatives to grow that part of the business.

Where might this new business arise? “We're finding that in some cases it's from virtual companies, commercialization ones,” said Mr. Meeker. “I think it's a real trend for commercialization companies, which are looking at licensing activity and leveraging their core competencies—product identifications, chemical entity identification, and licensing and registry of the products—while leaving the manufacturing to the specialists in the industry. And so we're finding some success with those virtual companies.”

Key Drivers

One vendor contended, “There seems to be a lot more outsourcing of solid dose products than there was five years ago,” and offered up several reasons for the trend:

1. More out-licensing of mature or “non-core” products by large Pharma companies to specialty Pharma.

2. More specialty Pharma companies without in-house manufacturing are out there doing research, filling in the gaps of large Pharma companies.

3. Rise in and acceptance of generics to reduce healthcare costs. This increases the number of solid dose projects available for outsourcing.

4. Consolidation of large Pharma companies during the last decade; subsequent internal evaluations of manufacturing capacities have led to decisions to mothball older non-GMP compliant facilities. This leads to more opportunities for solid dose outsourcing.

5. The GMP issues that large Pharma companies face has forced outsourcing of core products from these facilities whether they want to or not.

Extending the Market

Another CMO added that the line extension phenomenon is benefiting his market. “The model for a lot of oral dosage drugs has carried over from large Pharma companies to the virtual guys, as they deal with lifecycle management,” said the vendor. “They start with an immediate release version of the product, and then, when the patent life runs short, they roll out line extensions of a controlled release solid dose form. That continues the longevity of the product, and creates plenty of opportunity for CMOs with the right expertise.”

“The whole market is maturing and offering a lot of variety for companies that are looking at line extensions,” said another.

Brand X

While the development of CR forms and other line extensions is seen as a boon, we had a tougher time getting a consensus on the impact of generics on the solid dosage field. While there are more generic products on the market, some CMOs contend that the market for them mirrors the world of branded drugs:

the large generic companies keep manufacturing in-house, while the smaller players are more likely to work with a CMO. “Big generic companies are predicated on two things:

their patent-busting divisions and their manufacturing practices. It's very tough for them to move a product out of house when they operate on such thin margins overall,” said one industry analyst.

That said, expertise in generic manufacturing can provide benefits for a CMO. To help develop its finished dosage manufacturing business, Glatt Pharmaceutical Services recently hired Bill Bundenthal, a former vice president of manufacturing from a generic company. Tom Salus, GPS' business development manager, commented on the benefits of that move: “Think about the number of SKUs that a generic firm has to manage; bringing someone in from that world gives us more expertise to manage multiple companies' products. Plus, Bill is somebody who's well-entrenched in a manufacturing environment, with 16 years of experience in generic drug manufacturing. Having that knowledge is invaluable.”

Similarly, Bob Calabro, vice president of sales and marketing at Norwich, NY-based OSG Norwich Pharmaceuticals, remarked, “Being a CMO gives you the advantage of getting exposed to many clients, all of whom have their own viewpoints about what a contract manufacturer should be.”

Money Talks

Most of the CMOs we spoke to are adding to their capabilities, a sure sign of their growth forecasts for the industry. Glatt Pharma-ceutical Services is in the midst of a $15 million investment to facilitate organic solvent-handling activities. “The expansion will increase our overall contract manufacturing capacities,” said Mr. Salus.

OSG Norwich is also investing in its future. Mr. Calabro said that the company has added the capability to handle liquids and semisolids in hard gel capsules, and is in the process of increasing wet granulation in fluid bed processing. OSG is putting a second fluid bed in at present, increasing capacity. The company also added a Fette tablet press in 2005.

Some of the vendors were spoke to are also adding to their filling capabilities as part of their overall solid dosage offerings. Atlanta-based Mikart, Inc. recently added a new blister packaging line. The company's vice president of sales and marketing, Blair Jones, remarked that the new line enables the company to offer coldformed or thermoformed blistering for its products. “For our customers, when we did physician samples, for example, we offered small bottles or laminated foil pouches, but much of the market has gravitated to the blister sample. In the past, we had to outsource blister packaging to a third party,” said Mr. Jones, “but the new line will let clients save a step down the process, and reduce the amount of coordination involved in a project.”

Bayer Pharmaceutical Manufacturing Services is also adding capacity and technology at its facility. The company has secured and is getting ready to deploy IMA Nova's Conta C200 high-speed electronic tablet and capsule counter. According to Mr. Meeker, the new system provides for 100% counting accuracy and less prep time for product change. “This is our high-speed, high changeover, more flexible line,” he commented. “With an electronic, slatless filler, it's very adaptable to different product sizes and shapes. There are no specific product-handling parts. I think it provides benefits by giving good count accuracy and a wide variety of tablet machining capabilities with little or no investment by the customer. In the old days, when everyone was using slat fillers, in third party situations, you would have almost $60,000 worth of slats on your bill. With the slatless fillers, we don't have an additional change part cost (unless the bottle is an obscure size or neck finish).” The C200 will be one of only three in operation in the US; according to Mr. Meeker, it will the only one handling primary product runs.

Down PAT

Most solid dosage CMOs we spoke to said that the FDA's Process Analytical Technology (PAT) initiative is still too early for any real results on their practices. While a few have reported that some customers have inquired about it, none have said that they've lost clients by not having a PAT program in place.

Said one CMO, “PAT is more of a movement that FDA is beginning to impose on the industry through recent guidance documents. Its proponents argue that this in-process testing—conducted while product is being produced—will reduce cycle times and improve product performance and compliance. It is a huge capital investment for anyone to undertake to install in-process equipment sensors, systems (and develop new SOPs!) and automated analytical equipment. Unless you are doing high volume processing, it will be a difficult investment for smaller volume companies to get a decent return on. It makes sense for Big Pharma's in-house operations, as well the Patheons, DSMs, Cardinals of the world, since they are processing hundreds of millions of tablets for a product or tens of thousands of liters of a semi-solid product. Having said that, it will eventually be mandated by FDA that we will have to do it—and we rue that day.”

Others seem less bitter. Said one manufacturer, “I think ultimately, PAT can lead to better product, more consistent product, and a product that comes at a reduced cost. The move to PAT by CMOs could be driven more by our own ROI than client demands.”

This sentiment was mirrored by a vendor of sensor equipment, who expressed surprise that CMOs were a bigger share of her market than the major Pharma companies. “It seemed completely backwards to me, until I realized that the CMOs are under greater price pressure than the drug companies, and that they would see PAT as a more immediate return on investment, for improving product and reducing cost.”

Mr. Calabro said that his company is pursuing PAT even though demand has yet to arise. “We haven't had clients come in and ask about PAT specifically, but as a company that considers itself progressive and state-of-the-art, we're working on a PAT initiative.”

Supply & Regulatory Demands

As with every other aspect of the Pharma industry, regulatory pressures are the top concern for CMOs. One commented,

“If you look back at the recent history of supply problems for drug companies, keeping product in the supply chain, the #1 reason. It's not hurricanes, floods, labor strikes or truck accidents. It's regulatory. Ask Schering, Abbott, Lilly, Merck, and all the others that have had FDA interventions cripple a product's supply. If the FDA comes in and says you can't make product in a facility, you're in trouble.”

So are some major Pharma companies outsourcing manufacturing out of necessity (that is, warnings and consent decrees), rather than choice? “Let's put it this way: I don't think we'd see some of the major deals that have gone down recently if large Pharma companies were operating with plenty of capacity,” said one CMO.

Mr. Calabro believes that this pressure can be turned into a positive force. “Maintaining a state-of-the-art presence from a regulatory standpoint is our big challenge,” he said. “The thing to remember is: when anyone mentions GMPs, they are actually talking about CGMPs, and that 'Current' is the operating term. Standards are being raised all the time. We see that as an opportunity. When clients walk in and say, 'We see you operating at X, and we want to see you at X+1,' we take it as a challenge, and it drives us to be a better company.”