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PAT: Gateway to Advanced Control for Operational Excellence

By Rick Rys, President, R2 Controls, and Janice Abel, Director, Global Pharmaceutical and Biotech Industries, Invensys

PharmaManufacturing.com

Keywords: advanced process control, Process Analytical Technology, neural networks, model predictive controls and object-oriented architecture

Pharmaceutical and bioscience manufacturers have a new advanced automation toolbox.

Before the U.S. Food and Drug Administration (FDA) released its final guidance document on Process Analytical Technologies (PAT) in 2004 (see "PAT Means Revolution — For FDA, Too," Nov./Dec. 2004), it was very difficult for pharmaceutical manufacturers to optimize their operations without going through the costly and time-consuming process of revalidating them. Once a drug manufacturer submitted a New Drug Application (NDA) submission to the FDA, any changes to temperature settings, pH levels or other process conditions triggered revalidation, even if they improved efficiency or product quality.

PAT allows pharmaceutical manufacturers to optimize the way they use their plant assets to produce specific drugs, ultimately permitting them to reduce the price that the consumer pays for their products. PAT also allows pharmaceutical manufacturers to apply advanced process control (APC), even to such challenging cases as biopharmaceutical processes. Successful use of APC in biopharmaceutical processes simply requires fine-tuning, constant readjustments and updates. These changes were impossible before PAT, when simply retuning a single process-control loop could be considered a “significant process change.”

By encouraging drug manufacturers to broaden their focus from compliance and time to market, PAT allows drug makers to strive for “operational excellence,” a term that also includes the goals of improved efficiency and quality and lower manufacturing cost. This article outlines some of the APC and optimization technologies that PAT allows drug manufacturers to harness, discussing the strengths and weaknesses of each.

Eliminating variability

In a perfect world, processes would be immune from upsets. In reality, though, all processes — and certainly the batch processes that dominate pharmaceutical manufacturing — are subject to upsets from a variety sources. Even continuous processes have variations that are clearly seen in the differences between start of run (SOR) and end of run (EOR) conditions. These differences depend on equipment age and other factors. The Table below describes sources of process upsets that can be minimized through use of advanced automation.

A climate of openness and consensus building can help promote the use of more advanced process control in pharmaceutical manufacturing. “Open control” standards such as S-88 and S-95 allow drug manufacturers to take an integrated approach to automation. A comprehensive object-oriented IT architecture (Figure 1, below) enables open control, and should serve as the platform for any advanced control program strategy, allowing users to access batch and plant asset information from different sensors and databases within the plant.

Figure 1. Object-oriented architecture.

A flexible control system platform designed with the principles of S-88, S-95 and other standards in mind will allow users to categorize control functions that are similar throughout the organization and then validate them as individual templates or objects of information.

This solution also makes it easier to validate individual modules or objects of information for similar functions. For example, if pH or temperature control is the same on all mammalian cell cultures, you can create a template of these controls and pre-validate it for use in all cell cultures. Although the unique parameters for each culture will still have to be accounted for and validated, not having to re-validate the pH or temperature control strategy each time, will reduce validation effort and time considerably. A number of pharmaceutical manufacturers, such as Genentech [1], have taken this modular approach, using open batch control to develop procedures that simplify validation, expansion and startup.

Limits of certainty

While the accuracy of temperature, pressure, and flow instruments may be well understood, their impact on product quality usually isn’t. On-line analytical instruments such as pH and dissolved oxygen meters often require more maintenance and are harder to put directly into feedback control service — especially after they have been sterilized repeatedly.