“Does anyone not use QTPP?” was the original question asked to the ~21,500 scientists. Being a Quality-by-Design community, many claimed their organizations are using the essential element of QbD – the Quality Target Product Profile. Was it true?
However, data tells us otherwise.
Today, Adria Tyndall share her research findings from Johns Hopkins, published on Nature:
We cover the questions below:
- What is a Target Product Profile?
- What is the FDA’s expectation for Target Product Profiles?
- Will QTPPs reduce drug approval cycle times?
- When should QTPP be formally used?
- Who owns the QTPP document?
- Who should own the QTPP document?
Here’s the interview:
If you’d like a simple and effective way to organize your QTPP for QbD, check out the Lean QbD software.
Here’s our conversation.
Sun: Welcome Adria Tyndal, to our QbdWorks podcast, thank you so much for joining us today.
Adria: Thanks for the invite, I appreciate it.
Sun: I was reading your paper on the Bio business piece on regulatory watch, the title is The Target Product Profile as a tool for regulatory communication, as an advantageous tool to use. It is a very interesting article – short but to the point that I wanted to talk to you a little more in detail about what you were researching at the time. So maybe you could take a step back and give us a brief on why you started this research about target product profiles TPP, which is a very important topic in QbD drug development and how you went about doing it.
Adria: Sure, well the project started at John Hopkins University, I was a graduate student in regulatory science program and for masters degree I read regulatory science program there and one of our options was regulatory program so I was interested in being able to do that. I had that opportunity and reached out to the professor in charge of speaking with the professor and mentor of that program that agreed to be one of the authors on the paper as well. He wanted to do some work with the product target product profile, and understand how they are used within an industry and kind of how different groups are using them, how product development groups are using them, how laboratory groups are using them, to truly get to the regulatory impact of it, and the input to the laboratory science. As we discussed and kind of started turning up the project and I really came to look at specific data from different groups of packages to see how the target product profiles were being used and we looked first at the labeling type of target product profile, and the quality by design target product profile.
Sun: You were able to separate those two?
Adria: Yes, yes, we were able to separate those two and for my team including another laboratory science students of John Hopkins, so the three of us collaborated to look at these different types of applications.
Sun: And you mentioned the method, approach to getting that data, of how much people are using TPPs Target Product Profiles in business so for use you found that point in data base, is that correct?
Adria: Yes, so to get the data, there was a research done, so we were kind of using some key words that would lead back to the target product profile. Things like target, product, profiles, TPP, CQA, different key words were put in to basically pull these data effect and then from there we actually went into the publicly available approval packages. So going through the different approval packages, we then read through those, to get some kind of more key word searches too, you know this could be a hundred pages, so we look through the different sections where they can potentially be and we use the key word searches and kind of see where that mention came out. Because in some cases they would have where it will come out in some kind of podium that wasn’t necessarily inaccurate for whatever reasons. And then we were able to see what was going on with target product profile. So from the demographic perspective, we pulled a lot of data from the different documents so we were able to tell where the TPP first appeared, where the discussion appeared, was it the IND, was it the pre NDA, we look at what type of product that was, or what they were viewing kind of what they wanted to see, kind of what the different product types were likely to use the TPP, but the priority was, you know were there any product using going on, so we took a lot of different types of data for each of these applications to have a lot of information primarily so that we could get a good amount of information out of it.
Sun: Sure, that sounds like a lot of looking for a needle in a hay stack. So that brings us to the first graph in the paper which shows the number of target product profiles TPPs per year, found in regulatory documentation from the summary basis of the approval documents of the drug was biologically approved by the US FDA, exhibit A, shows interesting enough from 1994, all the way to 2016, now as far as I know allows the TPPs regardless issued in 2007 by the FDA. I am surprised that there were some TPPs found all the way in 1994, now what was that the rationale why you started from 1994?
(Source: HHS Public Access Nat Rev Drug Discov. 2017 March ; 16(3): 156. doi:10.1038/nrd.2016.264)
Adria: We put together were more researchable, different kinds of podium, and that was only the first kind of same thing, I would say those target product profiles you can certainly work with those but they weren’t necessarily per what the guidelines would say today, but have this element of you know, their target product profile, what they were calling it. So definitely not to the degree of you know the elements that you would expect to see today, they didn’t have that kind of regulatory dialogue and understanding of this is our target product profile and have that included.
Sun: Absolutely, and I start seeing that trend surge from 2005, 2006, and a big surge in 2008, 2009, and so forth and if you look at the graph, color code is attached with label type LTTP, and the QTTP comes in, in 2008, and starts increasing rapidly, so that was kind of the trend you saw right?
Adria: Yes and it just kind of coincides with the regulatory guidelines documents, so you have the labeling type LTPP document, the FDA guidance for industry and what to include in the labeling target product profile for that particular one. Although in March 2007, was still a draft guidelines but this is the one that target product profile strategic development process to tie it up with particular guidelines and it really talks about how within the IND, say you can go back and forte to that meeting to dialogue with the agency to update that particular TPP, and just going to clinical studies with your different results, little, little events to support with your labeling. And then they expect the QTPP, really did see that happen with the release of CQA and then FDAs adoption of that as well on their own separate guidelines document and so I think you just want to see that increase.
There were a few different applications where they could include both the labeling target product profile and the quality target product profile. And it’s interesting within the later application like you are reading especially how organized the FDA is with asking for this quality target product profile to be in place. So you look at the office of pharmaceutical quality and previous to that office within drugs had an actual checklist in these applications that said it has target product profile included. And then even looking at the MAPP guidance, their manual policies and procedures that were in that were also there in the MAPP guidance 2016, that talks about the expectancy of the minimum quality product profile type included. So I think it’s a definitely favorable increase to see them more kind of organized, requesting more formalized you know publications of what’s going on, requesting it.
Sun: So it’s safe to assume that FDA requires TPPs and now its part of their expectations.
Adria: It is a safe assumption, I mean just an from the map guidance that was released and even some of these documents documents where they got this checklist of where they were going, where the reviewers were going through and checking if it was included and if it was not included. I think it’s definitely advantageous to having that expectation and certainly from a certainty aspect to a more official review process.
Sun: That makes sense because the goal of TPP was to first of all take like your paper mentioned to ascertain the communication between the company industry and the regulatory industry and the regulatory agencies. Your first findings from the paper was that our analysis revealed that TPPs are infrequently used, potentially costing the applicants opportunity for more meaning meaningful regulatory actions that could result in better organizing more successful development programs. Why did you say that it was infrequently used? Which point of time were you referring to? What percentage were you referring to?
Adria: So we were looking at the percentages of the product application, so we would pull a data base of two thousand, one hundred and thirty approved NDA and we found 91 that mentioned the target product profile in that same period. Now we are definitely seeing an increase, I mean definitely that the uses are becoming more like averages, a very positive trend, but they weren’t included in those and the reason not mentioned in passing and just talk a little bit to but just a research methodology, and kind of go back to that for a second. In other to get a positive, in order to get to that target product profile that was included, we don’t even have to see the full table. We really just looked for if it was mentioned. Is there evidence that the target product profile was used? So we did work you know fully at any evidence with a positive effect. You know certainly there is a limit of public information and so from that perspective there could be information or pages that have never been in public where there could have been one included, you know we wouldn’t have seen it, it wouldn’t have been publicly mentioned. But probably would have been given a pretty wider knowledge had the TPP included it.
Sun: What you are saying is even if it wasn’t in a tabular format, in the text or a paragraph of the product description, mechanism of action, PK, pharmacology indication, route of administration, those type of information that you were counting as you mentioned QTPP, LTPP and so forth.
Adria: Well not necessarily on it, so we would say if they referenced or said something in the effect of we reviewed your target product profile and we think this. We would include that as a positive hit. If they mentioned a TPP element, you know if they discussed mechanism of action, if the discussed you know, this is our dosage, this is you know if they discuss certain critical quality attributes without it being in the TPP route, we would have included that as a part of it, I mean it wouldn’t necessarily indicate the presence of the target product profile.
(Source: HHS Public Access Nat Rev Drug Discov. 2017 March ; 16(3): 156. doi:10.1038/nrd.2016.264)
Sun: Sure, so second point was that TPPs are most frequently introduced into the regulatory dialogue at a late stage of the process, usually at the time of Pre NDA, or BLA meeting, or following NDA or BLA submission, and that refers to the second figure B. Could you elaborate further on that point?
Adria: Sure, so we looked at all of the different sections where we actually put a timeline together for these different applications. So we will put in the date of the first submission, or just the IND date, the date that the NDA went in, the date that we found critical clinical trials started, we really looked at a kind of different dates within the timeline of these different projects to see where the first mention of the target product profile occurred. So we looked at everything, from certainly the main pharmacological review, chemical reviews, they were brought too and looking at it, available drug approval package, so we used that to establish this date of when the TPP was first mentioned.
Sun: Got it. So what’s the conclusion based on your timing? I know you don’t attach any judgments on when it should be introduced, TPP or if it was introduced earlier or later it would have made a difference. You allude to that in the article, but could you explain a little bit about the timing? What would it be optimum timing , or what do you think should be the optimum timing of introducing TPP and how it would affect the outcome of the approval?
Adria: I think you know certainly from the research, as early in the clinical development as possible and that aligns well with the agency guidance, FDA’s response going to the critical and opportunity to plan for what they were expected to say and then be able to make those adjustments accordingly. I think even throughout I would say more complex development now a days where you got the complex delivery systems, you got a combination product, I think the earlier you got the quality product target profile is just as well and you can put that back into the clinical stage and understand how you are ultimately going to be delivering the product to the patient. It’s certainly useful from the dialogue perspective and to answer would I have gone for different research project, and the human factors studies as well, and other biological and combination parts and having some of that information earlier on and good planning from my findings certainly did yield better results. This was published in our second paper, that the meeting time was 30 days, a gain of 30 days for approval or other applications received a target product profiles which did not.
Sun: So you are saying that there was a 30 days medium or average of 30 days reduction of approval circle time if you mentioned TPP elements in the NDA’s or BLA is that what the second paper was referring to?
Adria: Yes so the second paper was published in an attempt to follow up in 2017, the first data really was a top line data, the second one talks through the waiting approval time, the other, one of the really interesting things that we have seen to what all that group that include those target product profiles, the one complete response for us. And so were were some really positive results out of using the target product profile.
Sun: So there is a strong signal that using TPP target product profile is favorable to reducing approval time.
I guess the next question will probably be you might be interested in how you use it, when to use it and so forth, will probably be the next research question, if I was a graduate student. So this second paper we would definitely follow up with, so we had an interesting question going on in a LinkedIn group, a quality by design group and the question was who does not use TPP, or QTPP and that because it was quality by design and a lot of people mostly use it whether they call it QTPP or not, so given that, the second question was who should be, who are the current owners of the quality target product profile, the information, the document related to that and who should be the owners. So I want to ask you that question as well.
Adria: Yes from the ownership perspective I would say probably the design team, I mean I probably that main point of contact within the product design team, and it certainly needs to be aligned to socialized cross functionality and so whether that do refers within the packaging and engineering group, your different formulations scientific to laboratory and certainly your regulatory group and that is going to be filling this in the long term analysis of what should be present and it should be well aligned too within the cross functionality event in form of updates meetings you know as its going through developments and revisiting that head of product profile and at least to where we expect it to be or intended to be, is an important question and I think that having the ownership of is an important thing, I think is equally important having that cross functionality and then from the industry perspective in quality regulatory affairs laboratory science in that perspective and having the regulatory various group certainly aligns to what elements is the product development team including and is there anything from the regulatory service and the perspective ones that are going to be built in that needs to be considered or is everything expressed in the right terms, so that you know there is not going to be any last minute questions before presenting to the different products so it certainly having that and reviving it is a good prospect, and but ultimately I would see the entire development team for the different.
Here is my question, what do people think about who should own it?
Sun: So far people mentioned quality, CMC, regulatory affairs as the majority of the owners right now from our survey, and agreed it should be cross functional but you know usually you need one owner to be accountable for that document.
Adria: By accountable, I mean that is just the thing but it’s like the entire development perspective and people letting it in everyday, like if you have a project team leader or something like that pertaining constantly, but I don’t think you will see that person that kind of the science is to know this thing and back and forte but I kind of think the regulatory should kind of be the ones that are accountable yes.
Sun: Right, we would add to that response, one of the last questions that comes up in discussing TPPs or QTPPs in particular is when you did your research, when your team did your research on TPPs, did you see much difference in the contents, in what they listed as the elements of TPPs, I know FDA has guidelines on it, but is it just one of the criticism, the critics of TPP just using TPPs as a compendious specs specifications? You know we could go beyond that. There has been some discussions on it. Have you seen much variation in the content of the TPP and what stood out in your findings, in your research, when you were doing your research?
Adria: I wouldn’t say any elements stood out, in terms of unique, I can’t recall anything particularly unique in terms of TPP element, but it was certainly much in consistency with what was included, in terms of what different elements were included within it. You will definitely see some commonality that were always covered and then pieces that just were variants were equally covered. From our findings there were some inconsistencies from our reviews.
Sun: Regarding that question, have you seen — this is a communication between the regulatory agency and the manufacturer so I am not sure they would have included any of the manufacturing related target product profiles and so forth such as yield and things like that, have you seen any of those that are not necessarily in the regulatory domain but more important to the manufacturer?
Adria: I think when discussing things within the commentary review that the yield and I can’t recall seeing something on it.
Sun: Okay, well thank you so much for your time today, this is really an interesting article and I think the main message, if you were to sum it up from all that research they put in would you be able to sum it up in one sentence or two?
Adria: I think it’s advantageous both from a business perspective and a regulatory perspective to be using the target product profile, and the agency certainly has signaled their interest and intent to have this included in the regulatory side and its certainly advantageous to start that dialogue both internally and externally early.
Sun: Use your target product profiles often and early.
Sun: Great, thank you so much.
Adria: Thank you, thank you so much.