By Ali Afnan, PhD, Principal, Step Change Pharma, Inc.
It was around 2002. The message of change was in the breeze. At FDA’s advisory committee meetings, the language of science was used to examine and discuss Good Manufacturing Practices (GMPs), both in practice and in law. To support and enhance the milieu for change, and to prevent GMP’s from getting in the way of innovation, the “GMP’s for the 21st Century” program was initiated.
But one area that industry remained unclear about was process validation, whose roots go back to a brief part of Chapter 21 of the Code of Federal Regulations (21 CFR). Validation is the GMP activity most frequently performed. Yet, after GMPs had become law, drug companies weren’t sure how they should interpret validation requirements.
FDA responded with a guidance in 1987, explaining its thinking about validation. Guidances are, by no means, law. It’s not “FDA’s way or the highway,” as has been proven in U.S. courts (see, for example, a judge’s decision regarding Utah Medical Products).
But the original process validation guidance was far less clear on principles and requirements, and led to misunderstandings. For instance, an example cited in that guidance was misinterpreted as requiring the “execution of three consecutive validation batches.” A string of engineering batches were needed to assure successful execution of 3 consecutive batches.
Let’s take a closer look at the original from 21 CFR 211.110(a), which states: “Control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability. . . .” Interestingly enough, “appropriate samples” is also another requirement of this same section of the regulations.
An entire industry has grown around the “three-batch practice.” Would any conscientious reader agree that three consecutive batches, even after a large number of engineering batches, satisfy either the spirit or the letter of the law?
Industry practitioners as well as most of the professionals at FDA agree that the “three consecutive batch” practice falls short of what it intended to achieve, namely validating the performance of processes responsible for variability.
Earlier this year, FDA published revised guidance on process validation. So, after 24 years, the Agency’s thinking on process validation has changed. What does this mean? The routine of “three batches and you are done” is no longer valid; truly “statistically significant” sampling is now a reality.
This guidance is far less prescriptive than what preceded it, even though that one wasn’t truly prescriptive either, just misinterpreted, with an example that became practice and reality.
Now it has three phases (see “A Practical Roadmap to Pharmaceutical Process Validation”) and the third phase seems like a never ending process! The reason is that a validated process is an outcome; in the past we have considered validation as a discrete activity and an input. I can hear many complaining that the 2011 guidance raises the cost of compliance; and asking how many batches comprise the “validation batches.”
Rocking the Boat
The FDA has rocked the boat. As a consumer, I am thankful that the Office of Compliance had the vision and drive to deliver a guidance of this nature—in line with common sense, science and good engineering practice.
Only reasonable guidance like this can bring the pharmaceutical industry’s quality and efficiency performance in line with that of consumer goods and other industries.
What “control procedures” have other industries like consumer goods established to “monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability”?
Is a three-batch process validation part of their control and manufacturing strategies? What end of line testing strategy do they rely on? Or do they simply run their processes to control the quality of the material attributes?
What about the cost of compliance? Surely a culture of compliance is inferior to a culture of quality. Should the medications that our well-being depends on come from a compliant mindset or a quality mindset?
Yes, the 2011 guidance will drive up the cost of compliance, if the mindset and hence the practice is that of mere compliance.
This guidance facilitates understanding the manufacturing process as well as the relationship between the product and the process, based on R&D information, and then facilitates real time control of the process. It requires, primarily, an open mind and an approach very different from the old three-batch mindset.
Once the process and the product, and their interrelationship, is understood and controlled, then the cost of quality will be reduced.
But how willing will a regulated industry be to change its practices, and how will the guidance be enforced?
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