Sizing Up Particle AnalysisBy James Netterwald, PhD, MT (ASCP)
Over the last several years, more methods have been standardized
The AAPS Journal published a report in 2004 by Burgess and colleagues about particle size analysis, from the fundamentals of particle structure and morphology characterization to measurement. The report, co-sponsored by the U.S. Food and Drug Administration (FDA) and the United States Pharmacopeia (USP), was based on a 2003 American Association of Pharmaceutical Scientists (AAPS) workshop on particle size analysis. The 2003 workshop and 2004 report (Burgess, et al. AAPS J. 2004;6 (3):23-24) reviewed what was then the current thinking about particle analysis.
Since that workshop and the published report, progress has been made in particle engineering of pharmaceutical products, but experts continue to call for harmonization of particle analysis methods. Quality by design approaches, sampling and sampling distribution methods, and methods for particle shape analysis have all been cited as areas that have improved since 2004, with progress expected to continue.
Particles have physical properties, as well as properties that can be attributed to the manufacturing process, particle “processability,” and quality, all of which determine the in vitro and in vivo performance of the particle. “There are a number of factors that affect particle size measurements, and this report touched on a number of them,” said William Kopesky, vice president of analytical services at Particle Technology Labs, Downer’s Grove, Ill. “The report covered a variety of techniques available for particle size determination; each presents their own pros and cons. Each technique should be applied to a different situation or set of samples depending on the question the researcher is trying to answer.”
The report also outlined the complexities and subjectivity of selecting an appropriate particle-sizing method and discussed how to express data generated by such methods. One problem identified by the report was the failure of sieving methods to control the extended release in tablets due to particle size effects.
The wide range of available dosage forms—solids, aerosols, suspensions, emulsions, liposomes, microspheres, and nanoparticles—was included in the report, as were the difficulties encountered in the size analysis of particles as diverse as those found in solid dosage forms and dispersed systems. For example, the impact of particle size on the therapeutic efficacy of an inhalation product “renders clinical bioavailability and bioequivalence potentially irrelevant,” the report noted.
Now, even if you have a handle on particle size, you still have to consider how shape plays a factor in the instrumental result.
—William Kopesky, Particle Technology Labs
Predictable therapeutic targeting, dose delivery, pharmacokinetics, and pharmacodynamics of liposome-delivered drugs are dependent on control of vesicle size. The report emphasized that sampling methods can affect both how particles are analyzed and how data generated by an analysis are expressed.
The overall purpose of the AAPS workshop was, according to the report, “to acknowledge the importance of each of these factors and to provide a forum for debate and discussion for individuals from all sectors of the scientific community with interest in pharmaceutical particle size analysis.”
Issue Is Harmonization
Andy Dunham, PhD, senior research director of technology resources at Baxter Healthcare Corporation, Deerfield, Ill., recalled the state of the field when the workshop was held. “Around 2004, particle engineering and dosage form design were starting to grow rapidly in the pharmaceutical industry. The industry recognized the need to establish common points for discussion and definition regarding process control and product characterization techniques.”
According to Kopesky, the workshop “was trying to illustrate that there has been and continues to be a harmonization issue using different techniques. With all the available different sizing techniques, each one working on a different analytical principle, you do get different data sets. One of the hurdles that everyone in this industry battles on a daily basis is comparing between analytical techniques, for example, microscopy versus laser diffraction … or even on the same analytical principle, say between different instrument manufacturers,” Kopesky said.
IMAGE COURTESY OF PARTICLE TECHNOLOGY LABS LTD.
A Malvern Morphologi G3S Particle Characterization System, a state-of-the-art automated image analyzer.
“I think that we’ve seen some standardization of methods over the last several years, but we are still not necessarily there yet on all particle sizing technologies. … To my knowledge, there has been more standardization of methods since the report was published,” Kopesky added. For example, in 2005, the USP released a monograph, “Laser Diffraction Measurement of Particle Size” (USP <429>), which outlined a technique commonly used in the pharmaceutical industry as manufacturers have moved away from sieving to obtain better resolution of particle size distribution.
The International Conference on Harmonisation (ICH) has pulled the USP, the Japanese Pharmacopoeia, and the European Pharmacopoeia together “to get everybody on the same page when it comes to laser diffraction, describing the technique, and trying to specify more about what the exceptions and criteria are for validating a particle size method. Diffraction has been used routinely in our laboratory due to its popularity, and we reference the USP <429> document, which has been very helpful in the pharma industry, especially to show compliance and to standardize the technique,” Kopesky said.
Determination of Particle Shape
Particle shape determination is another current concern in the field of particle engineering. The 2004 report stated that “the measurement and expression of particle size is intimately bound with the shape and morphology of the constituent units that make up the ensemble of particles.” The importance of particle shape was described within the context of measurement using different analytical methods. According to the report, if all particles were spherical, such measurements would have low variation between methods. Because pharmaceutical particles are rarely, if ever, spherical, however, measurement can be problematic. This challenge highlights the importance of particle shape and morphology.
“People have often been content with equivalence sphere diameter … but now they are saying that is not good enough anymore. Now, even if you have a handle on particle size, you still have to consider how shape plays a factor in the instrumental result,” Kopesky said. Major industry manufacturers have also adopted particle shape image analysis approaches that can be used in conjunction with more classic techniques like laser diffraction-based approaches.
Particle size analysis is just one element of the quality of the product, and much of the quality analysis of particles has been overtaken by design approaches, according to Anthony Hickey, PhD, DSc, professor of molecular pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill. “At around the time of this report, there was a new initiative that was just coming out of the FDA on quality by design. There were also new analytical technologies that enabled you to measure in real time or online with feedback properties of the products so that you could actually ensure the product’s quality without necessarily having to go back and remake it. You could do back sampling and continuous processes that would give you very high quality products.”
According to Dr. Dunham, progress has been made in particle size analysis since the 2004 report. The USP adopted written standards regarding lipid emulsions (USP <729>), and the FDA emphasized the need for improving the characterization of protein aggregates. Although Baxter is not currently participating in the working group, the company sees a continuing need for the outputs and actions described in the 2004 report. For example, the impact of particle size distribution on product safety and performance of emerging pharmaceuticals should be better understood.
Also, the report described the importance of developing descriptors for particle size distribution data. A mass-weighted descriptor, rather than one that is number- or surface area-weighted, is the most relevant descriptor of the content of active pharmaceutical ingredient as a function of particle size, according to the report.
But not everyone agrees that significant progress has been made. “I don’t think [the AAPS report] had a huge effect on the field because, in the conclusion, the suggestion was that we would have another meeting three years later, and I don’t think it ever happened,” said Dr. Hickey. The conclusion stated that “improvement of currently accepted methods for particle size analysis of pharmaceutical products will require ongoing participation by those involved with this activity. … A second meeting was proposed that would occur at a defined period following the first meeting (two years) to review the effect of the action items, and the passage of time, on industry and regulatory practice.”
Particle engineering and dosage form design were starting to grow rapidly in the pharmaceutical industry. The industry recognized the need to establish common points for discussion and definition regarding process control and product characterization techniques.
—Andy Dunham, PhD, Baxter Healthcare Corporation
Other experts contend that there was sufficient coverage of methods of particle analysis and therefore no need to develop additional techniques. Dr. Dunham said that “setting standards for how to use this technology is a current need for the industry and will require technically sound agreement between academia, industry, and regulatory bodies on the relationships between particle characteristics and product performance.”
Kopesky agreed that harmonization of methods is still a critical need. “The difference in the analytical techniques themselves is just one of the common problems that continue to hinder the advancement of particle size testing. Each analytical technique looks at a different parameter or different view of the particle because you are dealing with a 3-D object that is very often nonspherical and non-monodispersed. Also, there are several different variables to be measured by each technique, and each one is looking at a different set, so comparing between different techniques can be difficult.”
According to Dr. Hickey, “every particle sizing method has a range of functionalities. There is no one method that will let you measure particles of all scales and scrutinies, from boulders down to nanoparticles. The key is representative sampling, so that you are looking for something that reflects the properties of the product you are working with.”
The 2004 report clearly stated the need for harmonization of particle-sizing methods, Dr. Hickey said. “There is a need for written and physical standards for calibration of all particle-sizing methods. These standards should be reproducible, sensitive [for product control], and accurate, if absolute particle size is important.” Moving forward, harmonization will likely be a key issue in the field.
Dr. Netterwald is president and CEO of BioPharmaComm LLC. Reach him at firstname.lastname@example.org.
Impact of Particle Size on Aerosols
In 2004, the AAPS Journal published a report on particle size analysis, based on a workshop held the previous year, in which inhaled aerosols were identified as highly dependent on particle size and morphology. Anthony Hickey, PhD, DSc, professor of molecular pharmaceutics in the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, is an aerosol particle engineer who has done a good deal of particle sizing for other reasons.
Particle size is particularly important to the efficacy of an aerosol, Dr. Hickey said. “One of the things that came out of the 2003 AAPS workshop was that there are a lot of issues related to how to sample powder forms or droplet forms in the first place. … It is clear that sampling is key to really understanding your product.”
Because particle size is such an important element in the efficacy of inhaled drugs, particle size analysis must reflect the chemistry of the drug so that what is actually measured is the particle size of the drug, not just general particle size. “A lot of these aerosol products are not just drugs but are excipients or propellants or other things.”
Our understanding of laser diffraction and how to build bigger and better detectors and develop better algorithms that reflect particle behavior and size have come a long way. “Even more mechanical methods of sampling, such as inertial sampling, now have new impactors that are more suited to pharmaceutical products such as aerosol particles.”