Outsourcing Solid Dosage Manufacturing

The outlook for outsourcing of solid-dosage manufacturing is encouraging. Contract manufacturers point to increased outsourcing resulting from moderate growth in global pharmaceutical sales, internal manufacturing rationalization by large pharmaceutical companies, and continued growth from virtual pharmaceutical companies. Several contract players are expanding capacity. And, producers note opportunities in formulations involving high-potency actives and fast-melt technology.

Solid-dosage forms represent an established sector in the secondary manufacturing market. Annual global expenditures for commercial pharmaceutical manufacturing for finished-dosage forms is estimated at $83 billion, of which between $8–12 billion is outsourced, according to industry estimates offered by Patheon, Inc. (Mississauga, ON, Canada, www.patheon.com) in its 2005 annual report. Roughly $3 billion is spent on dosage-form development, of which roughly $1 billion is outsourced.

Industry fundamentals are positive

Industry players point to several drivers in outsourcing secondary manufacturing. "Pharmaceutical sales continue to grow," outlines Doug Ludwig, Patheon's executive vice-president and chief financial officer, who spoke at a recent investors' conference in late April. He points to IMS Health's (Fairfield, CT, www.imshealth.com) projected five-year compound annual growth rate of 5–8% for the global pharmaceutical market.

Moreover, "a major trend in the solid-dosage market is the number of large pharmaceutical companies looking to outsource their solid-dosage products as a result of rationalizing their own facilities," observes Terry Novak, business director at DSM Pharmaceuticals, Inc. (Parsippany, NJ, www.dsm.com).

This trend is evident by recent high-profile restructuring initiatives such as by Merck & Co., Inc. (Whitehouse Station, NJ, www.merck.com) and Pfizer, Inc. (New York, NY, www.pfizer.com) that include rationalization of manufacturing facilities. Under its new supply strategy, Merck plans to sell or close five manufacturing sites and two preclinical sites by the end of 2008 and eliminate roughly 7000 positions company wide, as outlined in its 2005 annual report. Pfizer is implementing its "Adapting to Scale Initiative," a multiyear productivity initiative that involves rationalization of manufacturing facilities, according to its 2005 financial report.

A coating system based on cellulosic polymers for immediate-release applications ("Advantia" Prime Coating System, International Specialty Products, Wayne, NJ) is being sprayed on placebo tablets in a "Compu-Lab" perforated-pan tablet coater from Thomas Engineering Inc. (International Specialty Products)

As part of Merck's new supply strategy, Patheon in January entered into a five-year master supply agreement with Merck. The pact includes two late-stage development projects at Patheon's facilities in Caguas, Puerto Rico and Cincinnati, Ohio, and an early-stage project at Mississauga, ON, Canada. Two of the three projects are for solid-dosage forms, explains Nick DiPietro, president and chief operating officer at Patheon.

Others see opportunities from emerging pharmaceutical companies. "In general, outsourcing by the large pharmaceutical companies has stayed fairly stable," notes Bob Calabro, vice-president of marketing and sales at OSG Norwich Pharmaceuticals, Inc. (Norwich, NY, www.norwichpharma.com). "We have seen growth in projects from virtual pharmaceutical companies."

Contract manufacturers expand

Reflecting increased demand for outsourcing, several contract players are expanding or recently expanded solid-dosage manufacturing capabilities.

Cardinal Health, Inc. (Dublin, OH, www.cardinal.com) is in the process of expanding its solid-dosage manufacturing facility in Winchester, Kentucky by adding four additional processing suites. The suites, scheduled for completion in July 2006, provide additional capacity for tablet coating using perforated pans and laser-drilling of tablets. Cardinal's facility in Winchester makes 15–500-kg batch-scales of bulk granulations, tablets, and capsules.

In 2006, DSM added an additional capsule-manufacturing suite at its solid-dosage manufacturing facility in Greenville, North Carolina to handle demand from a new customer. DSM also completed a major investment to debottleneck its solid-dose manufacturing facilities.

On the technology front, DSM developed a tablet using a multilayered coating process in which one active pharmaceutical ingredient (API) was in the tablet and the other in the coating. The product is currently under review by the US Food and Drug Administration.

"This product was an example of using a multilayered coating process to resolve the issue of having two incompatible actives in the same tablet," explains Novak. "We seal-coat, then apply the other active, and seal-coat again. We used process analytical technologies to overcome problems encountered with the end-point."

Glatt Pharmaceutical Services (Ramsey, NJ, www.glattpharmaeuticals.com) is in the midst of a significant investment to expand its facilities in Ramsey, New Jersey.

"The investment builds our capabilities in pelletized or beaded technologies for controlled-release solid dosage forms in both contract manufacturing and research and development," says Tom Salus, director of business development at Glatt Pharmaceutical Services. Glatt is adding capacity through the addition of several new fluid beds, high-shearing granulators, and blending equipment through the pharmaceutical equipment business of the Glatt Group. The expansion involves equipment and engineering design to facilitate organic solvent-handling and Glatt's "CPS" technology. It also is adding tablet and encapsulating capacity. The expansion, which began in the second half of 2005, is scheduled to be completed in the fourth quarter 2006.

OSG Norwich Pharmaceuticals is building a manufacturing suite at its facility in Norwich, New York to house a second fluid-bed process system (Aeromatic S-6, Niro, Inc., Columbia, MD www.niroinc.com) for wet granulation. The expansion, which doubles the company's fluid-bed processing capacity, is scheduled to come on-line in 2007.

Norwich also is expanding and upgrading its analytical, microbiological, and stability laboratories. The first phase of the multimillion-dollar project will be complete in the third quarter 2006. Norwich will use a leap-frog approach to complete the expansion and upgrade, so it can continue to meet its clients' ongoing requirements.

In 2005 Norwich invested $4 million to expand its facilities, which included $2.5 million for three major projects. The first project was the addition of a new tablet press ("Fette 2200," Wilhelm Fette GmbH, Schwarzenbek, Germany, www.fette.de).

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Norwich also added a new "Bosch GKF 1400 L" commercial-scale encapsulation machine (Bosch Group, Stuggart, Germany, www.bosch.com) for filling liquids or semisolids into hard-shell capsules. It also added a low-humidity (17-20% humidity) manufacturing suite.

Bayer Pharmaceutical Manufacturing Services (Shawnee, KS, www.bayerpharmamfgservices.com) plans to bring on-line a new high-speed electronic tablet and capsule counter ("IMA Nova Conta C200," IMA Nova, Leominster, MA, www.imanova.com) at its facility in Shawnee, Kansas. Manufacturing and testing of the filler is currently ongoing, and the filler should be installed on-line by July 2006. This filler will complement other process and packaging equipment, including sterile liquids manufacturing, housed in Bayer's central campus in which the company has invested more than $150 million since 1996.

Mikart (Atlanta, GA, www.mikart.com) recently added a new blister packaging line as part of its solid-dosage capabilities, notes Blair Jones, vice-president of sales and marketing. The new line allows the company to offer coldformed and thermoformed blistering for its customers' products.

Patheon is investing $5–7 million to upgrade its capabilities for high-potency manufacturing and liquid-fill hard-capsules at its facilities in Manati, Puerto Rico. The enhancements are expected to come on-line in late 2006. Patheon acquired the Manati site and facilities in Caguas and Carolina, Puerto Rico in 2004 with the acquisition of Mova Pharmaceutical Corporation, a contract manufacturer of solid, liquid, sterile-liquid dosage forms and solid-oral cephalosporins.

"In solid-dosage manufacturing, we see two key trends," explains Colin Minchom, Patheon's vice-president of pharmaceutical development services, Canada. "One is toward lower dose, high-potency formulations, and the second is demand for formulations for poorly soluble drugs. Our addition of capabilities for high-potency actives and liquid-fill hard capsules address both of these needs."

Patheon is investing $7 million to add high-potency manufacturing capabilities (solid-dosage product forms) at its facilities in Bourgoin-Jallieu, France. The expansion is underway and is expected to be completed by the end of 2007.

Patheon is evaluating adding clinical packaging capabilities (primarily for solid-dosage forms) at its sites in Canada and Puerto Rico. It further is evaluating establishing a pharmaceutical development services center for all dosage-product forms in India.

Part of Patheon's manufacturing strategy includes increasing capacity utilization for its Puerto Rican facilities, which it is addressing in part by adding capabilities for high-potency formulations and liquid-fill capabilities. It also is validating these sites to augment existing capacities in Canada and as second supply sites for products from its Toronto-based facilities.

High-potency actives on the rise

Other producers point to opportunities in specialized formulations. "The biggest single recent trend in outsourcing solid-dosage processing has been the movement toward discovery and synthesis of more potent APIs," says Michael Valazza, vice-president of business development, oral technologies for the Pharmaceutical Technologies & Services business at Cardinal Health.

"As recently as two or three years ago, most potent oral solids being presented to us for consideration were cytotoxic," says Valazza. "Since that time, we have seen a significant rise in the number of noncytotoxic compounds with occupational exposure limits of less than 10 mcg/m³ to the point where more than a third of the oral solid-dosage processing opportunities that we have considered in 2006 are potent," he says.

In February, Cardinal's Pharmaceutical Center in Somerset, New Jersey began operations in a newly expanded pilot-plant that is capable of handling potent oral solid compounds in batch sizes as large as 75 kg.

Fast-melt technology advances

Orally disintegrating tablets (ODTs) is another sector gaining momentum. "Another key trend is the increasing number of products being developed and commercialized using fast-melt technology," says DSM's Novak.

The global ODT market (based on ex-factory sales to wholesalers) was $2.4 billion in 2004 and is expected to reach $3 billion in 2006, estimates the consultancy Technology Catalysts International (Falls Church, VA, www.technology-catalysts.com). The technology is important in patient groups that may have difficulty swallowing conventional oral medications such as geriatric and pediatric patients or in the administration of certain central nervous systems drugs.

In March, Johnson & Johnson (New Brunswick, NJ, www.jnj.com) released two additional dosages (3 and 4 mg) of "Risperdal M-Tab" (risperidone), a fast-dissolving form of the antipsychotic mediation "Risperdal." Other examples of ODT formulations are Eli Lilly and Company's (Indianapolis, IN, www.lilly.com) "Zyprexa Zydis," an orally disintegrating formulation of olanzapine, an antipsychotic drug and Schering-Plough Corporation's (Kenilworth, NJ, www.schering-plough.com) "Clarinex RediTabs," a fast-dissolving formulation of the antihistamine desloratadine.

Cephalon, Inc. (Frazer, PA, www.cephalon.com) is increasing capacity at it facility at Nevers, France for products using its "Lyoc" technology, an ODT platform using freeze-drying methods. Cephalon manufactures several drugs in France using the Lyoc technology, including "Spasfon Lyoc" (phloroglucinol), "Paralyoc" (paracetamol), "Proxalyoc" (piroxicam), and "Loperamide Lyoc" (loperamide).

Cephalon strengthened its position in ODT with the 2004 acquisition of Cima Labs, netting two technology platforms: "OraSolv," which uses lower levels of compaction pressure, and "DuraSolv," which uses higher compaction forces in the tableting process.

The specialty pharmaceutical firm Eurand Inc. (Milan, Italy, www.eurand.com) expects to complete its development program for its ODT formulation of cetirizine, the active ingredient in Pfizer's antihistamine "Zyrtec" by the end of 2006 and will then pursue regulatory submissions. The formulation is based on Eurand's "AdvaTab" ODT technology that uses an external lubrication system.

Antares Pharma, Inc. (Exton, PA, www.antarespharma.com) is developing a nonsteroidal anti-inflammatory drug ("AP-159") using its "Easy Tec" ODT technology. Antares plans to file an abbreviated new drug application by the end of 2006.

Cardinal Health's "Zydis" fast-dissolve technology uses a freeze-drying process to make fast-dissolving oral tablets. Cardinal also is partnered with Phoqus Pharmaceuticals, Ltd. (West Malling, Kent, England, www.phoqus.com) for comarketing and providing contract manufacturing services for Phoqus' tablet-coating drug delivery technology, including Phoqus' "Qdis" fast-dissolve technology that enables conventional packaging materials to facilitate tablet handling and storage.

Ingredient suppliers expand

Ingredient suppliers also are responding to ODT opportunities. International Specialty Products (ISP, Wayne, NJ, www.ispcorp.com) will begin commercial production at the end of this summer at a new multimillion-dollar CGMP plant in Texas City, Texas that significantly increases the production of "Polyplasdone," its polyvinylpyrrolidone polymer that is used as a tablet disintegrant. ISP also manufactures the product at its facility in Calvert City, Kentucky.

"The capacity increase is being driven by increased demand for fast-dissolving oral tablets as well as for use in enhancing the solubility of poorly water-soluble actives," explains Tim Bee, ISP's senior director of pharmaceuticals and oral care.

ISP also is adding manufacturing capabilities in the United States to produce its "Advantia" coating systems for oral solid-dosage forms. The product line consists of cellulose-based coating systems for immediate-release and aesthetic applications and acrylate-based coatings for modified-release applications. "We added the Advantia coatings line in 2005, and we are expanding our manufacturing capabilities in the United States and our pharmaceutical laboratories on a global basis," says Bee.

Spray-dried dispersion is another recent technology added to ISP's formulation toolbox. It gained the technology through its 2004 acquisition of the pharmaceutical technology business of Niro Inc., which provides contract formulation, scale-up, and manufacturing services with a focus on the use of spray-drying technology for bioavailability enhancement. In connection with the acquisition, ISP entered into an alliance with Niro to promote and further develop the technology.

Oral thin-film technology emerges

Taking a cue from consumer healthcare, oral thin-film (OTF) technology is emerging in the over-the-counter (OTC) drug and nutraceutical markets, although OTF technology has not yet penetrated the prescription drug market.

"The spark in OTF technology occurred with the launch of Pfizer's 'Listerine Pocket Paks' several years ago," says Jared Hahn, Technology Catalysts International's manager of drug delivery and pharmaceuticals. "As a result, other companies with polymer or transdermal technology began to target OTFs for pharmaceuticals. "

Companies with OTF products are LTS Lohmann Therapy Systems Corporation (West Caldwell, NJ, www.lts-corp.com), Adhesives Research (GlenRock, PA, www.adhesivesresearch.com), and Applied Pharma Research SA (APR, Balerna, Switzerland, www.apr.ch).

Adhesives Research is building a new 25,000-ft² pharmaceutical manufacturing facility at its site in Glen Rock, Pennsylvania for the company's "ARx" division. The ARx division currently supports six commercial dissolvable-film products for the OTC market. It expects to launch 20 new dissolvable film products for both oral and topical delivery over the next three years. The new facility is scheduled to be completed in the first half of 2007.

APR signed a strategic partnership to license its "RapidFilm" OTF technology to Labtec GmbH (Langenfeld, Germany, www.labtec-pharma.com) in March.

Although OTF technology is used in certain OTC drug and nutraceutical products (Table I), it has not yet penetrated the prescription drug market. FDA, however, approved a suitability petition (1) for an abbreviated new drug application for famotidine orally dissolving strips in a 10-mg dose as an alternative dosage form for "Pepcid" (famotidine) chewable tablets in a 10-mg dose.

"This suitability petition is significant in that it potentially would open the door for pharmaceutical companies to leapfrog over the orally disintegrating delivery form into oral thin-film technology," says TCI's Hahn.

The pros and cons of oral thin-films

OTF delivery has advantages and disadvantages. "The key advantage for OTF delivery is patient compliance and convenience," says Hahn. "It is a dosage form that can be used with older and pediatric patients or in any patient group that may have difficulty in swallowing. It also is more convenient in that it can be administered without water."

Table I: Select examples of oral thin-film pharmaceuticals and nutraceuticals

There are drawbacks, however. "One is with drug loading," says Hahn. "Drug loading for an oral thin-film product is generally limited to roughly 20 mg. Companies can address this by increasing the thickness of the strip, but that in turn may change the dosage form from a fast-dissolving strip to a slowly dissolving or chewable strip."

Moisture is another concern. "This would be a specific problem for a prescription drug product to gain regulatory approval as there would have to be assurances that each thin-film strip was kept dry and stable in order to deliver the indicated amount of active," says Hahn. "This can be addressed in packaging, where each strip is individually wrapped, but then those additional packaging costs would have to be taken into consideration. Also, for pediatric use, child-resistant packaging would have to be taken into consideration."

Candidates for oral thin-film delivery

The 2004 global market (based on ex-factory sales to wholesalers) for OTF technology in pharmaceutical (OTC) and nutraceutical products was estimated at $25 million, says Technology Catalysts. The market is projected to increase to $500 million by 2007, conditioned on the entry of higher revenue-generating OTC products and possibly prescription drug products entering the market.

"We see nicotine OTF delivery as the next higher value entry in the OTC market with the potential of OTF replacing transdermal delivery of nicotine as a smoking-cessation product," says Hahn. "Also, we see potential for OTC drugs that are now delivered as orally disintegrating tablets such as the antiulcerant drug famotidine and the antihistamine loratadine. For prescription products, we see potential in OTF products for drugs such as the antipsychotic 'Risperdal' (risperidone) and the sleeping disorder drug 'Ambien' (zolpidem)."

References

1. "Suitability Tracking Report as of April 11, 2006," (US Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD), http://www.fda.gov/cder/ogd/DrugSortpage.htm, accessed May 1, 2006.