1:33 – Key regulatory guidelines for biopharma companies to follow
3:00 - Recent guidance changes/additions that impact biopharma
3:37 - Areas where additional guidance is needed
4:36 - Common regulatory milestones that can turn into stumbling blocks for companies developing new therapeutics
7:12 - Best practices to navigate the regulatory approval path
9:44 - The impact of filing accelerated review applications on process development
11:41 - What quality teams should do to ensure quality standards are maintained in the absence of traditional regulatory oversight
Rita Peters: Many regulatory guidelines for bioprocess development are well established. What are some key guidelines for biopharma companies to follow?
Steven Lynn: I think, first off, it depends on where the company is manufacturing and marketing their products. From the US perspective, there's a bunch of different guidelines on the FDA’s website you can look for, and you can also look on the European Union's website as well.
Looking at various International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Q10, Q9, Q8, going back into the pharmaceutical development, it depends on where the company is in their actual product pathway.
One thing to note that you don't hear a lot of people talking about all the time is different trade organizations. Two examples are the International Site for Pharmaceutical Engineers and the Parenteral Drug Association, which have a lot of different guidelines or technical reports that are developed by groups of industry experts.
But what a lot of people don't realize is while different regulators—the EU, FDA, the Therapeutic Goods Administration down in Australia, or whatever regulator it may be—while they do not offer and approve, oftentimes, they review them.
A lot of times, the various regulators review and provide input before they put technical guidance out. Especially in the biopharma area, there's some good guidance on various technical and trade groups.
Rita Peters: Are there any recent guidance changes or additions that impact by processing operations?
Steven Lynn: In biopharma, there are some things to keep an eye out for. COVID has changed a lot, and there's been a lot of different COVID guidance from the FDA.
Another thing to look at is from the cell and gene therapy area. FDA has issued a lot of guidance earlier in 2020 that’s affected the cell and gene manufacturing area, since we have a huge amount of research and development going on right now in there. And I think there’s more that's going to be coming.
Rita Peters: Are there any areas where you see that some additional guidance is needed?
Steven Lynn: Yes, I think, as we move forward, more technical, specific guidance or product specific guidance depends on the area. I think there's been some push for the FDA and other regulators as well to look into that, especially as things are changing so rapidly.
Looking at how the various COVID vaccines have come to market so fast through the emergency use authorization, I think this is going to change some of the ways regulators are thinking in the future, just for the fact that these vaccines are proven safe and effective to date. Then, how can we do that with other products in the future? I think those are things to look for moving forward with the various regulators.
Rita Peters: What are some common regulatory milestones that can turn into stumbling blocks for companies developing new therapeutics?
Steven Lynn: It depends on the company. Oftentimes with a lot of startup companies, I've seen a lot of stumbling blocks as they get to the R&D process and they're starting to inch forward into commercialization. When they get to that phase, they're like, “oh, God, we have to do X, Y, and Z to commercialize and start to market this product.”
Whether it be putting the application in and or even scaling up and getting a contract manufacturer, oftentimes it's about having a realistic perspective on that and what it entails. What does a quality unit entail? It's just not two guys and a bunch of standard operating procedures. There’s a lot more to it than that. I've seen that being a big stumbling block for some companies.
And with that said, as a stumbling block, it not only takes a certain amount of work to do it, but also the financial investment to do it right. I've seen companies not do it right—they put in the application and the application fails, then they wonder why. And usually, it's a stumbling block when they just mess up with that. Big, small, any kind of company—it takes the tech transfer to get that right.
Once you get a product (an R&D-scale kind of product), and you want to scale it up—whether in your own manufacturing plant within your company or in a contract manufacturing organization/CDMO—getting that tech transfer right is what I've seen as a stumbling block. Especially if you're going to a CDMO, make sure you have all the requisite information that the company needs to actually start manufacturing that product.
With that said, sometimes all the information isn’t shared because a lot of it is proprietary. It's like another realistic viewpoint of what these companies are going to need to manufacture a product, or even if it's your own internal site, what they need.
Scale up is another one where things go wrong. And like I said, a lot of times, that runs in with a tech transfer as well. When you get it up to a commercial scale, you’re starting to do bigger batches of product and then things start happening. Once things start happening, figuring out what's going on in no time is a big stumbling block—especially when it's a big, juicy investigation where you maybe stop and figure out what's going on, things can and do happen.
Rita Peters: As you suggested with that answer, the regulatory approval process is quite complex. What are some best practices to navigate this approval path?
Steven Lynn: It's a good question, Rita. I think from the perspective of know your process. Know your process in and out. Why do I say that? Oftentimes, especially in a bigger company, you got your R&D people, your regulatory people, your manufacturing people, and your quality people.
All of them go into putting the final application together and getting that approval. How do you ensure that all those different groups know what you're doing and why it's been done or how it's been done? A lot of times that knowledge transfer, as it's called, doesn't get to different people thoroughly and adequately—especially the regulatory affairs people who are dealing with the health authorities, or even the quality people or the chemistry, manufacturing, and controls (CMC) people. Know your process in the out and ensure that knowledge transfers across the organization.
Another good practice to think about is as you get in that commercialization and get the application ready, you're putting all the different pieces together—the clinical side, the CMC side, on and on. Basically, as you're getting ready to submit for a preapproval inspection from FDA, the EU, whoever it may be, whatever regulator—look at it from the lens of a regulator. Put yourself in a regulator's chair. How would you look at this application, all the information that's in there, and assess it? And sometimes that's easy, sometimes it's hard, but those are just some things to think about.
Are there are any sticky, juicy investigations you did? Think about if there's a micro issue that you did an investigation on. You rolled it out, you went forward with the process and product. What did you do? Relook at those things, because those things can kind of be sticking points.
And looking into that more, we've got the lab issues as well. You think out of specs or even out of trends, how you're working on that. Look at your CMC section really in depth with a regulator's eye. Just think about stuff like that because those are the things that might come back to bite you, especially once the application is submitted and the questions start being fired at you.
Rita Peters: Thanks, that's great advice, Steve. We've talked a little bit before about the speed of development. Many companies are now filing accelerated review applications. What impact does this have on process development?
Steven Lynn: Yeah, I know, a lot of companies are doing that now just to speed the market and start making money faster. But when companies in the commercial side of things are moving forward with this kind of strategy, it completely compresses your timeline.
If you think about the regular development path, the non-accelerated approval, you have time to actually learn, make mistakes, correct them, fix them, carry that knowledge forward and get a better product forward. Not saying you shouldn't do that with accelerated approval by any means, but if things are compressed, things need to move a lot faster.
Think about do you have enough people to do the job faster? Do you have the technologies to do it right faster? How do you get the various pieces of the application together faster?
This leads into, “There's little room for error.” If something does happen, it could stymie your efforts in that accelerated approval. You might never even get to that accelerated approval. Like I said before, with a regular process that’s not accelerated, you get time for learning, growing, and making sure you can get it right going out the door.
An accelerated approval is compressed. A lot of times, things can and do happen. How can you do more thorough and adequate investigations in a very fast, rapid succession? Having those different processes nailed down, investigations, resolutions, capital, change control, stuff like that. That’ll help you.
Rita Peters: Thanks. So the past year with the pandemic has been unusual times. FDA cutback on routine facility inspections due to pandemic related travel restrictions. And we've even seen some drug approvals delayed due to difficulties in inspecting manufacturing sites.
What action should quality teams take to make sure quality standards are maintained, deviations are properly addressed, and the facilities are producing safe and effective drugs in the absence of your traditional regulatory oversight?
Steven Lynn: I think first and foremost, nothing has changed; either pandemic or non-pandemic, companies should be maintaining quality right now. Specific to my time at FDA and since I've left FDA, they've been very clear that the FDA or even other regulators are not industry's quality unit.
Industry is by far responsible for their own quality. Now, with that said, in the pandemic, you think about the various clients I've had and companies I've known. The pandemic has affected getting people onto the sites. I think a lot of companies have had to figure out how to do remote investigations.
You might have certain manufacturing people on site, maybe some quality operations people, but the compliance people and others that would normally be on site to be part of that investigation might be off site. Companies have had to figure that out, and I think they've done quite well.
Just from my own perspective, I've gotten a lot better with computer technology and video conferencing than I was back in March of last year, little things like that. But by far, quality standards should not have changed. The message here is that the regulators are starting to inspect again.
The companies that have had issues that haven't addressed these issues in a timely manner are going to get cut because, I think, the regulators coming out are going to know that sometimes that happens with companies. And they're going to have an even more fine lens looking for various problems, and how the companies have dealt with the problems. So we'll see what happens in the coming months and year.
-- Transcript edited for clarity --