We asked around about what issues were driving firms crazy and these same three issues surfaced most often: 1) getting resolution of compliance status after inspection or re-inspection; 2) getting a straight answer from the Agency; and 3) what to do about maximum daily exposure issues relative to the Inactive Ingredient Database (IID).
Taking each issue in order:
Resolution of Compliance Status
Most of the compliance issues we hear about are after a firm’s inspection or re-inspection where the investigator tells the firm that there are no issues or where there is no 483 issued. According to some of our clients, approvals may be delayed because of this lag time. We assume (but are not sure) that the results (even after forwarded to CDER headquarters with the Establishment Inspection Report [EIR]) must be reviewed and concurred with by HQ staff. I can tell you that, once you are in that position, there is nothing you can seem to do to shake the final evaluation loose except wait. We have heard this time and time again. I often get calls asking what can we do to get things moving – in our experience the only thing you can do is wait!
While CDER does control the decision process post EIR, there must be a significant backlog of evaluations that must be reviewed. It does seem, however, that if the only thing holding up an ANDA approval is the final inspectional clearance, there should be a way to expedite the finalization of that specific review. Compliance review priorities were discussed with the Office of Compliance on a weekly basis when there was a backlog of approvals held up by final inspectional decisions back in the 1980 and early 90s and that proved effective in many cases. We are not certain what the process is now, but at least, according to responses we get from clients, this is an area of great concern. And it is not only associated with the approval delay, but the issue of who one can talk to, to see what is causing the delay. The only thing for certain is that, until the computer designation is updated reflecting current compliance status of the facilities in question, no final approval action on the ANDA can occur.
Getting a Straight Answer from FDA
Obviously this is not always a problem; however, we are hearing from firms and we have personally experienced the following scenarios. A sponsor emails to ASKGDUFA with a procedural question. The sponsor receives a reply telling them that this is an OGD issue, so the sponsor sends the same email to the OGD Question Line and OGD tells the sponsor that the question should be responded to by ASKGDUFA. There have also been instances where the cycle went full circle with three emails telling the sponsor that they needed to ask a different entity, closing the loop with referral back to the original email recipient as the one that should answer the question.
The second scenario is where there is confusion on behalf of a sponsor about a specific Guidance or procedure. The question is phrased to outline the potential different interpretations upon which the sponsor seeks clarification, and asking either which is correct asks for an explanation of something that is not clear. In many instances, the response from the FDA office simply cites back to the specific section of the Guidance without further clarification. Industry can read the Guidance documents, but the clarity for a specific circumstance or issue is not always obvious. That is why industry asks. Reference back to the Guidance is not usually helpful without the extra step of making the requested clarification.
There are other scenarios that occur related to this issue… but you get the drift. And, of course, there are many responses that do respond adequately to the questions that are posed to the Agency, as long as you have the time to wait.
Issues Relative to Maximum Daily Exposure (MDE) in the IID
Until the IID is completely revised to include the FDA’s listing of the MDE for specific inactive ingredients for various ingredients in various dosage forms, the formulation departments of drug sponsors continue to pull their hair out. I don’t know the way to solve this problem, but it is a big issue and one that we hear about almost every week. The information in the IID is only useful if your product’s MDE is less than or equal to the amount listed in the IID, if the listed amount is not listed as an MDE. Why? Because you cannot tell from the IID what the product is or how it might be dosed (i.e., once, twice, or more times a day), as many of the values only reflect the amount of an ingredient in a single dosage unit. In that regard, it becomes more of a “you pay your money, you take your chances”-type situation. And if you are wrong, you get a Refuse-to-Receive (RTR) letter. We tell clients all the time that the IID has limited utility at this point in time and explain the types of other investigations that a sponsor can undertake to lessen the chances of receiving an RTR.
So those are the major issues we are hearing about with the highest frequency. If you would like to let us know about other issues that you are seeing frequently that you think should be raised to your colleagues, please email me at firstname.lastname@example.org. I will gather them up and prepare a blog outlining the other most frequent issues (blinded of course), so everyone can say – hey that happens to me too!