Foreign particles in drug products represent a quality problem for all pharmaceutical manufacturers. They are of a particular concern in the production of pulmonary-inhalable drugs, where the critical size range extends down to 2 microns. These fine particulates, which can be introduced during the manufacturing process, have been associated with numerous health risks and can have a significant impact on product quality costs. Interest in the detection and analysis of these particulates has increased substantially due to FDA recommendations for a full characterization of foreign particles, including size, shape and elemental composition, during the development and production of these new drugs. In response to this need, Aspex Corporation has developed the Aspex Rx system to find and characterize sub-micron particles in a pharmaceutical environment.
NGP. What makes the Aspex instrument important for the pharmaceutical industry?
The Aspex Rx rapidly produces the kind of timely, reliable, and detailed test data required to document the quality of your product and forestall expensive product recalls and liability issues. Our instruments are fully automated to provide detailed particle-by-particle information orders of magnitude faster and much more consistently than can be achieved by manual methods.
Aspex instruments have been used for some time in various industrial processes where detailed size, shape, and compositional analysis of sub-micron to millimeter particles is critical. More recently, our products have been adopted for assessing potential particulate contaminants in a dry-powder pharmaceutical developed for pulmonary delivery, which is now FDA approved. The decision to use our technology for this application was made after an evaluation that concluded that no other commercial technology provided the level of sensitivity and consistency required for production monitoring of foreign particles in the critical 2-10 micron respiratory range. It is becoming increasingly apparent, however, that the instrument has broader application in the pharmaceutical industry, both for contaminant monitoring in other types of pharmaceutical formulations, and as a more consistent and precise means of measuring particle sizes and shapes in drug formulations.
NGP. What’s unique about Aspex particle analysis technology?
Virtually every other instrument used to analyze particles is based on light in some fashion. The technology we employ is based on a focused electron beam. The switch from photons to electrons opens up new possibilities and translates into significant performance gains in terms of detection sensitivity and selectivity, the accuracy and precision of size and shape information, and the ability to characterize particles in terms of their elemental composition. In short, by using electrons, we can more reliably detect all sizes of particles, and especially very small ones, and tell you much more about them.
We’ve taken this powerful electron-beam technology, which in the form of the traditional laboratory SEM/EDX instrument (scanning electron microscope equipped with an energy-dispersive x-ray spectrometer) has long been recognized as the “ultimate” technique for analyzing individual particles, and implemented it in a fully automated and highly-optimized configuration that makes it practical and affordable for routine use in a wide range of facilities.
NGP. Why is it so advantageous to use an electron beam?
It all boils down to physics. Per theory, the lower limit on the size of features that can be distinguished (spatial resolution) is roughly the wavelength of the entity being used for imaging. For photons, the range of visible wavelengths is ~400 to 700 nm (0.4 to 0.7 microns). For an electron in the energy range normally used for imaging, the wavelength is more than 1000 times smaller. Now by clever optical design, one can somewhat extend the resolution of a photon-based optical system and there are other factors that limit the practical resolution of an electron-based system, but the unavoidable fact remains that micron-scale particles are at the extreme fringe of what light-optics can deal with, whereas they are very easy to resolve with an electron beam. A general “rule of thumb” is that in order to do any meaningful assessment of the size and shape of particles one should be able to resolve about 1/10th the particle diameter, which means that electron-beam measurements are still obtaining realistic dimensional information for 0.1 micron particles while using practical settings – whereas particles would have to be at least 10 microns in size before they can be viewed with equivalent detail with light optics, and then only with considerable care in setup.
But there’s also a lot more working for electron beam analysis. The electron beam energies used in these instruments is sufficient to interact with the inner electronic shells of the atom, which gives rise to two useful properties. First of all, you obtain a contrast mechanism that reliably distinguishes between different materials of differing atomic number – heavier materials appear brighter than carbon-based materials, for instance. This makes it simple and reliable to detect minerals and metals on a filter paper, as one important consequence. The interaction of the electron beam with the particles also produces x-rays whose energy spectra uniquely identify the elemental composition of the material being viewed. What this means is that not only can one reliably distinguish particles from the substrate on which they are presented, but one can also determine the precise elemental composition of the particle (e.g., the specific mineral or alloy). By comparison, light-based measurements are sensitive to a multiplicity of factors that confuse the interpretation. The consequence is that even for particles larger than the limit imposed by simple spatial resolution considerations, electron beam analysis provides a more reliable and vastly more specific way to analyze individual particles.
NGP. Are there limitations?
Every technology has limitations. The advantage that electron-beam analysis has over light-based analysis is that it is very sensitive to elemental composition. This makes it a very sensitive technique for identification of inorganic materials. However, organic materials tend to be comprised mostly of carbon, hydrogen, and oxygen in very similar ratios – the chemical differences are in the molecular structure and electron beam analysis isn’t sensitive to that. (Conversely, optical methods such as FTIR and Raman that are sensitive to molecular structure, can’t analyze materials that produce no molecular spectrum – such as metals.) So although an electron beam analysis can tell you that a particle is organic in nature, it generally can’t identify the specific organic compound (unless other characteristic elements are also present, e.g., in the form of fillers).
NGP. Isn’t electron imaging a lot more complicated than light-based?
That’s a matter of perspective. If you are looking at large particles or you don’t really require much in the way of detailed information, a relatively simple light-based system may do the job very well. But if you need to get reliable and detailed information about particles below ~50 microns and/or you need to know the composition of particles, you may not be able to get what you need from a light-based system, and the further you push that technology towards its limits, the more complex and expensive it becomes. This is particularly true when you automate the measurement process. A light-optical microscope is an intrinsically mechanical device, which lends itself to simple manual control, but requires a lot of interface effort to put under computer control. By contrast, electron optics are purely electronic in nature, and the interface to a computer is simple, fast, and reliable. You also don’t want to confuse a modern automated electron-beam particle analyzer, which is a highly integrated and optimized system designed for this specific task, with earlier generations of “hybrid” instruments where the particle analysis subsystem is grafted onto a scanning electron microscope designed for general laboratory imaging. The modern integrated design results in a much simpler, faster, and more reliable installation.
NGP. What about the vacuum issue? Doesn’t electron-beam analysis take more sample preparation?
The necessity of analyzing the specimen in a vacuum is a reality of the electron-beam technology. However, with modern reliable high-speed “turbo” pumps, this isn’t the inconvenience and source of problems that it once was. As to sample preparation: there’s no longer the need to coat non-conductive samples. For the vast majority of samples, there’s virtually no difference between preparing samples for analysis in an electron-beam based particle analyzer, and one based on an optical microscope. For example, particles may be deposited on an ordinary filter paper and, after drying, placed directly into the instrument. In many practical instances, it is actually easier to prepare samples for electron-beam analysis since the vastly larger depth-of-focus of such instruments makes them much less sensitive to the flatness of the substrate on which the particles are deposited. Then too, the necessarily enclosed and controlled environment of the electron-beam instrument lends itself to consistent measurements, whereas control of illumination and stray light is something that must be considered with a light-based instrument.
NGP. What can I expect in terms of performance?
Performance comparisons can be misleading if one states them out of context. The results quoted here are based on Aspex’s unique Performance Grading System™ (patents pending) which challenges the instrument with a large number of low-contrast features of known size, shape, and position. With this system, it is simple to make very large numbers of measurements and extract detailed performance metrics. Typical results are as follows:
• Rate of particle detection: over 600/minute (densely loaded specimen).
• Missed particles: less than 1% for circular features 2-100 microns in diameter (Z~9).
• “False positives” (reported particles that have no physical basis): estimated to be less than 0.5 per square mm.
• Particle sizing: average diameter measured to better than 0.5±0.25µm for features 1-100µm in size (no significant variation with size).
• Aspect ratio (ratio of major diameter to perpendicular): median error of .05 for circular particles in 1-100 µm diameter range.
NGP. Is this instrument qualified for regulatory approval?
The Aspex Rx configuration comes equipped with the Audit and Authorization package that enables users to comply with 21 CFR Part 11 requirements. A “Permissions Editor” is part of the software package that is used to define users and groups for role-based access. The system is backed by rigorous IQ/OQ procedures to meet cGMP requirements. The newly developed Performance Grading System™ (PGS – patents applied for) provides a fast, simple, but rigorous means for users to routinely verify the operational suitability of the instrument and its setup.