Process Analytical Technology and Process Control in Solid-Dosage Manufacturing - Pharmaceutical Technology

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Process Analytical Technology and Process Control in Solid-Dosage Manufacturing
Industry is moving toward closed-loop control of continuous processing.

Pharmaceutical Technology
Volume 37, Issue 4, pp. 56-61

Continuous solid-dosage manufacturing

PAT can be used in continuous solid-dosage manufacturing, in which individual batch-processing units are connected in one process train. Advantages of continuous manufacturing include a smaller equipment footprint, production volume flexibility, and higher production efficiency, in addition to the potential for improved quality and process stability as a result of employing PAT. Continuous processing also allows more efficient process development. Because parameter-change effects can be measured in nearly real-time using a continuous setup, dozens of conditions can be tested in hours rather than days or weeks, notes Douglas Hausner, associate director for industrial relations and business development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), which is based at Rutgers, the State University of New Jersey. In most cases, the same equipment used in the development stage can be used in production, which eliminates the need for scale-up.

Although most solid-dosage processes today operate as a series of independent unit operations, pilot programs for continuous processing have made progress, and commercial implementation could occur within the coming year. The design of a continuous direct-compaction line built at C-SOPS, for example, was recently used to construct a commercial line at Janssen, which will be filed for FDA approval.

GEA Pharma System’s ConsiGma continuous manufacturing platform is an example of a commercially available continuous-manufacturing system. It can incorporate several different continuous technologies for the production of solid-dosage forms, such as wet granulation, dry granulation, and direct compression. The ConsiGma wet-granulation line consists of a blender, twin-screw granulator, fluid-bed dryer, granule conditioning unit, rotary tablet press, and continuous coater. This new generation of continuous manufacturing technology minimizes start-up and shut-down material losses because steady state can be reached quickly, notes Kris Schoeters, product manager for continuous processing at GEA Pharma Systems. PAT plays a crucial role in the GEA system. In the granulator, online optical systems are used to measure CQAs. Moisture content and blend uniformity are measured using NIR. Particle size is measured using an online laser-diffraction system, and tablet-content uniformity is measured using Fourier Transform (FT)-NIR transmission spectroscopy. Measurement data feeds into a process-control system to reach the goal of closed-loop control.

Sampling challenges

Incorporating PAT into a continuous process for solid-dosage drug production has not been a simple task, however. One challenge has been retrofitting the equipment to enable collection of the correct data from PAT devices. Some measurements (e.g., flow, pressure, and temperature) are readily available from inline sensors. Other measurements, such as online NIR spectrometry, are more complex and have required creativity in the physical interface with processing equipment. Enabling the sensor to collect good data, for example, has often required that probes and windows be retrospectively engineered into the processing equipment.

“NIR is a reflectance measurement that measures whatever is sampled by the probe. If a sample is stuck to the probe lens, it will be measured repeatedly,” notes Hausner. The C-SOPS line incorporates a window for the NIR measurement in the transfer pipe directly above the tablet press to measure blend content as close as possible to the tablet press. C-SOPS researchers investigated several different designs of modifying the pipe leading into the tablet press. The researchers concluded that plug-flow without turbulence was crucial to minimizing noise and allowing the analysis to run quickly.

Figure 1: An in-process optical probe enables process analytical technology (Lighthouse Probe, GEA Pharma Systems).
GEA Pharma’s self-cleaning Lighthouse Probe, developed with J&M Analytik, was designed as a solution to the problem of sample adhering to the lens (see Figure 1). The viewing windows can be cleaned during the process, and a self-calibration feature indicates if a window is contaminated.

Work at Pfizer included developing solutions for sampling, such as screw transfer devices that enable sampling points to be inserted in flowing powders and developing heated probes to avoid material sticking, notes Steve Hammond, senior director and team leader of Pfizer’s Process Analytical Sciences Group. Pfizer also conducted experiments to determine reflective properties of powders, depth of penetration, and return of radiation in loose and compressed powders. Other aspects of sampling, such as mass of material contributing to a measurement, integration times for scanning, and the effect of reference scanning had to be extensively studied and understood, adds Hammond.


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