Feature

Investing Time to Make Money: A PAT Implementation Perspective

John E. Carroll, CPhC, is a managing partner at Cadrai Technology Group, a Carroll Ventures unit, 1208 Queensway, Bel Air, MD 21014, tel. 410.838.8444, jcarroll@cadraigroup.com

Process analytical technology (PAT) is a fact of life in some manufacturing industries and it's more than conceptual in small-molecule drug manufacturing. In a startling role reversal, the US Food and Drug Administration introduced PAT as a way to radically change pharmaceutical quality methods and assumed a missionary role in promoting it. The concept was formalized when FDA issued a guidance in Sept. 2004 (1). The European Medicines Agency, working with the International Conference on Harmonization Q8 document, has a parallel effort in place. Why are regulators taking this active stance? Enlightened self-interest is the short answer. The industry is under pressure from the public to reduce consumer cost while assuring safety.  It has trouble doing so because its ability to produce consistently is strained by its own operational efficiencies. Regulators cannot keep up with mandatory inspection requirements, let alone the review and approval cycles necessary to keep the flow of new drugs on the market. Therefore, FDA is promoting PAT to help maintain consistent quality while improving pharmaceutical manufacturing efficiency. Those radical changes allow a departure from rule-based good manufacturing practices (GMP) testing and approval to good, current science as the norm. Regulators are greasing the skids for pharmaceutical manufacturers that adopt PAT methodology. FDA's PAT draft guidance states, "FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tool. FDA's routine inspection of a firm's manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods.)" (1) FDA's  Pharmaceutical Inspectorate also will support the PAT initiative. The Inspectorate will be a cadre of inspectors trained to be experts in pharmaceutical manufacturing, including PAT. PAT pundits draw on the doctrines of Six Sigma variability reduction and the continuous quality evolution of the Kaizen continuous improvement method (2) to show that PAT will benefit pharmaceutical manufacturing (see Figure 1). In practical terms, PAT is intended to increase pharmaceutical manufacturing efficiency from a low of 3% to at least 60%—a change that would dramatically improve costs and time-to-market (see Figure 2). And for the research and development (R&D) community, PAT may make drug development more competitive. So, why aren't all pharmaceutical manufacturers implementing PAT at breakneck speed? Rooting out the problems At present, the pharmaceutical industry is plagued with sparse pipelines, corporate mergers, less time before commercial drugs go off patent, market dropouts from pivotal blockbuster drugs, and pressure from consumers and politicians to produce high-quality drugs quickly. PAT cannot fix all of these problems, but it might affect the business picture of a pharmaceutical manufacturer. In announcing a $4-billion cost-cutting plan, Pfizer Chairman and CEO Hank McKinnell told the Chicago Tribune, "2005 will be a transition year. In addition to the loss of exclusivity on several important products, we are facing a number of uncertainties." He went on to say, "We expect our performance to rebound quickly in 2006 and accelerate in 2007 as we increasingly realize the benefits of the continued growth of major in-line products, new product launches, and productivity initiatives" (3). These productivity initiatives are likely elements of Pfizer's "Right First Time" (RFT) program, a global quality and efficiency improvement component of PAT (see Figure 3). In a recent Pharmaceutical Manufacturing interview, Robert Miller, PhD, Pfizer's director of quality operations for North America and Puerto Rico, defined Pfizer's RFT effort as predictive quality control. According to Miller, Pfizer launched the initiative in 2003 by asking every manufacturing site to identify two or three RFT projects (4). Most of these sites have trained the personnel to Six Sigma black belt levels and have interactive information technology tools in place. The projects ultimately involve root cause analysis of out-of-specification (OOS) and out-of-range (OOR) problems, with the goal of identifying critical-to-quality manufacturing parameters. Alphabetic acronyms notwithstanding, RFT is Pfizer's PAT program. When asked by Pharmaceutical Manufacturing whether the company's PAT projects have changed the way Pfizer handles quality control, Miller replied, "Our ultimate goal is not getting rid of traditional methods. We envision three stages to PAT implementation. First, get a better process understanding, then, once you have that understanding, identify variables critical to quality and monitor them, then, finally replace traditional quality assurance and control." He added, "When we make a batch, we're absolutely comfortable that that batch will be well within specification. And we won't have deviations. That's the real driver for PAT" (4). (continued)