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Is QbD a Mandate for Generics? FDA Responds to Confusion

    Is QbD a Mandate for Generics? FDA Responds to Confusion

    By Paul Thomas, Senior Editor

    Last fall, FDA’s Lawrence Yu, deputy director for science and chemistry in the Office of Generic Drugs, said the following:

    “As we’ve said many, many times, FDA Office of Generic Drugs expects QbD applications starting January 2013. You heard right, full implementation of QbD in January 2013.”

    The “full implementation” part got people buzzing, arguing, and feeling a bit unprepared. More than half a year later, there is still confusion. Was Yu saying that QbD-based submissions will be mandatory for all generics manufacturers come January 1?

    Not so fast, say many experts—many of whom have come forward on this LinkedIn thread on the topic. (Membership is required to read–request an invite of the Quality-by-Design group manager.) As our in-house expert Emil Ciurczak quickly pointed out, to mandate something requires much more than someone at FDA saying so. “As far as I am aware, QbD isn’t a requirement, just a strong suggestion,” Ciurczak wrote. “The FDA doesn’t have the courage/ability/legal basis to require it just yet. It stands as a wonderful concept that will help decide the viability of the industry as we know it.”

    In a following post, a representative of generics giant Teva joined in: “FDA is preparing the generic industry for a 2013 ‘deadline’, when QbD submissions will be expected.” She suggested to group members that they prepare themselves by reviewing recently published case studies.

    Ciurczak and the professional from Teva are, for the most part, correct. (For an official response from FDA, read below.) And yet there is still uncertainty about the degree to which generics manufacturers must be prepared. On the same LinkedIn thread, a representative from Piramal Healthcare in India then posted: “Considering various workshops and the model case studies published by FDA, its clear they are strongly recommending it. Industry is yet not clear to what extent they need to comply with QbD.”

    To which Ciurczak responded: “The market will bury the slow, lame, and stupid in time, I believe, so QbD is optional . . . as is breathing, eating, and living.”

    Yet another poster from JB Chemicals in India expressed a common fear regarding QbD: “I think it is going to be very reviewer specific rather than a uniform review of our (developers’) product and process understanding.”

    The Teva member chimed in about her concerns: “I would say that the biggest challenge and key to implementation is in the mind-set change” within one’s own organization. QbD is not a “paper exercise,” she pointed out.


    Just when it seemed the discussion had reached a consensus—QbD is highly encouraged for generics, but not “mandated”—another group member brought up Yu’s quote again. Read the quote, he wrote. FDA will require QbD for generics starting in 2013.

    Ciurczak jumped back in: Dr. Yu, he said, “expects to be able to receive and understand QbD applications by January. OGD will post examples and has and will hold workshops. The examiners will be trained so they can read and understand any applications submitted . . . by January 2013. In no way did he say it would be mandatory, only that THEY will be ready to accept QbD applications by then.”

    Ciurczak continued: “I wish it was made law, but the vast amount of misunderstanding in the (entire) industry would mean a scramble to do anything on everything; the cost of simply buying all that equipment in a short amount of time, not allowing a learning curve, would be a disaster. If QbD becomes law, I am quite sure more than six months will be allowed for the changes needed.”

    Another LinkedIn member from China then joined the conversation: “Dr. Yu told me a few days ago, it is mandatory and January 2013 is the deadline.” Another member agreed, saying that at Generic Pharmaceutical Association (GPhA) meetings this year, FDA “clarified it is planning to mandate QbD in the development of Generics from January 2013.”

    “I thought I put this to rest,” Ciurczak retorted. “There have been NO notices, NO legal proceedings, and NO concrete plans to make QbD the law. The site where Dr. Yu is quoted shows he is preparing FDA inspectors to accept QbD applications. Now in one-on-one conversations, he has implied that it will become law, but there are no legislative steps being taken to make that happen. Right now, it is merely a good idea . . . not the law.”

    Another of our frequent contributors, Pedro Hernandez, added: “It is totally unenforceable! Not enough resources by the regulatory agencies and there is not a viable global standard. New products? All products? What percent of products? What is enough QbD? Darwinism will sort them out!”

    Fun and Games

    A Swiss consultant to generics manufacturers helped clarify as well: “I think we could see some fun and games around Dr. Yu’s insistence that it will be mandatory . . . there is no guidance that I can find that makes it mandatory . . . and in fact if you look at the most recent ICH Q11 it still preserves the traditional approach as one possibility, provided of course that you have the appropriate controls. I can just see some interesting court cases if the FDA ever tried to do a refusal to file because of the lack of a QbD approach.”

    He continued: “This is not to say that QbD is a bad idea. I am only discussing its legality as the only approach.”

    This consultant indicated that he is recommending to clients “a gradual introduction of QbD using a risk-management approach with an eye on Return on Investment—I hope maintaining the best traditions of Juran.”

    FDA’s Official Stance

    So what does the Agency say? I wrote the OGD, and got this response today from Lisa Kubaska, PharmD, a CDER spokesperson:

    Over the recent years, the Office of Generic Drugs (OGD) has presented our Quality by Design (QbD) expectations at various meetings, workshops and roundtables including the interview as addressed in your inquiry. Throughout this time, the generic industry has been engaged and allowed to provide feedback to assure that these concepts are clear. Our expectations are highlighted within the Immediate Release and Modified Release QbD examples posted on OGD’s Information for Industry webpage noted below.  

    Beginning this year, OGD has communicated to ANDA sponsors QbD expectations with the following text:

    We encourage you to apply Quality by Design (QbD) principles to the pharmaceutical development of your future original ANDA product submissions. A risk-based, scientifically sound submission would be expected to include the following:

    •  Quality target product profile (QTPP)
    •  Critical quality attributes (CQAs) of the drug product
    •  Product design and understanding including identification of critical attributes of excipients, drug substance(s), and/or container closure systems
    •  Process design and understanding including identification of critical process parameters and in-process material attributes
    •  Control strategy and justification

    Examples illustrating QbD concepts can be found online at FDA’s Generic Drugs: Information for Industry webpage:

    As January 1, 2013 draws closer, OGD will continue to communicate such expectations.  The ANDA checklist will be updated to include QbD elements. As such, ANDAs will not be accepted for filing without these QbD elements starting January 1, 2013. For further inquiries or clarification, individuals are asked to contact OGD via email using the following: GenericDrugs@FDA.HHS.GOV.

    The key phrase may be: “ANDAs will not be accepted for filing without these QbD elements starting January 1, 2013.” This suggests a sort of mandate (to be spelled out in the checklist) and that, indeed, starting in 2013, filing requirements for generics manufacturers will be much different than in the past.


    photo courtesy of



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    3 Responses to “Is QbD a Mandate for Generics? FDA Responds to Confusion”

    1. siegfried says:

      Thank you Paul for providing this much needed clarification

      The important fact is that still no agency mandates the submission of applications as “QbD submissions”
      Good science- and risk-based submissions are required – nothing wrong with that


    2. One cannot force anyone to do any thing unless it is a LAW. QbD is not a law. No QbD path details have been published and no public hearings have been held. Thus QbD is not a law.

      Girish Malhotra


    1. [...] dice, he said. "I have to be very careful about what I say to the media," he said, referring to a LinkedIn discussion that implied FDA mandates on QbD. So we may have to wait awhile for any official interview on this [...]

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