Today, pharmaceutical companies show heightened interest in reformulating their existing drugs into new dosage forms, and the strategy has many arguments in its favor. One relatively new dosage form is the orally dissolving strip, a thin film formulated with hydrophilic polymers that rapidly dissolves on the tongue. This format is currently used for some therapeutic products such as Novartis’s (Basel) “Triaminic” cold-relief treatment.

The equipment needed to manufacture orally dissolving strips is familiar to the pharmaceutical industry. It includes standard mixing or compounding vessels, coating lines, drying ovens, and packaging equipment such as standard pouching machines. 

One common method of producing orally dissolving strips entails solvent casting and film coating. First, a manufacturer mixes a solution of active pharmaceutical ingredients (APIs) and film-forming excipients with volatile solvents. Next, operators cast a thin coat of solvent blend onto a moving, inert substrate. They then move the coated film through a drying oven to evaporate the solvent before die-cutting the dried film into strips.

Manufacturers also can produce orally dissolving strips using hot-melt extrusion (HME). This technique involves melting an API–excipient polymer, then extruding it through a die under molten conditions. Finally, the thin film is cooled to room temperature and die-cut into small strips. Extruders are not common in the pharmaceutical industry, however, and this method would call for many manufacturers to invest in the necessary equipment.

Switching from development-scale to commercial-scale production of orally dissolving strips poses particular challenges. The speeds of the coating and drying operations are the most important direct influences on production, says Albert Manser, chemist at Werner Mathis (Oberhasli, Switzerland). These speeds must be increased to appropriate levels for commercial-scale throughput. The wet-coating thickness and the properties of the coating solution affect production by limiting the product’s drying speed and final dry thickness. These properties can be adjusted to enable efficient commercial-scale production. 

Selecting the correct type (e.g., horizontal-nozzle, bow, or hot-flue) and number of dryers also helps operators achieve production capacity for a continuous-coating line, says Manser. Companies are increasingly adopting continuous-coating equipment and corresponding dryers in their research and development departments. “This is a great advantage to scale-up because web-guiding and drive systems, including machine controllers, give perfect basic information for high-capacity manufacturing,” Manser says. Incorporating extra dryers into the line sometimes increases process speed, he adds.

During scale-up, companies must take care that air and moisture do not become incorporated into the orally dissolving strips, says Avani Amin, principal and in-charge director of the Institute of Pharmacy at Nirma University of Science and Technology (Ahmedabad, Gujarat, India). The incorporation of air would produce an uneven film surface, and moisture would change the film’s mechanical properties (e.g., tensile strength, flexibility, and folding endurance), Amin explains. A manufacturer should observe strict humidity and moisture controls in the manufacturing area and use optimal vacuum machines.

Other critical parameters to consider during scale-up generally revolve around the properties of the API, according to Patty Frey, director of operations at ARx (Glen Rock, PA). For example, heat and shear sensitivity, the form in which the API is readily available, and the materials with which the API will react (e.g., solvents) must be evaluated.

“We are fortunate, in that the manufacturing techniques for orally disintegrating films are well understood and lend themselves to holding exceptionally tight tolerances throughout the process,” says Frey. Scale up should be no more challenging for the production of orally dissolving strips than for other common dosage forms. 

On the other hand, manufacturers are looking for ways to make these well-understood processes more sophisticated. For example, simultaneous segregated coating (e.g., side-by-side coating or spot coating) could separate APIs that would otherwise interact with or neutralize each other. No pharmaceutical company is producing commercial quantities of orally dissolving strips using these methods, according to Frey. Manufacturers are investigating whether simultaneous segregated coating would be cost-effective or change therapeutic outcomes. And pharmaceutical companies still need to develop an efficient way to integrate these manufacturing strategies. 

Pharmaceutical companies that seek new dosage forms for their existing products might find orally dissolving strips to be a format worth considering. The dosage form’s portability and ease of use appeal to patients, and the product can be created using equipment and procedures familiar to the industry. For these reasons, the coming year may see more manufacturers pursue orally dissolving strips.

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One relatively new dosage form is the orally dissolving strip, a thin film formulated with hydrophilic polymers that rapidly dissolves on the tongue.

Are Orally Dissolving Strips Easy for Manufacturers to Swallow?

Clark Solutions 
 Small pumps handle liquids and gases


 Clark Solutions (Hudson, MA) recently introduced its “Boxer 5100” and “5200” diaphragm pumps, which can be used as sampling or fluid-transfer pumps for small volumes of liquid and gas. The devices are available in single-head models and dual-head models. The dual-head units can be configured for serial or parallel operation and provide a maximum combined flow of 10 L/min of gas and 900 mL/min of liquids. The products’ wetted parts are made of silicone and polyphenylene.

The 5100 and 5200 devices can operate at an ambient temperature of 40 °C and handle media as hot as 50 °C. The compact pumps are supplied with clips for easy mounting. Customers can choose from various direct-current motors to power the diaphragm pumps. The devices are self-priming and provide maintenance-free operation, according to the company.

Neopac
 Tube includes pressure-activated valve


 Neopac’s (Oberdiessbach, Switzerland) “Polyfoil” tubes are now available with the “Pinpoint” applicator, a cone-shaped silicone valve that dispenses microliters of gel or cream. The valve opens in response to pressure on the tube and automatically closes after pressure is released. This design prevents leaks and keeps the package hygienically clean. The product can be applied directly onto the skin to reduce the risk of contamination. The package is designed for medications that require controlled, small doses of product.

The Polyfoil tubes are made of a five-layer laminate that includes a polyethylene sealant layer and a polyolefin layer. A laminate that includes a polypropylene layer is also available. The laminate has effective barrier properties and protects sensitive formulations from light, moisture, oxygen, and organic substances. In addition, the foil is corrosion resistant, and Neopac can print on the laminate’s entire surface. 

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the January 2009 edition from Clark Solutions and Neopac.

January 2009 Editor's Picks: Products from Clark Solutions and Neopac

Pharmaceutical companies, spurred by industry forces and a changing regulatory climate, seek new processes and approaches to improve manufacturing efficiency, productivity, and quality. New cost pressures related to dwindling pipelines, greater competition from generics, and a challenging global economy have reduced pharmaceutical manufacturers’ traditional reluctance to embrace advanced manufacturing processes. 

The US Food and Drug Administration has been urging drugmakers to build quality into the manufacturing process from the start, as opposed to relying on end-process testing, with its process analytical technology (PAT) and Pharmaceutical CGMPs for the 21st Century initiatives. These initiatives seek to enable consistent and predictable product quality (i.e., higher sigmas). PAT requires manufacturers to understand how manufacturing variables affect product-quality attributes and to measure quality using those attributes during the manufacturing process. To adopt the PAT model in a continuous-manufacturing environment, pharmaceutical organizations must monitor key product attributes during production and make in-line adjustments to the manufacturing process to keep the product within specifications.

An integrated information technology (IT) environment that captures and displays data from every part of the supply chain and manufacturing process is essential to the PAT approach, as is a flow of information across the enterprise. Information flows, enabled by an organization’s IT infrastructure and enterprise applications, must complement and keep pace with the flow of materials in a continuous environment. The flow of information supports long-running product orders of various sizes, captures in-process quality-test results electronically, includes them in the electronic batch record, and enables timely interventions.

To understand the relationships between manufacturing-process parameters and product quality, pharmaceutical manufacturers must transform data from every part of the supply chain and manufacturing process into accessible and usable knowledge. For example, pharmaceutical manufacturers sometimes purchase one active pharmaceutical ingredient (API) from several suppliers, and the API’s strength and particle size might vary according to its source. It is therefore important for pharmaceutical companies to know the source of each API, the typical quality profile of the API, and how to make process adjustments to compensate for material variability. 

An integrated IT infrastructure is essential to enabling manufacturers to capture the secure, analyzable, and actionable data needed to identify variability and make appropriate production adjustments to ensure consistency and high quality. The infrastructure must also be able to collect and interpret data from multiple internal systems and contract manufacturers. 

Advanced software suites available today help manufacturers manage in-process material variability within a particular batch and its corresponding manufacturing processes. Such solutions allow manufacturers to adjust for differences in potency between different lots of the same API. For instance, if a user selects a lot that has substandard potency, the system will instruct the operator to use more of the API or less of a buffer ingredient to reach a consistent batch potency. This type of flexibility and functionality is critical to effectively manage the pharmaceutical process to produce consistent product quality. 

Pharmaceutical manufacturers face great challenges today, but they have new opportunities to deploy effective and efficient manufacturing and quality-control processes that were not viewed as necessary or viable until recently. The industry also has access to a new generation of advanced and integrated IT solutions that support PAT and other initiatives by enabling the essential flow of actionable information from the supply chain through the manufacturing and distribution processes. By harnessing the power of new processes and technologies, the industry stands to make great strides toward achieving new levels of operational efficiency, quality, and corporate performance.

John Danese is the life-sciences product strategy director at Oracle, 560 White Plains Rd., Tarrytown, NY 10591, tel. 914.239.3788, fax 914.524.1673, john.danese@oracle.com.

In the Mixer

An integrated information technology environment can help pharmaceutical companies find new processes and approaches to improve manufacturing efficiency, productivity, and quality.

Equipment and Processing Report-01-21-2009

Are Orally Dissolving Strips Easy for Manufacturers to Swallow?

January 2009 Editor's Picks: Products from Clark Solutions and Neopac

IT Can Transform Pharmaceutical Manufacturing