By David C. Castaldo

The world is getting smaller. Or, perhaps more accurately, the world has always been small – but it’s only been in recent years that companies have begun to realize that particles once thought insignificantly small can have a significant impact on product quality.

Nowhere is this phenomenon more apparent and relevant than in the pharmaceutical industry, and especially in regard to inhaled pharmaceuticals. The industry has come to realize that increasingly smaller particles must be examined. These smaller particles affect pharmaceutical production and quality in a way that hasn’t been understood in the past – pushing the limits of particle identification and characterization technology.

This new understanding of the impact of particle size has developed through work conducted by the Environmental Protection Agency (EPA) during its development of air quality standards. In its publications on one such standard – PM 2.5 – the EPA states that particulate matter smaller than 2.5 microns “are so small they are able to penetrate to the deepest parts of the lungs.” The EPA has also concluded that a link exists between “fine particulate matter and numerous health problems including asthma, bronchitis, acute and chronic respiratory symptoms such as shortness of breath and painful breathing, and premature deaths.”

As a result of the knowledge gained from these EPA studies, concern has developed regarding the presence of very small particles in inhaled pharmaceutical products. Although EPA studies have focused on particles below 2.5 microns, other studies have focused on particles that have passed into the lungs at sizes of up to 10 microns. While no regulations have yet been developed, manufacturers of inhaled pharmaceuticals have begun to explore methods to ensure that their drugs do not contain these extremely small particles.

The problem is that most of the technology applications that the pharmaceutical industry has traditionally used for foreign particle detection cannot identify particles below 10 microns. And this problem is precisely what led one of the world’s leading pharmaceutical manufacturers to ASPEX LLC.

At PITTCON 2002, representatives from this pharmaceutical company approached the ASPEX booth to discuss foreign particle characterization. This company was faced with developing quality control measures to enable it to quantify and characterize particles below 10 microns in its inhaled drug product, which was in development. The manufacturer was unable to accomplish this with the techniques it was using, which included laser, video, and X-ray systems.

As the ASPEX staff began to speak with representatives from the pharmaceutical manufacturer at PITTCON, it quickly became clear that ASPEX’s system for foreign particle detection could meet the exacting requirements of this application.Within three weeks of the initial meeting at PITTCON, the pharmaceutical manufacturer came to the ASPEX facility to learn more about the system. A month later, the manufacturer purchased an ASPEX PSEM (personal scanning electron microscope) unit. The ASPEX PSEM is a microanalysis system comprising a scanning electron microscope (SEM) and an energy-dispersive spectrometer (EDX) with automated feature analysis capability.

Over the next year, the manufacturer worked with ASPEX as the company created a “dedicated interface” for inhaled pharmaceutical applications. The result of that collaboration is ASPEX Rx – a completely integrated solution for the automated identification and characterization of inorganic foreign particles as small as 0.1 micron in pharmaceutical manufacturing processes.

ASPEX Rx features a special sample carrier system for powder-based inhaled pharmaceuticals. The system can establish continuous automated runs for discrete analysis and statistical sampling in 24/7 operations.

To meet the exacting requirements of quality control for inhaled pharmaceuticals, ASPEX added an audit and authorization system. A “Permissions Editor” was added to the software to enable manufacturers to define users and groups by role-based access. Additional security features were included to ensure that people could not arbitrarily change information that was created during the quality control process. These additions and other capabilities were added to enable users to comply with 21 CFR Part 11 requirements.

Built to the quality standards that are required for cGMP facilities and IQ/OQ standards, ASPEX Rx features control software that incorporates highly sophisticated data mining techniques capable of automatically locating classes of patterns in extremely large numerical data sets. In addition to establishing the shape and size of particles, ASPEX Rx also determines the particles’ elemental composition, enabling manufacturers to easily identify the source of contamination upstream in the production process.

Today, the pharmaceutical manufacturer that first approached ASPEX at PITTCON two years ago is beginning to implement ASPEX Rx in its production quality control program. With the ASPEX Rx systems in its production facilities, the manufacturer can ensure that inorganic foreign particles – and their source – will be found swiftly in its inhaled pharmaceutical product during the production process.

Given the success the scientific staff of this pharmaceutical company has had in developing new methods for foreign particle characterization, the manufacturer is exploring the use of the new capabilities provided by ASPEX Rx in its quality programs for other products.

From an industry-wide perspective, inhaled delivery systems are quickly becoming prevalent for administering a variety of pharmaceutical products because of their improved efficacy and ease of use for the consumer. As increasing numbers of companies begin to develop and produce inhaled pharmaceuticals, the need for pinpoint accuracy in quality control for these products will become even more vital, both to guarantee consumer safety and to ensure the long-term success of the manufacturer.