Michael Kraft

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? 

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 

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. 

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? 

Biopharmaceutical production is a growing area and a natural application for PAT as most processes are relatively new and many are still being optimized. Furthermore, most operating facilities are new because of ongoing expansion in capacity and are more easily automated. The entire biopharma process, beginning with feedstock quality control, through to the upstream process, downstream purification, lyophilization, formulation and ending with the final product test, has multiple opportunities to apply PAT sensors and statistical control processes. These may be as simple as singlepoint sensors or as sophisticated as full feedback control loops. 

Each of the many steps and degrees of freedom in the entire process significantly affects the end product. Therefore, control of any step will improve the process and, consequently, control of the entire process through application of PAT tools will justify the investment.  

Economic advantages of process automation can be seen be reviewing the history of successful, highly automated process industries. However, a number of issues must first be resolved to obtain wider acceptance and deployment of PAT in biopharma. 

• The pharmaceutical industry, in particular, seeks improvements with interfaces to process equipment and samples, reproducibility and calibration stability. Pharmaceutical companies are looking for rugged 'factory-ready' instruments with robust sources, alignment and calibration. PAT technology must comply and keep pace. 

• Managers want simplified interfaces for updating the chemometric model and more standardized models, and compatibility with other equipment and software, such as in-plant control systems. Again, the technology must keep pace. 

• The pharmaceutical industry expects sophisticated laboratory instruments to be tailored for PAT needs and used in place of custombuilt equipment. PAT would, therefore, be much cheaper than at present. Cost and value considerations are substantial barriers that must be overcome before PAT is widely used. This is a function of market volume and standardization, as well as adaptation to the production environment. In the pharma and biopharma industries, PAT will probably require more specific qualification guidance from FDA to develop standardized solutions. This is an ongoing objective. 

• Most companies prefer to purchase instrumentation directly from instrument manufacturers, but will work with systems integrators (SIs) and other service providers on a projectbyproject basis as needed. 

• Larger companies have resources — specialized teams at the corporate level and sometimes at plant level — that will broker a partnership with process control or process equipment manufacturers. 

• Pharma companies are mostly interested in system integration help as they usually buy from instrument manufacturers and not SIs.  

• Ease of use is important in all applications. These instruments have to be 'operator ready' — meaning they are easy to run, understand and maintain, with simplified internal diagnostics and expert system capability. 

• Service and support is important for all industries as many have been disappointed with what is available so far. 

• Most companies, especially those that have implemented solutions on their process lines in several geographies, generally want to have service and support globally rather than regionally. 

• Pharma and biopharma would additionally like vendor help with qualification (operational qualification/performance verification).

The industry is narrowing down the options to decide where to begin with PAT. Simultaneously, measurement solution suppliers are also making their choices in how to most effectively support their customers' workflow while achieving their short and longterm business goals by offering hardware, software, consulting and support.  

As an example, the Six Sigma Projects approach, developed by Motorola, could become the preferred method in PAT biopharma production investigation projects. The goal of Six Sigma is to systematically identify the most important process step; that which creates the greatest variability in the overall process, 

Define the scope of the project (i.e., the process step to be optimized).  

Measure the current process and certify that the information gathered relates to the scope of the project.  

Analyse the root causes and confirm with measured data.  

Improve the process step, test and implement changes that address the root cause, and use measured data to evaluate the solutions.  

Articles

PAT guidance has been available from FDA for more than 4 years, but there have been no apparent breakthroughs in large-scale upstream production. Will companies consider using on?line chromatography to change this?