Solid dosage is the most prevalent form of dosage today, accounting for close to two-thirds of prescribed medicines. Proper testing of solid dosage not only assures that the medicine dissolves correctly and absorbs properly into the patient’s system, but also that the tablet, capsule or other solid-dosage form is free of contaminants or adulterants.
Providers of dissolution testers, near-infrared solutions, friability testers, hardness testers and other such devices have an inside look at current industry trends and challenges that are influencing solid-dosage testing. To learn more about these trends and how they are affecting pharmaceutical manufacturers, Pharmaceutical Processing spoke with providers of various testing solutions.
Patrick Mahn, Validation Services and Analytical Support Manager at Distek Inc., a provider of pharmaceutical dissolution testing instruments, validation and qualification services, explains that the FDA recently gave pharmaceutical manufacturers “a second way of validating their dissolution units.” Mahn says that “For years, U.S. Pharmacopeia (USP) had a procedure for this purpose, and the FDA, along with a lot of other people, found it rather cumbersome.” To improve this procedure, “they asked for American Society for Testing and Materials (ASTM) to create a new standard.”
The FDA now allows companies to use either the old standard or the new standard, as long as standard operating procedures (SOPs) are followed closely: “Some companies have changed their SOPs to go with the easier mandate,” but since “changing an SOP is a little bit like trying to get an act through congress, a number of companies are either in the process of getting it changed or have just decided that it’s not worth the time or trouble.” Since the introduction of this mandate, Distek has seen “requests for services as it relates to prednisone tests the USP has always wanted to have done … cut down by a good 30 to 40 percent.”
Mahn explains that this recent development did not change the methodology, but it does have the potential to “improve the quality of the results, because there’s a little more definition as to what a USP 1 or USP 2 apparatus as it pertains to dissolution is.”
Testing Unique Compounds
Highly potent compounds and other such products present some challenges when it comes to solid dosage testing. We asked the experts how testing processes have evolved as these products have become more common.
“Highly potent active pharmaceutical ingredients (APIs) are more challenging than traditional APIs, since they are used at much lower dosage levels,” explains Robert Mattes, Applications Scientist at FOSS NIRSystems Inc., a supplier of laboratory, at-line and process near-infrared (NIR) solutions. “The sample presentation and signal-to-noise are very important factors when trying to measure content uniformity of these dosage forms with NIR.”
Distek has noticed changes when it comes to handing long-release products: “As time has gone by, people want more of a sustained-release product, where it will actually stay intact long enough to get farther into your digestive system … and last a good five to six hours,” explains Mahn. “In some respects, from a dissolution point of view, we’re just getting to a point that we’re able to keep up with [sustained-release dosage].”
“When you’re doing a dissolution run, you have an autosampler or you’re pulling the samples manually … but the problem is that you’re going to have multiple time points: You’re going to want to know how it went 30 minutes, 2 hours, 6 hours, and some cases as much as 12 or 24 hours into it, you want to know exactly how much liquid you pulled out of that so you know exactly what the volume is left in that vessel so that you can make accurate calculations.”
Because companies often want to avoid employing someone to take samples manually for 24 hours, autosamplers with timers have become popular: “Our timers are accurate all the way out to days. In the past, that wasn’t all that important, because you’d never have a 5-day run,” says Mahn.
Bradford Klements, Product and Application Specialist at Pharmatron Inc., a provider of various physical tablet testing solutions, explains that automation’s importance extends beyond autosamplers to other testing areas.
“Quite simply put, automation increases productivity,” Klements says. “Take, for example, the difference between manual disintegration and automatic disintegration: If one is to test for end time disintegration of a tablet on a manual tester it would be necessary for the operator to visually assess the procedure, raise the basket to verify the tablet condition and to log results.” Yet, “When conducted in an automatic fashion, the operator starts the test and can return later. The equipment has detected the full disintegration and reports the statistics for each tube.”
Klements notes that in addition to enhancing productivity, automated processes offer other benefits, perhaps even helping companies overcome regulatory hurdles: “Investing … in more automated testing equipment and processes can add up to big savings in efficiencies and possible elimination of product recalls and FDA violations.”
Looking Forward to a Solid Future
Which current trends will continue to shape testing methods? We asked the experts what they foresee when it comes to the future of solid-dosage testing.
“More and more we are receiving inquiries from project planners which include the use of Fourier transform near-infrared (FT-NIR) content uniformity analysis along with the current physical testing performed in the production QA environment,” says Klements. “We see that there is some movement towards using this technology in order to implement real-time-release (RTR) testing.”
Mattes believes that NIR measurements will become increasingly common as time goes on: “From a quality perspective, as pharmaceutical manufacturers reduce the number of time-consuming, labor-intensive measurements, e.g., with high-performance liquid chromatography (HPLC), there will be a greater need for NIR measurements throughout the process stream for quality attributes like blend uniformity and content uniformity.” According to Mattes: “In a global sourcing environment, qualitative analysis of raw materials at incoming inspection is increasingly important with the advent of identification of every container demanded by the regulatory agencies, and the need for detection of counterfeit and contaminated products.”
Technology has come a long way, and it appears that even technological advancements may be around the corner. Mahn has observed that technology is starting to look at both much smaller and much larger molecules, especially when it comes to separation sciences such as ultra-high-performance liquid chromatography (UHPLC). “They’ve made strides in [UHPLC] over the last 10 years that are just unbelievable.”
Mahn worked with HPLC on a routine basis in the 90s, and at that time “columns were typically 15 to 30 centimeters, and you might find the occasional 10-centimeter long column.” The packing that is contained in those columns, used for filtering, used to have a particle size of “about 5 to 10 microns.” Although the previous particle size was already very small, “Today, it’s not unusual to find a 5-centimeter column that’s packed with a 1 micron, maybe even a .5 micron packing.” Columns and particles are not only smaller, but also more efficient: “What used to take 30 minutes to get through that column, they get it through there in 5 to 10 minutes max.”