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What Will the FDA Say? Time to Change the Question

    What Will the FDA Say? Time to Change the Question

    By Ali Afnan, Contributing Editor

    The drug industry takes pride in providing for patients who depend on its products. But whenever a new product, process or analytical technique is being considered, or an improvement to an existing process, the first question invariably is, “What will the FDA say about this?”

    FDA’s approval is critical to every pharmaceutical manufacturer’s existence and survival, so it’s understandable that companies spend considerable time, effort and energy trying to optimize the outcome.

    Until FDA formally responds, however, there is uncertainty. Over time, this has set up an adversarial relationship between the regulator and the regulated.

    Often, and especially with newer initiatives such as Quality by Design, those within industry question the level of training and education of FDA inspectors and reviewers. “Do they have enough training to be able to review a QbD-based submission?” some ask.

    Perhaps this is the result of past disappointment with a particular inspector or review process.  But will a passive response from industry lead anywhere? As Einstein once asked, isn’t insanity defined as doing things the same way over and over again and expecting a different response?

    FDA opened the door to dialogue with pharmaceutical manufacturers several years ago, with the PAT initiative, its guidance on dispute resolution and other programs designed to increase transparency and communication with both field staff and reviewers.

    However, the basis for meaningful dialogue with FDA or any regulatory agency remains the same: the ability to show process and product understanding, good science, and process control.

    How many drug manufacturers today have mastered even the rudiments of this language?

    Consider the following:

    • The pharmaceutical industry’s Lean indicators have changed little in over a decade, with stock turnovers averaging 2.33 this year, only 0.03 higher than they were 10 years ago [1].
    • Manufacturing issues continue to result in critical drug shortages, suggesting insufficient product and process knowledge and control [2].
    • The number of pharmaceutical recalls has increased [3].
    • Drug approvals are down [4].

    FDA’s job is to be reactive. After all, regulators stand in for consumers, the patients that this industry is proud to provide for. Their stance cannot change. What would today’s increasingly well-informed public say or do?

    However, by failing to engage FDA actively, and to question its responses, when warranted, with science, pharmaceutical manufacturers have only themselves to blame for the current impasse and industry’s lack of innovation and process improvement.

    And those are the manufacturers that already have process knowledge, and know how to get it. Many more manufacturers don’t know which questions to ask or what information to provide.

    At this point, regulatory uncertainty, rather than process and product understanding, still drives the approval and inspection processes—and the industry’s subpar quality performance.

    Regulation will always be subordinate to good science. As my friend and former boss Ajaz Hussain would say, “Science will prevail.”

    Surely, one of the biggest questions facing the industry today is how to utilize the best science and engineering practices to understand the causal relationship between product and process, and better manage and control the manufacturing process.

    Are not sound science and engineering practices the best, and perhaps the only, means to achieve the “Desired State?”

    The questions, and the supporting knowledge behind them, are often far more critical than the answers.

    But who must take the lead on all this? Hint: It’s not the FDA.

    Pharmaceutical quality and innovation demand a cooperative interaction between the regulator and the regulated. A culture of operational excellence and continual improvement can only be achieved, within industry and even, perhaps, within FDA, when our first question changes from “What will the FDA say?” to “Can I demonstrate knowledge and control of the process and product to the FDA?”.

    Unless firms are willing to use or learn this language—to be open with the Agency, proactively communicate process and product knowledge and demonstrate real-time process control, all regulation-dependent activities will continue to depend on what the FDA says.


    1. How Lean is Pharma?: A 10-Year Progress Report.
    2. Time, Cost Cited as Key Roadblocks to PAT, QbD: Expert Disagree.

    3. The Gold Sheet, reported on August 17th via

    4. FDA Expects Record Low Applications This Year

    About the Author
    Ali Afnan, formerly a scientist at CDER’s Office of Pharmaceutical Sciences, and a member of FDA’s original PAT Team, is now principal of the consulting firm, Step Change Pharma.

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    One Response to “What Will the FDA Say? Time to Change the Question”

    1. pkbasu says:

      Ali, historicaly, in other industries such as petroleum, petrochemicals, energy, defense, etc. industry has not invested much in basic research. Even today, just look at the federal budget on energy research for example. There is a CBO report on pharmaceutical research and development verifying this fact. Industry traditionally has been good in applied research. In pharma the fundamental science on many areas is sadly missing. One good example is the science of organic solids. While there are a lot of knowledge in the public domain on inorganic solids, the status of science and engineering of processing organic solids is a sad story. If the federal government is seriously interested in improving healthcare, reducing cost of healthcare and preserving jobs, they need to invest in fundamental research in pharmaceutical product development and manufacturing. The tremendous disparity between investment of federal dollars in pharma research vs. research in other industries tells me that there is total lack of understanding of the drug discovery and development process people who make decisions at the federal level. Very little (may be less than 1%) of the ~$30B that federal government gives to NIH is spent on basic research in product development and manufacturing. NIH likes to talk about translational research, but they are yet to put their money where their mouth is. I am unwilling to put all the responsibility on our industry. They just don’t have the necessary tools to implement QbD quickly and cost effectively. It’s no use beating up on our industry if we cannot provide them with the necessary tools. It is not the industries’ job to develop basic science. If the industry should be blamed, it should be for not educating our administration, senators and congressmen specifically about the futility of spending so much money with NIH with almost no research funding on the science of how to bring a new molecule to the market. It is hard for me to understand why our industry has not done a better job at that so far since they have one of the strongest lobbying organizations on the hill. May be there are some other factors that I do not understand. I think we should openly ask industry why they are not implementing QbD, what are the hurdles, why does it cost so much and how can we help them and remove the necessary obstacles so that QbD can be widely implemented. I agree with you that regulators are not the cause of the current problems.I would like to restate a very familiar phrase used during President Clinton’s campaign “It’s the Science Stupid!”


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