For decades, pharmaceutical companies have accepted dissolution testing as a valuable method for controlling the quality of tablets and capsules. Dissolution testing helps manufacturers measure the batch-to-batch consistency of their products and also can confirm that dosage forms release various formulations at the correct rate over the intended period. The 

 describes a standard method for conducting dissolution testing of tablets and capsules, and regulators expect companies to adhere to this technique.

The drive to extend patents by reformulating products as new dosage forms has contributed to the pharmaceutical industry’s increasing interest in inhaled drugs, but 

 does not describe a method to perform dissolution testing on these products. Until recently, most manufacturers considered dissolution testing unnecessary for inhaled drugs and preferred to rely on other tests that they considered adequate. Yet a standard dissolution test for inhaled products could be at least as useful a quality-control tool as it has been for tablets and capsules. It also could allow innovators to set dissolution standards for their products that makers of generic drugs would have to meet. These considerations have prompted several researchers to propose standard dissolution-testing methods for inhaled drugs.

In 2003, Neal Davies, associate professor of pharmaceutical sciences at Washington State University, and graduate student Majid Feddah proposed a technique based on a 

 type 4 flow-through cell, a device commonly used to test the dissolution of tablets and capsules. Their method used an in-line high-performance liquid chromatography pump to control the drug’s flow rate. Because no 

-certified lung fluid was available for dissolution testing, Davies and Feddah developed one that contained a lung surfactant after reviewing the literature.

Unlike previous dissolution-testing methods, the Davies technique linked the flow-through system to a cascade impactor, which separates emitted doses into fractions according to particle size and measures particle-size distribution. Particle size is critical to a drug’s disposition and action in the lung, and particle-size distribution is “an absolutely essential part of dissolution testing of inhaled products,” says Davies. Davies’s intent was to concentrate on the dissolution of the respirable fraction of the active ingredient because the behavior of larger, ingested particles is of little importance to drug action. 

Although they agree that Davies had the right focus, some observers say that his method opened up an opportunity for further improvement. Because the technique gathered the dose in the cascade impactor’s induction port before dissolution testing, it measured data for the total emitted dose, rather than for the portion that would be deposited in the lung. “The size-fractionating capabilities of the cascade impactor were not really exploited to the full,” says Mark Copley, sales director of Copley Scientific (Nottingham, UK). 

Davies’s method has not been proven appropriate as a dissolution test for air-classified particles and does not provide a clear picture of inhaled drugs’ overall dissolution profiles, according to Jason T. McConville, assistant professor of pharmaceutics at the University of Texas at Austin. On the other hand, it potentially could overcome the problems associated with dispersing powders using a standard dissolution. These problems often can result in poor homogeneity, particles that stick to the dissolution apparatus, or sampling undissolved particles, says McConville.

In May 2010, Yoen-Ju Son, McConville’s graduate student, proposed a new technique based on a modified dissolution tester. The tester incorporated a membrane-containing holder, which was designed to enclose air-classified formulations for uniform testing in the dissolution apparatus. Son’s technique used a Next-Generation Impactor (NGI) (MSP, Shoreview, MN) to separate and classify inhalation powders. An NGI is a high-throughput cascade impactor with a design that lends itself to this type of modification. The method tested each particle-size fraction for its own dissolution rate.

Son’s technique seems to have several advantages. Its dissolution procedure, apparatus, dose-collection method, medium, and test conditions were based on those listed in 

 method is straightforward and well established in most pharmaceutical laboratories, says Copley, a coauthor of Son’s paper. In comparison with previous dissolution-testing methods, Son’s technique limits the amount of solvent used, thus posing less risk of influencing the drug’s observed rate of dissolution. The reduction of solvent also allows the technique to simulate conditions in the lung more closely. 

But the Son method also creates conditions that may be different from those in the lung. The technique is a stirring-paddle method, but the “overall respiratory tract is a stagnant system and is not well stirred,” says Davies. The respiratory tract contains a small amount of aqueous fluid, and its flow rate would favor stagnant conditions, he adds.

Other characteristics of the Son technique could potentially bias test results. As a result of drug-wetting issues, drug loading on the holder influences the drug-release rate. “This characteristic may limit its utility and reproducibility compared with other methods,” says Davies. In addition, Son has not yet attempted 

 correlations, which must be examined and have been explored by other groups.

“Dissolution studies for inhaled products are still in their infancy,” says Davies. Further experiments could bring greater understanding, help refine testing techniques for these drugs, and advance toward 

 correlations. The growing interest in inhaled products, the emergence of new modified-release formulations, and the development of advanced drug-delivery systems will likely underscore the importance of dissolution testing in the future. The pharmaceutical industry now understands the need and potential benefits of this procedure more clearly, and the development of a standard dissolution-testing method for inhalable products may not be far off. 

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The pharmaceutical industry?s increasing interest in inhaled drugs has prompted several researchers to propose standard dissolution-testing methods for these products.

Seeking a Dissolution-Test Solution for Inhaled Drugs

Gems Sensors and Controls 
 Flow sensors offer visual indication


 The RotorFlow RFO fluid-flow sensors from Gems Sensors and Controls (Plainville, CT) provide a pulsed 4.5–24-V output that is proportional to the rate of flow. The direct-current output can be integrated into most digital logic units easily. The sensors include a highly visible paddlewheel that provides verification that fluids are moving.

As liquid passes through the unit’s body, a magnetic rotor spins at a rate proportional to the flow rate. The magnetic fields turning with the rotor excite a static Hall Effect sensor located in the body and generate a series of voltage pulses. Digital rate meters, totalizers, and other electronic controllers then use the output signal.

The RotorFlow sensors are available in port sizes of 0.25 to 1 in. and monitor fluids with flow rates ranging from 0.1 to 60 GPM. The units are appropriate for applications such as water purification, dispensing systems, chemical metering, and chillers and heat exchangers.

Telstar 
 Biosafety cabinet protects operators


Telstar’s (Terrassa, Spain) CytoUltra biosafety cabinet is designed to protect operators from cytotoxic and hazardous products that contain small amounts of volatile chemicals. The unit produces laminar airflow and incorporates three stages of high-efficiency particulate-air filtration. Operators control the device through microprocessor electronics. The unit has two independent controls with dedicated fans for the laminar flow and the exhaust fan, each of which is regulated by a dedicated speed probe. The cabinet’s sash is a 20-cm opening, and its sloped glass door is moved electronically.

The unit’s dedicated fan creates an inflow of more than 0.5 m/s. The inflow speed and laminar flow can be adjusted to different set points if required. The inflow and the device’s multistage filtration help shield operators from hazardous materials. Testing has shown that the CytoUltra device protects operators from 20-nm particles. The cabinet is appropriate for pharmaceutical manufacturing processes.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the July 2010 edition from Gems Sensors and Controls and Telstar.

July 2010 Editor's Picks: Products from Gems Sensors and Controls and Telstar

Today’s life-sciences manufacturers increasingly are working with contract manufacturing organizations (CMOs) as part of their business strategies. Outsourcing can provide flexibility, improve time to market, and reduce scale-up costs. The strategy also helps reduce costs from excess plant capacity and can help exploit specialized manufacturing operations.

But maintaining quality standards and managing process stability and improvement is challenging when a manufacturer works with outsourced sites around the world. Life-sciences companies are still learning to manage their own sites, and hiring contractors with various manufacturing-process data systems adds a layer of complexity.

In addition, the US Food and Drug Administration is focusing on CMO–sponsor relationships as a result of quality problems that have surfaced with increased outsourcing.  Sponsors always have been legally responsible for their drugs, regardless where the manufacturing operations take place.  It will no longer be enough simply to pass paper records between organizations;  FDA wants sponsors to conduct on-site audits at CMO sites just like those they conduct for their own in-house operations.

This new paradigm requires parties to share data and information in real time to enhance product quality and the CMO–sponsor relationship. The right technology tools allow manufacturers to gather and share process data with CMOs while preventing the unauthorized disclosure of proprietary information. Both the sponsor organization and the CMO can have self-service, on-demand, and scheduled access to all manufacturing, quality, and process-development data to support regulatory filings, and to use in process-performance analysis and visibility. 

By installing a manufacturing-process intelligence (MPI) software platform, the sponsor and contract manufacturing sites can access all relevant data easily. MPI software must provide easy access to data about raw materials, processing parameters, and process outcomes in a meaningful context. The software should assist investigations and analysis when process parameters are trending near out-of-range limits, for example. When the goal is simply to report the values of one or two parameters, a simple context might be sufficient, but when the goal is understanding for process improvement or technology transfer, multiple contexts (i.e., the organization of related data elements to enable analysis and interpretation) are required to help develop and test hypotheses that explain variability and predict outcomes. 

An appropriate data-access and contextualization software platform helps ensure successful CMO relationships in the following ways:

	By eliminating geography as a barrier to collaboration and helping the parties compare process outcomes and solve problems.

By reducing report preparation and distribution time, thus eliminating data-transfer problems with a real-time view of data for the CMO and the sponsor. This arrangement eliminates errors that may result from manual work with emailed spreadsheets.

By helping to increase the predictability of quality and yield by identifying causes of process variability and atypical batches.

By maintaining a centralized repository of accurate paper-based data that complies with 21 

 Part 11 and is scalable to accommodate future growth.

By aggregating and contextualizing continuous and discrete data from multiple sources to improve process understanding. 

A pharmaceutical company on the east coast of the United States, for example, might work with CMOs in New Hampshire and South Korea to produce one drug. Data generated by both CMOs can be stored in a central database at the sponsor’s headquarters. MPI software allows CMOs to enter data into a Part 11-compliant form with automatic verification settings available through a network connection. The software’s centralized archiving and contextualization capabilities help the sponsor and CMOs collaborate and control the process better.

Benefits for the sponsor include better process visibility and on-demand access to results and other data. Central availability of high-quality data saves time that might otherwise be spent looking for lost spreadsheets and analyzing trends. Life-sciences manufacturers that work with dozens of CMOs often have to send many highly skilled employees to and from remote sites on a regular or crisis basis. With MPI software in place, sponsors can reduce travel and personnel costs and prevent crisis-related disruptions. A software platform enables the sponsor–CMO team to act quickly when things go wrong and requires less time to get the process back on track when deviations or failures occur.

An MPI software platform also can help improve record-keeping and control of intellectual property for the sponsor and the CMO. The platform makes process technology more readily available to the sponsor and for technology transfer (e.g., when working with additional sites or CMOs using the same process). Ultimately, the platform can help sponsors meet regulatory requirements for control and management of the CMO and product.  Another advantage for sponsors is better preparation and defense of chemistry, manufacturing, and controls (CMCs) submissions and other regulatory filings and investigations. 

CMOs gain similar value from MPI software. They can use the data access and analytical capabilities for their process-improvement programs and for distributing reports to sponsors after internal review. Some CMOs have multiple operations and process expertise around the globe. With the appropriate MPI software platform, they can tap into expertise at many locations for better use of scarce talent.

With better process visibility and on-demand data and reports, CMOs experience fewer distractions from sponsor visits and data requests, and inspections go more smoothly. Ultimately, better process understanding and control leads to fewer production crises. 

In the end, a shared MPI software platform enhances collaboration and improves the reliability of sponsor–CMO relationships. Strong relationships, in turn, improve investigational and observational data analysis, enhance process and product performance, and shorten time to market. With the problems of managing data from disparate manufacturers and locations under control, sponsors and CMOs alike can reap the benefits of outsourcing.

Justin O. Neway, PhD, is executive vice-president, chief science officer, and cofounder of Aegis Analytical, 1380 Forest Park Circle, Suite 200, Lafayette, CO 80026, tel. 303.625.2100, 

. Aegis Analytical owns an MPI software program called Discoverant.

In the Mixer

With the right technology tools, the sponsor organization and the contract manufacturer can have self-service, on-demand, and scheduled access to all manufacturing, quality, and process-development data.

Equipment and Processing Report-07-21-2010

Seeking a Dissolution-Test Solution for Inhaled Drugs

July 2010 Editor's Picks: Products from Gems Sensors and Controls and Telstar

Intelligence Platforms Can Strengthen Relationships with Contractors