Unit operations

PharmTech: With regard to solid-dosage manufacturing, is it now feasible to apply process analytical technology (PAT) throughout all unit operations or are certain operations not conducive to on-line or at-line testing?

Vaisman (Malvern Instruments): Not only is it possible, it is being done. A wide variety of PAT equipment is already commercially available for monitoring, for example: homogeneity, composition, particle-size distribution, density, moisture content, and other parameters. These technologies are being applied across the spectrum of unit operations used by the pharmaceutical industry. While certain applications are particularly exacting in terms of the demands they place on an analytical technique, I believe progress is being made in almost all relevant areas.

We expect to see improvement in measurement technologies across the board though, which will continue to improve the ability to monitor for process control purposes and provide analytical measurements for quality control.

PAT applications in solid dosage

PharmTech: Can you offer some specific examples of PAT being applied in solid-dosage manufacturing? How would the data used at this particular step be used for the real-time release of a finished solid-dosage product?

Vaisman (Malvern Instruments): A common unit operation in the pharmaceutical sector is milling, to produce actives and excipients of defined particle-size distribution for subsequent processing, and/or formulation. On-line particle size analysis enables the automatic control of a mill and provides continuous monitoring of the exiting material.

In "A PAT Solution for Automated Mill Control," published in Pharmaceutical Technology's January 2010 issue, the authors describe the use of on-line laser diffraction particle-size measurement to automate mill control at a commercial site. The generic solution developed has widespread application. With automated control in place, the operator selects a particle size set point for the product. The speed of the mill rotor then varies automatically in response to real-time particle-size data, so that the specification of the exiting material is consistently maintained, even during fluctuations in the feed. The result is better product quality, higher throughput, and less waste.

This solution could be directly applied for RTRT provided that correlations between laboratory QC and the process instrument are in place. This is a readily achievable goal with laser diffraction particle-size analysis.

Redman (Mettler-Toledo AutoChem): In solid-dosage manufacturing, the size distributions of particles and granules are known to be critical parameters affecting final product quality (i.e., influencing critical powder properties such as compressibility and flowability, which in turn impact the tableting step that determines final product quality attributes such as dissolution rates and bioavailability.) Recently, in-line techniques, such as focused beam reflectance measurement (FBRM) and at-line techniques such as laser diffraction, have been shown to provide the capability to measure the progress of size enlargement processes by roller compaction, high-shear wet granulation, and fluid-bed granulation. The ability to monitor particles in real time permits the control of continuous roller-compaction processes through the manipulation of roller speed, gap size, and roller pressure. Likewise, batch processes, such as high-shear or fluid-bed granulation can be monitored until the granule distribution hits a predetermined endpoint. In either case, measuring the particles in-line or at-line provides the ability to control the granule-size distribution.

Farquharson (Real-Time Analyzers): We have used Raman spectroscopy to monitor drug synthesis and crystallization (kinetics and yield) in-line, and polymorphism at-line, steps that precede compaction, tableting, and so forth. We have also used chemometrics, full spectral analysis, to relate process parameters to product quality (e.g., product to by-product ratio). The greatest advantage of RTRT is the ability to identify when a process/manufacturing step is heading out-of-control so that corrective action can be taken. Even if an out-of-specification product is made, savings can be realized by not continuing with the remaining steps. For example, blending an out-of-specification active (e.g., too much byproduct) with the incipient, followed by compaction, coating, and so forth, can be a substantial financial waste.

Changing analytical methods

PharmTech: How does analytical-methods development change when working in a PAT environment? What are some of the challenges that might arise in scaling up a process from a laboratory scale to the manufacturing scale?

Godec and Yourkin (GE Analytical Instruments): Analytical methods, if properly validated to the requirements of the International Conference on Harmonization Q2(R1) guideline on analytical validation, and for their intended use, will not generally change. Analytical methods can be subject to scaling problems, however. For example, scaling problems can occur when the automatically collected or measured sample is not representative of the bulk-material analyte concentration.

Vaisman (Malvern Instruments): Method development for a PAT system must take into account a wider scope of parameters than just the measurement system and material. In particular, the process interface must be carefully considered to ensure representative analysis. Techniques where results can be affected by multiple variables tend to cause more difficulties during scale up, and in many cases, a new method must be developed for larger scale.

For example, contrast the example of particle-size analysis by laser diffraction and by ultrasonic extinction. The former technique is based on first principles and is relatively insensitive to variations in environmental factors. Laser-diffraction results will change only if the particle size of the product changes. On the other hand, the results produced by ultrasonic extinction are dependent on multiple factors, including temperature, moisture, bulk density, and others. Should any of these factors change during scale up, the result will be affected even if the monitored value (particle size) has stayed the same.

Farquharson (Real-Time Analyzers): The greatest challenges in scaling up a process is maintaining yield and minimizing byproducts. This difficulty is largely due to the fact that mixing and heat are not uniform at larger scales. Consequently, a laboratory-based analytical method may not be easily transferred to the process. For this reason, Raman and IR may be preferred over NIR because of their greater information content, and because the analysis may need to be changed. If complex models are used, such as chemometrics, model transfer from analyzer-to-analyzer may be an issue. X-axis stability and resolution must be maintained. The latter is problematic if a dispersive analyzer is planned for the process, but an interferometer-based Raman analyzer was used in the laboratory. It is also worth stating that full-scale reactors are not always as pristine as laboratory-scale reactors, and fluorescence interference can occur when using 785 nm lasers to generate Raman.