PAT Provides New Insights Into Drying

PharmaManufacturing.com

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.”