I started in the pharmaceutical industry more than 50 years ago, in what would seem like the dark ages to many. As a young chemical engineer, I supported small molecule active pharmaceutical ingredients production, primarily with scaleup and troubleshooting. The production environment and process equipment were quite primitive, though well suited for the processes. Automation was virtually non-existent, instrumentation was largely limited to temperature and pressure, and analysis was performed using wet chemistry.
Pathway to Validation
A career change into drug production manufacturing introduced me to cleanrooms and process formulations. Some of the equipment was more sophisticated, notably lyophilizers and sterilizers that were electro-mechanically controlled. Working closely with Richard Wood, PhD, we successfully validated steam sterilization using a multi-channel chart recorder and biological indicators. We also made lethality accumulation determinations using a look-up table and an adding machine. This initial foray led me to what became my life’s work – validation.
In 1980, another career change put me in a new and challenging role, which involved establishing validation in a major pharmaceutical firm. In its infancy, validation had been defined as confirmation that the process does what it purports to do by various U.S. FDA spokespersons. Devoid of details beyond that core premise, there were no rules, guidances, or well-documented prior art.
I often articulated to my colleagues, “We’re making it up as we go along.” Without defined requirements, we were free to validate as we wished. We soon recognized the need for the development of some consensus practices. My superior, Gerald Jackson, PhD, suggested we develop a discussion group to share experiences and compare practices with other firms which were different from our own. This was the start of the Validation Discussion Group (VDG), which, at its greatest, encompassed more than 20 firms, embracing almost every major firm east of the Mississippi. Collectively, we largely established the discipline of validation that exists today. What might be surprising is that virtually all of this was in place before the availability of any FDA or other regulatory guidance. As a group, we identified issues, considered alternative approaches, reached consensus opinions, and set forth executing them independently. The collective efforts of the VDG led to many of the validation practices and approaches found in the industry today. The contributions of these individuals shaped many of PDA’s Technical Reports addressing validation-related subjects.
The Growing Presence in Computers
The next chapters of my career resulted from the growing presence of computers in pharmaceutical facilities. Process and analytical equipment were increasingly being equipped with microprocessors for operation. Mainframe computers were being used for the collection and retention of clinical data, analytical results, stability data, inventory, and other good manufacturing practices (GMP) applications. The need to confirm the correctness of execution, accuracy of results, system security, and more required confirming information. Computerized system validation across the industry was championed by a group at PMA (now PhRMA) led by James Harris and Ken Chapman.
As a participant in this effort, I advocated for terminology that could be used in process validation. The deliberate avoidance of terms not already prevalent in the GMP environment enabled a greater understanding of the principles supporting computerized systems implementation. A major breakthrough in approach came with the PMA’s 1985 recommendation of a life cycle concept for computerized systems validation, which was prompted by off-line discussions I had had with Phil DeSantis. We had already adopted this approach internally for both computerized systems and process validation by 1986! The FDA formally acknowledged the utility of the life cycle for the first time in 2008.
There is a clear lesson in this partial history of my professional career. As individuals and as an industry, we need to be leaders, not followers. Disrupters, pushing the envelope, taking risks, doing what no one else has done before, networking to the max, sharing our experiences, and learning from others. Whatever you do, whether new or simply a different approach, please do not wait for someone else to tell you how to do it. Be the disrupter that demonstrates how it can be done and become the leader that others will follow. While much has changed in our industry, there is still much more work to be done.
Technology continues to move forward, and the complexity of products continues to increase. But it will take disrupters to take the industry where it needs to go. If you remain complacent in your career or in the improvement of your organization, the impetus for change will be missing. One final point to reflect on and ask oneself: Where do new regulations and guidance come from? Remember that regulators are often working to keep up with the technical advances just like the industry is. Regulations and guidances often look backward at practices that are already in place. Where do those new practices come from? The disrupters are those who dare to do things differently. Be the change you want to see in industry and enjoy the ride. I know that has always been my passion.