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Process Validation: Can We Now Get Back to Basics?

    Process Validation: Can We Now Get Back to Basics?

    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.

    Three-Batch Generation

    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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    3 Responses to “Process Validation: Can We Now Get Back to Basics?”

    1. epcotint says:

      Process validation is being thrust on the industry so there will be resistance. Industry does not want they be told how and what to do, as they are profitable. cGMP guidelines have been there but they have not stopped bad quality products getting to the market. We can write, cajole and even threaten prosecution, change if it comes, will come at a slow pace. All of the associated costs will be passed on to the customer when they should not be.

      About ten years ago PAT and QbD became the buzzwords. We have yet to see their full adoption. We are still debating. Pharmaceutical Processing magazine website is running a QbD implementation survey and there are more against votes rather than for votes.

      Chemical engineering has been around more than 80 years. It is not being practiced in the manufacture of pharmaceuticals like in other chemical based industries. Has anyone considered why? Answers are simple. There is no need to change when I can make money based on my laboratory methods. If I am forced to change, I will practice but will not make an effort to become good or excellent. Since I can pass all inefficiency costs and make my desired profits why change.

      Many are singing the QbD song but everyone in the fortress considers it is just a noise nuisance. In pharmaceuticals, science based practices have never been the mantra. Unless a true science based maverick comes along and changes the playing field not much will change. Change has to come from within. A teacher can teach but unless student wants to learn, nothing will change.

      I am not saying we should stop singing or cajoling. May be some day the pharmaceutical industry will really appreciate the “sound of good science” and begin to sing. Let us hope our efforts will bear fruit some day.


    2. malcolm ross says:

      I was delighted to see the title of this article-back to basics. If you follow, as I do, the 483′s being issued you will see that the majority of non-compliance issues are absolutely classic. They are the same sort of issues that were prevalent in the industry 20 plus years ago. Most of them were eradicated in the 90′s and now they have come back to haunt us. We should try carrying out a root cause analysis as to what has happened. Now, I can only make some general suggestions but they are based on activities that I have been carrying out over the last 6 years as a consultant. One area is that more and more people are coming into QA without the traditional apprenticeships in the industry, i.e. 10 plus years in QC or production. A second problem is the involvement with such things as QbD, design space etc. which are not as simple as people would like to make out. Quality management spends its time focussing on these ideas, often without full comprehension, meanwhile the basics, like well trained staff and well written operating instructions and SOP’s.


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