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QbD: Enabling Process Knowledge Beyond Validation

    QbD: Enabling Process Knowledge Beyond Validation

    By Pedro Hernandez, Pharmaceutical Consultant

    If drug manufacturing is not to remain an anachronism, more scientific ways must be advanced to improve product quality. Shown here, young Thomas Edison

    As a result of the FDA’s Process Analytical Technologies (PAT) and Quality by Design (QbD) meeting in Bethesda last month, a number of good comments and articles have been posted here and elsewhere on the state of QbD acceptance, or lack thereof, in the pharmaceutical industry, as well as whether incentives and/or mandates would help wider acceptance.

    Incentives should not be necessary, beyond the simplification of post-approval changes. If we, as an industry, do not take to heart that improving quality, science and process knowledge is in our patients’ and shareholder’s best interest, then we deserve the same fate as the Big Three car makers. The business case for QbD needs to be better articulated, as this is the only argument that some in the industry may consider.

    Mandates will not work. It is precisely blind compliance that has stifled process knowledge beyond validation, and, perhaps, even earlier, at the technology transfer stage.

    In the past fifty years, what progress has been made in advancing pharmaceutical manufacturing science? Not much, most would agree. We mix powders and press tablets, only now we can make more, faster. Is that enough?

    Making a Better Victrola?
    Drug manufacturing has become an anachronism, like the phonograph industry. In a world of LPs, CDs and iPods, the pharmaceutical manufacturing seems to operate in a time warp, churning out more and bigger cylinders, and larger, louder horns for extended listening at ear-blowing volume levels. These are products that nobody wants, made using yesterday’s technologies.
    Unfortunately, the undesired side effect of the three-batch validation pill has been the end of knowledge generation and process understanding after validation. Ask many a technology transfer scientist what he or she learned after completing a several-hundred- page validation report and the answer will likely be, “It met specification.”

    The actual process knowledge from scale up, through development, clinical and validation batches is usually unrecognized, shunned as errors, and buried in deviation investigation reports.

    This is where QbD comes into play, with its tools, including PAT, Lean Six Sigma, chemometrics, statistical process control and modeling. Besides generating process robustness and product knowledge during R&D, and sometimes during technology transfer, it enables more scientific drug manufacturing, and continual improvement.

    QbD can be used to generate “timeless,” rather than “reactive,” knowledge.  

    Timeless knowledge

    Reactive knowledge
    CAPA at its best

    Thus, the industry today is challenged to change a culture which, at best, has said, “If it works, do not fix it,” to one that asks, continually, “It works, but can we do it better?” We must transform a culture that has blindly abhorred change beyond validation, for whatever reason, to one that embraces change and innovation for quality.

    In the end, cultural transformation in the drug industry and FDA can only result when there is cross-functional collaboration, and a mixture of expertise and efforts. Above all, we must recognize and commit to the idea that achieving continuous quality assurance is everyone’s responsibility.

    Related posts:

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    One Response to “QbD: Enabling Process Knowledge Beyond Validation”

    1. epcotint says:

      Dollars, Yen, Euro or any other currency play in the decision to invest in any process, buying a new car for personal use or doing anything for share holders.

      Few years ago I wrote “Big Pharma: Who’s Your Role Model Toyota or Edsel?”

      Bottom line is financial justification for anything a human does. If at API level a company needs e.g. less than 1000 pounds of API (factory cost = $25.00 per pound) and generate revenue of about ONE Billion dollar, there is no justification to invest in any technology innovation i.e. QBD is out the window. However, if the cost of API at factory level is $10000 per pound and it is high dosage drug e.g. 500 milligram to generate ONE billion dollar revenue, there is value in incorporating improved methods QBD could become a reality even though reluctantly.

      Money talks only if I have return on investment. If I can make the money by passing the costs, I have no worries HAKUNA MATATA.



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