“How a Consultant can Support Your Regulatory Compliance with a Gap Analysis” Featuring Dr. Debra Barngrover
Transcript
James: Our company name is Biologics Consulting, and the reason for that is we are consultants, but what would you use a consultant for? Joining me is Debra Barngrover, to talk about why you would hire a consultant. This is Insight at Biologics. With me now is Debra Barngrover, and Debra, why don’t you tell them a little bit about yourself.
Debra: Okay. Well, I’ve been with Biologic Consulting for a little over 11 years now as a senior consultant in the chemistry, manufacturing, and controls area called CMC. Prior to that I was in industry with both small and large companies, helping develop a wide variety of products, proteins, gene therapies, cell therapies, small molecules, devices. You name it, we developed it. So I have a lot of background in both process development and now regulations of those products and how to get them approved by the various agencies.
James: Okay. Thank you for sharing that and. The crux of what we’re gonna talk about today is the various things that we can do for people, as Biologics consulting. What are our services that we provide? Just an example.
Debra: Well, an example is a regulatory gap analysis, which is how we often start a lot of our engagements with clients. A regulatory gap analysis is where we look at what studies the sponsor has done to date to both develop and or validate the product and tests, and then compare that to what needs to be done for the next stage, either at the initial IND, a phase two/three IND or BLA.
So for the company, this really gives them an idea of what further work they need to do, how much more development they need to get to the finish line, whatever that is at this point in time. The real goal is then to be minimizing requests from the agency as they’re reviewing the IND and BLA for missing studies and data, because those requests will always delay your review and approval of wherever you wanna be. The idea is that you’re developing this regulatory strategy, if you will, for how you’re gonna get to that next stage of your development process.
James: Okay. And is the gap analysis limited in terms of who can take advantage of it?
Debra: Well, no, certainly not any company, large or small can take advantage of that. I’ll give an example of where we had a specific case study where the gap analysis led to a very successful development strategy for a unique situation. Each product and process is very unique and the guidances are very general. It’s always a case of, how do you apply those guidances to your specific case, and that’s what we do a lot of.
So we had a small company that came to us that had licensed an approved drug from a much larger company. Part of why the large company was wanting to sell this product off is, the CMO that had made it for 16 years was going out of business. So the first thing the small company had to do was find a new CMO and then transfer this process, get it validated so that they could continue to make the product and sell it.
But since it was a very small market, doing a full validation program of three large runs, was just gonna make so much product that it was gonna financially ruin the company – they just couldn’t afford to make that much product. And so we developed a strategy and actually worked with the FDA and, and modified this.
Because the equipment was being transferred from the previous CMO to the new CMO, we could support the validation just by doing a lot of equipment validation and qualification, not having to actually run the full process. And that in the end, they only had to run one run, split into three at key steps so that they could get data from three different runs, so to speak. And that was sufficient to satisfy the FDA requirements for validation.
James: Okay. And that is an example of a situation with a smaller sized company. But do we ever do this sort of work for larger companies?
Debra: We definitely do, and that’s often in conjunction with a large writing project that the company is faced with, such as a meeting package or often a BLA.
Large companies don’t really wanna maintain a large in-house regulatory team that only gets used from time to time because they’re not writing BLAs constantly. Or they don’t wanna pull the subject matter experts from their normal day jobs to write the BLAs. So we will come in with a team of highly trained writers.
The first step, again, will be a gap analysis just against, you know, what are the BLA requirements: what studies do they have? What studies are still coming? What studies do they probably need to think about? And then we can turn to writing the BLA.
We’re very adaptable to working and writing styles at different companies, cuz we’ve done a lot of different ones, but we’re knowledgeable of all the nuances that the FDA and/or other agencies are looking for, because again, not everything is in guidances. A lot of times it’s just knowledge of having written several documents like this in the past, and bringing that knowledge to the writing project to make it more effective and more efficient.
James: Okay. Now our consultants here have extensive process development experience. So do we ever provide process development troubleshooting for people who are in a bit of a jam.
Debra: Absolutely. That’s another key piece of what I do. It might be very simple questions about, I’ve got an assay that’s not working, what can we look at there? Or it might be a much more involved one. A specific case that happened not too long ago is, we had a manufacturer of a product that was a mixture of peptides, and the problem was, they’d made one drug product just fine, looked great, and they went to make their second run, and suddenly the peptides were degrading very severely during the the manufacture of the drug product.
So we performed a very complete root cause analysis, investigating over 60 potential root causes, and finally narrowed it down to three. It was such a complex process that there were actually three different root causes involved. And so the first one turned out that the synthesized peptides that they’d gotten from some new lots had quite extensive heavy metal elemental impurity – contamination in the peptides.
We traced it back to the manufacturer who eventually confessed that a plant engineer had gone to their local hardware store and replaced some of the hardware on the purification equipment with some brass pieces instead of the stainless steel that they were supposed to use. And so these brass pieces were leaching lots of heavy metals into the peptides.
So we had a long talk with that manufacturer about good manufacturing practices and making sure that you don’t substitute equipment when it’s not the appropriate quality. They also instituted a quality agreement between the drug product manufacturer and the peptide manufacturer, so that the peptide manufacturer would alert the sponsor when there were changes made in their manufacturing process so that they wouldn’t have this kind of surprise happening.
But that wasn’t enough. Even when we got cleaner peptides, we discovered that the formulation, which had basically been pulled off the shelf, was just not sufficiently robust, if you will, to accommodate any potential peptide impurities and manufacturing variation. And so we instituted a formulation development program to help them come up with a more stable and robust formulation.
Lastly, we discovered that the larger scale drug product manufacturing, which is what they’d done for their second run, meant that they had a longer manufacturing process at higher temperatures, which accelerated this degradation that we were seeing. So we had to rework the manufacturing process to minimize that timeframe and higher temperatures. And when they instituted all these changes we had successful drug product changes. So we can work, in very short term, quick answers or very detailed analyses as we have done in this case.
James: All right, so you can break it down. Like, you know, you were Sherlock Holmes analyzing a case in terms of this was not just a single element. There were a cascade of things, several things all contributing to the degradation. And you can do that, I’m assuming, because of the years of expertise that you and the others in the department have, correct?
Debra: That’s correct. We’ve learned to look at the big picture. You never wanna stop at the first root cause you find, that might answer part of the question, but you fix that and something else then becomes the issue and you haven’t really fixed the overall process. So that’s why we’ve learned to do very extensive root cause analyses and make sure we look at all possible factors, not just the first one we find.
James: It also sounds like there’s a little bit of teaching involved because the fellow that decided that it really didn’t matter what type of nuts and bolts he used, created at least part of the problem. So not only did you have to find out that was the problem, but you had to remind the manufacturer that you need to follow good manufacturing practices.
When I first started in this industry, I started in the SOPs and I wondered why we had so many instructions on how you do this and the way you do this. And then as a story such as yours comes along, it becomes clear why you have to follow the good clinical practice and the other parameters that are established in order to run development processes. Am I correct in that?
Debra: Oh, definitely. You know, a lot of people look at the good manufacturing practice guidelines and think it is very long and detailed. But it’s all developed from experience. You know, the FDA and the EMEA and other health authorities have done a lot of inspections of plants. They’ve seen a lot of issues come across, so they have learned what things can go wrong, and that’s why they write these good manufacturing practice guidelines: to cover a whole host of different ways that you can best control your manufacturing process and make sure that you produce a quality product every time.
And that’s the main thing that we always wanna think about when we’re in pharmaceutical manufacturing, is the patient, who expects to have that quality product and expects to have it every time they take it. That’s what we’re always aiming for.
James: Awesome. Now, you’ve mentioned that one of the things that using our services can do for people is that it can reduce the amount of wasted time that a company might experience if they were trying to do things that they didn’t either have the staff for or the knowledge for, and in this industry, would it be fair to say that time really is money?
Debra: Oh, absolutely. The faster you can get a product on the market, the faster you can start to recoup some of your investment in the very involved development and clinical development process. So reducing your BLA writing from two years to a year or less could be several million dollars of revenue that you now can obtain. Based on that, it certainly outweighs the cost we bring, in terms of being able to write that BLA much faster.
James: Awesome. And is there anything else about what we provide that you would want people to know?
Debra: Well, you mentioned training and that is certainly something that we do on a daily basis as part of providing advice and and consultation to our clients. We also develop standardized training courses on demand or as part working with specific training companies. There’s several times that a client will come to us and they want a specific GMP type related course that covers certain topics that we could certainly develop for them based on our expertise.
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James: Thank you to Debra Barngrover for joining us. If you’d like more information, just email us at insight@biologicsconsulting.com. That’s Insight, @ Biologics Consulting, all one word, .com. Also, we’d love it if you’d like, subscribe to, and rate and review our show.
The executive producer of Insight at Biologics is Kris Kraihanzel. This episode is produced and edited by James C. Taylor, technical supervisor is Jeff Weis. The Insight at Biologics theme is by Tom Rory Parsons. I’m James C. Taylor. Thank you for joining us. Please come back for more Insight at Biologics.