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The long awaited Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance was released by FDA in September 2004 as a nonbinding recommendation for pharmaceutical manufacturers. The driving force behind the document is the realization that the industry must improve product quality and production efficiency, drive down costs and provide effective treatment options at sustainable prices. The evident means to this end is to effect production automation and production analytical techniques in pharmaceutical production that are now routinely used to good advantage in other process industries.

However, more than 4 years after its issuance, PAT implementation is still a work in progress with test installations, but no real breakthroughs in either pharma or biopharma largescale upstream production. Why?

It is well known that other industries, such as hydrocarbon processing, semiconductor manufacturing and food, have a long history in costefficient process analysis. Process spectroscopy, online or inline, for manufacturing in these industries is commonplace. By contrast, even the largest pharma/biopharma companies rarely have more than a handful of online or inline instruments used in their facilities, and most of those are used for monitoring environmental emissions rather than production.

So what is driving (or preventing) the pharma and biopharma industries from using on-line technology in production processes beyond simple, singlepoint, noninvasive spectroscopy techniques? Will they consider more capable techniques such as on-line chromatography to implement Quality by Design (QbD) in production?

Industry perceptions

A brief survey of on-line instrument users, conducted by Groton Biosystems (MA, USA) as part of its business planning process in 2003, yielded the general opinion that on-line instrumentation causes high instrument and project costs, complex operation and regulatory headaches. In other words, the perceived value of PAT is questionable. Specifically:

• instruments have a high initial purchase price
• operating costs are even higher than before
• project costs can be three times that of instrument costs
• instrumentation sensitivity is still not good enough
• calibration is difficult
• oneoffs are the rule and not the exception
• reliable physical interfaces to get access to the sample with processing equipment are difficult to achieve and maintain.

These reason explain the reluctance to move forward with PAT technology. However true these perceptions may have once been, there have now been many advances in modern PAT instrumentation.

Change for the sake of change?

Even as technology barriers to PAT are eliminated one-by-one, there will continue to be business and regulatory challenges to widespread PAT implementation in the industry; for example:

• Plant management is conservative. Plant managers and engineers do not want to modify manufacturing equipment unless it is absolutely necessary. However, most current PAT measurement equipment can be fit to process streams with minimal modification.
• In regulated pharma and biopharma, the substitute PAT measurement solution must be validated and qualified with a regulatory agency. To streamline the process and to accelerate 'buyin', FDA has incorporated 'safe harbour' and other inducements in PAT guidance. ICH guidelines are following suit.
• Software validation requirements hinder adoption as a large number of chemometric software applications are difficult to validate or do not meet a company's quality criteria. While this is true for many existing chemometric platforms, an alternate approach is to use existing wellqualified, easytovalidate and familiar software products to perform the appropriate level of data reduction. Often, data only need to be reduced to the same format and standard as that which is found in a typical laboratory assay and familiar to all users.
• Sophisticated process analytical instrumentation is difficult for plant operators to use. This is true, but modern graphic user interfaces simplify operation. Totally automated feedback loops will control the entire process with minimal intervention required.
• The European community's ATmosphères EXplosibles (ATEX) rating is important for plant floor installations. Most systems and instruments can easily meet ATEX or equivalent requirements with only moderate modification — most often through use of offtheshelf enclosures.

As technical and regulatory arguments against PAT implementation are successfully and positively addressed as the industry moves forward, the remaining arguments become financial. How does one make it work in the current and future economic climate?