PAT and QbD Implementation in the Pharmaceutical Industry

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Introduction

Changing Practices in the Pharmaceutical Industry

The pharmaceutical industry is implementing Quality by Design (QbD) and Process Analytical Technology (PAT) more and more, making their symbiotic nature even more obvious. PAT and QbD are catalysts towards the achievement of a transformed way of working. This article investigates the changing practices within the pharmaceutical sector, using real-time particle size analysis as an example to study the analytical solutions required and the benefits they deliver.

In spite of its development in many areas, the pharmaceutical industry still remains traditional in its manufacturing practices, mainly because of the regulatory framework in which it functions. Batch processing is still being performed in production facilities, leaving little scope for embedded automation.

Figure 1. Current – Transforming manufacturing practice within the pharmaceutical industry.

Figure 2. Alternative – Transforming manufacturing practice within the pharmaceutical industry.

The FDA aims to change this production model to resemble that of the bulk chemical industry (Figures 1 and 2). However, such a transformation is very difficult and requires the industry to focus on processing in an entirely different way.

Continuous and Automated Real-time Analysis

In new manufacturing processes, continuous real-time analysis will be a major element, and this will mean using technologies that are unique to the pharmaceutical industry. Particle size, homogeneity, and composition are only some of the variables for which consistent analytical solutions are required. Furthermore, real-time measurement also enables processors to monitor and control the quality of products continuously rather than just test for it at the end stage of the process. Therefore, continuous real-time analysis can potentially enhance equipment utilization and reduce the amount of waste produced.

Automated real-time analysis can considerably reduce the issues related to establishing the operating window for regulatory approval and this is a main QbD activity. The recommended approach to developing pharmaceuticals involves identifying key product quality attributes and developing an understanding of the production variables affecting them.

Since PAT helps in examining these critical control parameters (CCPs), it speeds up the product development cycle. For instance, with in-line or on-line particle size analysis, it is now possible to examine the impact of different milling variables in hours, in contrast to days or even weeks. At present, PAT instruments are being used in research and development pilot centers and also in full scale production.

Specifying a Process Analytical System

In order to ensure continuous process monitoring, the pharmaceutical industry requires solutions that satisfy a set of limitations. The three main requirements of a process analytical system are: process relevant information, in a process relevant timeframe, and from a process appropriate device.

First, the analyzer must quantify a defining parameter for the process. For instance, in milling process the aim is to develop material with a specific particle size and size distribution so as to ensure optimal processing downstream. Therefore, real-time particle size data is highly relevant.

Many analytical technologies often fail when it comes to delivering measurement results in a process-relevant timeframe. This can be overcome by two important parameters; measurement acquisition time (MAT) and data acquisition time (DAT). MAT is the time taken for the device to obtain and examine adequate data to create a measurement result, while DAT is the time taken for the device to acquire a piece of data. MAT is more important among these two parameters, as it will determine the effectiveness of control and monitoring.

Lastly, automation and reliability are also important, and ideally the instrument will contain self diagnostics. Another requirement in the pharmaceutical sector is the need for cGMP/GAMP compliance. Communications between the controller and device are also crucial because connecting the device with other analyzers into a centralized control system will boost its value.

Laser Diffraction Technique for Online Particle Sizing

Laser diffraction is a well-established technique for particle size measurement and is extensively used in a wide range of industries. This technique is fast, non-destructive, and does not require calibration. It has been effectively integrated in robust devices that meet the rigorous needs of the pharmaceutical processing environment. It is versatile enough to be used for both wet and dry systems on the pilot plant, in the laboratory, and for full scale production.

Figure 3. Demonstrating the effect of multiple scattering on the accuracy of laser diffraction results and the effectiveness of a patented algorithm for data correction.

In order to function as a true real-time measurement device, an on-line particle size analyzer must deliver precise results in changing process conditions. If it does not, multiple scattering can affect the accuracy of data for more concentrated particle streams. This issue is addressed by patented algorithms integrated into Malvern’s systems, enabling precise measurement in varying concentration conditions (Figure 3), and thus extending the applicability of the method.

Spray Drying

Figure 4. In-line particle size analyzer installed on the existing line from a GEA Spray Dryer type SDMicro.

Spray drying is a single unit operation for which particle size is a key parameter. Figure 3 illustrates an in-line laser diffraction analyzer measuring the output from a lab scale dryer. The instrument is capable of measuring the total product stream, generating data with high statistical significance. A feedback control loop helps in manipulating feed or atomizer pressure to maintain the size of particles at a given set point.

Conclusion

Continuous and automated real-time analysis plays an important role in the transformation of the pharmaceutical industry. At the development stage, it delivers the data needed to economically implement a QbD approach, while at the production level it will strengthen the shift towards continuous process monitoring and real-time release.

Although the PAT initiative promotes the adoption of novel analytical technologies, it is yet to make a significant impact on full-scale production. Laser diffraction is a suitable method for both wet and dry systems. Exploiting the true potential of such technologies will allow the pharmaceutical industry to manufacture in a cost effective way. Moreover, by building on the expertise of other industries, it would be possible to implement optimum processing techniques using modern technologies.

About Malvern Instruments

Malvern provides the materials and biophysical characterization technology and expertise that enables scientists and engineers to investigate, understand and control the properties of dispersed systems.

These systems range from proteins and polymers in solution, particle and nanoparticle suspensions and emulsions, through to sprays and aerosols, industrial bulk powders and high concentration slurries. Used at all stages of research, development and manufacturing, Malvern’s instruments provide critical information that helps accelerate research and product development, enhance and maintain product quality and optimize process efficiency.

This information has been sourced, reviewed and adapted from materials provided by Malvern Instruments.

For more information on this source, please visit Malvern Instruments.

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