PAT Provides New Insights Into Drying

Vendors, manufacturers team up to roll out the latest in mass and NIR spectrometers, effusivity sensors and other PAT-worthy technologies.

By Angelo De Palma, Ph.D., Contributing Editor

Now that pharmaceutical manufacturers have enthusiastically embraced Process Analytical Technologies (PAT), the real fun starts. With FDA’s encouragement, innovation is suddenly in fashion.

Solids, particularly blends and processed powders, have always challenged analytical chemists. Traditional analysis of drying and solvent operations through loss-on-drying involves removing samples and measuring how much mass is driven off through combined heating and vacuum. One could hardly imagine a semiconductor manufacturer or even a candy maker employing such an antiquated technique. Loss-on-drying is so time-intensive, dryers must be powered down to avoid possibly overshooting the dryness mark. Too-dry batches may be rescued by adding water and repeating the blending/drying/analyzing cycle, but now a process that might take one shift takes two or three. Often such batches are simply thrown out.

Because manufacturers have had difficulty controlling drying operations, specifications for drying have been defined so broadly as to be meaningless. “You can drive a bus through some of those specs,” notes Nancy Mathis, president of Mathis Instruments (Fredericton, New Brunswick).

Drying has been a favorite target for PAT-happy manufacturers, who have snapped up the latest in PAT instruments, sensors, probes, samplers and automation-related equipment. Mathis Instruments, whose specialty is effusivity sensing, has placed evaluation instruments in and maintains evaluation projects at around a dozen pharmaceutical facilities.

A nondestructive technique, effusivity supplies heat, then measures how rapidly heat flows out of a material. As an online method, effusivity requires that materials be diverted from a fluid bed dryer. Its speed (one measurement per minute) and resolution (about 0.25%) permits moisture determinations in near-real time.

The goal is process understanding

Increasingly, says Mathis, manufacturers interpret the PAT guidance as covering only direct product measurements. “Although the guidance clearly does not discourage use of temperature, pressure drops, and even torque measurements, people believe these are secondary measurements. This point of view holds that FDA is looking instead for physical, chemical, or microbiological measurements of the product itself rather than the process stream, although one could make an argument for either side.”

Fluid bed dryer vendors, whose instruments contain built-in exit gas analysis, will argue against retrofitting equipment with additional layers of analytics which provide only minimal benefit. “This is fine,” comments Mathis. “If it works, there’s no need to fix it. After all, the goal is not PAT itself or sensor technology, but process understanding, which exit gas analysis can certainly provide.”

According to the PAT guidance in its new risk-based GMPs, FDA does not discourage companies from using any technology – including those that may not fall under a particular definition of PAT – as long as those techniques provide greater process understanding.

Effusivity-monitoring technologies jointly developed by Invensys and Mathis Instruments measure moisture end points quickly and precisely. Courtesy of Mathis Instruments.

Vendors are also teaming together. Invensys Validation Technologies (Foxboro, Mass.) has joined Mathis Instruments on developing a fully automated, on-line PAT system for fluid bed dryers. The two companies have just completed a six-month development program to provide a compliant control system for online end-point product moisture determination. The system extracts material from the fluid bed dryer and delivers it to a testing apparatus where the effusivity sensor determines moisture content. Product is then returned to the dryer. Analysis occurs without opening the dryer, modifying the analyte, or interrupting the process, and is free of human intervention.

Although not as well known and characterized as near-infrared (NIR) analysis, effusivity has many believers judging from the number of partners, vendors and pharmaceutical firms alike that Mathis has recruited for joint ventures.

Invensys plans to introduce its turnkey FBD moisture monitoring systems as part its overall PAT offering at Interphex 2005 (April 26-28; New York). The company will also unveil advanced control software, automation systems and online sensors and instrumentation.

Mass analyzers have feelings, too

The argument that exit gas analysis is not really PAT because it does not measure product properties directly is dubious. Were direct measurement a necessary criterion for PAT, very few analytic techniques would make the cut. More relevant for drying is the fact that dryness measurement is not about the product, but rather looks for solvents which are distinct from the product. One could say the product only gets in the way of this analysis.

As Tony Slapikas, product manager at Ametek Instruments (Paoli, Pa.) points out, exit gas analysis measures, in a fashion, the entire contents of a dryer. “A sample you analyze by pulling it out or from behind a window is just a small subset of what may be a very inhomogeneous blend. Whereas even if caked material is sequestering solvent far from the sensor or sample, exit gas analysis will see it.”

Sales of Ametek’s ProMaxion process mass spectrometer, which is used to monitor drying in real time, have been brisk. Customers include “all major pharmaceutical producers in both the United States and Europe,” according to Slapikas.

As a process-worthy mass spectrometer, ProMaxion lacks most of the bells and whistles of research instruments. “As MS instruments go the ProMaxion is a Ford pickup rather than a Ferrari,” Slapikas notes. The instrument also analyzes fermentation off-gases, mammalian cell culture, and assists in solvent swapping studies and reaction end-point monitoring.

Ametek can retrofit the instrument to tray dryers, centrifuge dryers, cone dryers, filter dryers and vacuum dryers. Slapikas claims Ametek’s Process 2000 software, which drives the ProMaxion, was specifically written for MS-shy technicians and complies with 21 CFR Part 11.

MS addresses several shortcomings of more common optical methods such as poorly-resolved spectra and difficulty with solvent mixtures. Plus, MS has a demonstrated sensitivity greater than both NIR and Raman, the two most popular optical methods.

Optical methods require a fair amount of application and calibration development, especially when dealing with multiple solvents, which makes them more difficult to use than mass spectrometry.

“Industry uses more than 40 solvents,” says Slapikas, “and sometimes three or four are present in one process. With NIR you need a separate method for each combination. You can’t just give the instrument pure solvents and assume it will detect them in mixtures.”

MS also requires a solvent response curve, but the molecular weight peaks are unmistakable, even in complex combinations. Generally, MS concentration linearity is excellent from about 90% to 0.1% – the “business” region of most process analytic efforts. Linearity is not an issue when complete solvent removal is desired, for example with organics.

While a Process MS instrument can be expensive, the multi-dryer sampling capability provides a low cost-to-dryer ratio. Deployment, design, and engineering costs are also somewhat lower for exit gas analysis than for optical measurements taken on samples or through windows. Slapikas claims large manufacturers can realize time savings of anywhere from 30 to 70% per drying run, a brisk return on investment assuming a cost of $500 to $1,500 per hour for running a dryer.

Micro-sized NIR spectrometers by Axsun Technologies allow for non-invasive inline measuring of expensive or potent APIs. Courtesy of Axsun Technologies.

But optics still rule

Despite the promise of MS and effusivity analytics in drying applications, optical methods still rule the world of chemical analysis. In terms of numbers most successful PAT-for-drying implementations, and a good deal of analytic innovation, will probably emerge from this area of spectroscopy.

For example, Axsun Technologies (Billerica, Mass.) was founded in 1999 to create miniaturized optical instruments for the telecommunications industry. Although successful technologically, the telecom downturn left Axsun without its key customer base. So the company has entered the PAT marketplace with some early successes. One of its instruments, the NIR-APS (Application Prototyping System) NIR spectrometer—as small as a matchbook—bravely goes where no full-sized instrument has gone before: into the working environment of an active pharmaceutical ingredient (API) process dryer.

In one early installation, Axsun designed a special gas cell and interfaced it to a two-inch diameter gas exhaust line. NIR-APS interfaces to that cell, monitoring vapors as they emerge. Axsun has installed several of these monitors at GlaxoSmithKline facilities in the United States and Europe.

Inline NIR has the advantage of not requiring sampling or handling of expensive or potent APIs. Richard A. Crocombe, director of marketing for Optical Micro-Instrumentation at Axsun, estimates that inline PAT for drying saves between one and two hours per measurement.

“The interest in PAT could not have come at a better time, both for the industry and for Axsun’s micro-spectrometers,” says Crocombe. “The ability to place a high-performance NIR spectrometer in a process is a tremendous advantage. These tools simply didn’t exist until now.”

Axsun is also developing a miniaturized Raman spectrometer, which works similarly to the micro-NIR device, but Dr. Crocombe believes the NIR device has a better chance at gaining acceptance in pharmaceutical manufacturing because the industry has more experience with the technology.

Axsun’s success will be in part based on NIR’s wide acceptance and familiarity among PAT-savvy manufacturers. The technique’s ability to analyze non-invasively through inline instruments or probes, or through existing site glass ports, allows integration of analyzer and drying equipment without major overhauls.

A fiber optic probe on the job. Courtesy of Bruker Optics.

Bruker Optics (Billerica, Mass.), which specializes in optical PAT technology, offers instrumentation, and methods for fluid bed dryers, filter dryers, and tray dryer monitoring. Each application has unique challenges.

Fluid bed drying process analytics offer the most options since the analyte powder is free-moving within the dryer. Bruker’s setup uses a bundle of light-delivering and -reading fibers inserted directly into the process through a port. A non-contact alternative works through a sight-glass.

Filter dryers are more complex because the analyte sits atop a filter bed and must be sampled. Bruker’s solution uses a tapered probe with a sheathed optical fiber that punches directly into the cake and takes readings.

For tray dryers containing multiple stacked trays, NIR analysis is most easily achieved using exit gas analysis. For all these methods (and others) spectrometer response must be normalized to signals from material in different states (e.g. fluidized, cake) using mathematical pretreatments that account for scatter, vector normalization and particle size. “Data pretreatment is not unique to these applications,” says Dan Klevisha, Bruker’s VP. “It’s used in a wide range of real-world PAT applications.”

Happily, PAT has become more than just another industry buzzword. Industry’s genuine enthusiasm for analytics sets PAT apart from other FDA initiatives. With the potential to significantly lower cost of goods for many drug products, PAT will almost certainly save manufacturers money. How lower costs will affect competition or, ultimately, drug prices is anyone’s guess.



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