In this latest episode of Off Script: A Pharma Manufacturing Podcast, Andrea Corona is joined by Derek Duncan Product Line Director, at Lighthouse Instruments to discuss the significance of CCI and the evolving landscape of CCI testing, regulatory guidance, and the unique considerations posed by innovative therapies with extreme storage and transport requirements.
Hi, I'm Andrea Corona, Senior Editor for Pharma Manufacturing Magazine, and you're listening to a special solution spotlight edition of Off-Script, a Pharma Manufacturing Podcast about what's happening behind the scenes in our magazine and what's trending in the drug industry. Joining me today to talk about the critical significance of container closure integrity and its far-reaching implications within the pharma industry is Derek Duncan, the Director of Product Line at Lighthouse Instruments.
In our conversation, we discuss container closure integrity's role in maintaining sterility, preserving sensitive formulations, and safeguarding headspace gas conditions. We also discuss the evolving landscape of CCI testing, regulatory guidance, and the unique considerations posed by innovative therapies with extreme storage and transport requirements. Good afternoon for you. Thank you for joining me today.
Derek Duncan: Yep, good afternoon.
Andrea Corona: I have a few questions here for you, so let's go ahead and get started with them. So the first question that I'm wondering about is what is container closure integrity and why is it critical for sterile injectable products?
Derek Duncan: Right. Yeah, so historically container closure integrity has always been linked to the maintenance of sterility of a sterile injectable product. Obviously, if a sterile container loses its container closure, there's a danger then for microbial contamination. So that means microorganisms getting inside and contaminating the product. And for a sterile product, this is the worst quality failure you could have.
Over the years that's broadened because now you have a lot of pharmaceutical injectable products that require the maintenance of the headspace gas composition. So for example, a lot of current pharmaceutical formulations, especially the bio-pharmaceuticals which are large protein molecules, there is some risk that they will interact with oxygen, for example, that they're oxygen sensitive. So when you actually package these pharmaceuticals, you need to overlay an inert gas in the headspace of the container, for example, nitrogen, to protect the formulation from oxygen.
So now the container closure requirements are actually more strict for this type of product because not only do you want to prevent microorganisms from coming inside, you actually also want to prevent gas molecules from coming inside. And so a lot of the modern injectable products want to maintain a certain gas composition. And so I think today, in today's world, there are actually stricter requirements for container closure integrity.
Andrea Corona: So what are the main considerations for CCF, for a sterile product?
Derek Duncan: Right. The most typical container that is used in the pharmaceutical industry for a sterile pharmaceutical product is a stoppered vial. And so there a couple, and I'll just use that as the common example. There are a couple ways that a sterile product vial can lose its container closure. Either there's some sort of damage on the container which causes a container closure failure or the vial itself is just not sealed properly.
So the rubber stopper and the cap and the crimp that are used to seal the vial just do not work well for some reason, and the vial is not sealed properly. Now for damaged vials, most companies, in fact, all companies, I think, are required to do a visual inspection process to look for damage on the container. But there are other types of container closure failures that can happen.
For example, a stopper that's not seated properly, you'll never detect that with visual inspection. So you need to generate container closure integrity data either in studies or as part of the manufacturing process itself to make sure that all of your samples or that the batch of this pharmaceutical product, that you can guarantee or have confidence that container closure, good container container closure integrity, is being achieved.
Andrea Corona: With that in mind, how have companies traditionally handled container closure integrity testing?
Derek Duncan: Right. So traditionally, again, this was in the realm of microbiology because people were worried about microbial ingress. And so one of the early tests, which is sometimes used today is what's called a microbial ingress test. And what people do is they will have a container of, let's say a microbial soup, and they actually will submerge containers into this microbial mix, and then wait for a while, take them out, and see, using incubation and microbiological methods, see if any microbes actually did ingress into this container. So that's a very direct microbial ingress test.Of course, this is very messy. This test actually is not really advised any more by the regulators because there's lots of possibilities for failures in this test. And so the industry moved to what's called a blue dye ingress test. And here, instead of dumping your containers into microbial soup, you actually submerge your containers into a bath of blue dye liquid. And the idea here is if there's a leak in this container, then blue dye molecules will make their way inside the container and color the contents inside blue. And then you have an operator who visually inspects these containers to see if they can detect any color change inside.
Now, this is, again, kind of a little bit of an archaic test. It's not analytical, it's not really science-based, and there's some subjectivity to this because you're relying on the operator to make this decision whether the color has changed or not. So USP 1207, so this is a chapter in the US Pharmacopeia, was implemented in 2016 and actually recommends moving away from these traditional methods to detect or to test for container closure integrity.
They call those methods probabilistic because the outcome, there's some uncertainty, and you're really relying on some probabilistic events to make the detection. Instead, this USP 1207 chapter recommends to move towards, "analytical deterministic methods," is what they call them. And these methods are actually based on an analytical measurement. So either you set up a test method which detects, for example, the flow of gas in and out of a container because it's leaking. So this is where the industry is evolving, and I think some more regulatory guidance has recently come out in Europe, the EU Annex 1, and they also have a new language for their container closure requirements. And I think all of this is moving the industry from these traditional probabilistic methods to these new analytical deterministic methods. So we're in the middle of this process of the industry evolving towards new methods for container closure.
Andrea Corona: How has new regulatory guidance inspired the pharma industry to make changes in container closure integrity testing best practices?
Derek Duncan: Right. Yeah, so I can expand a little bit on what I said before. So I mentioned two kind of regulatory guidances or regulatory documents, the US Pharmacopeia Chapter 1207, and the new EU GMP Annex 1. So from the language in these containers, it's clear that regulators are trying to do two things, move to these new deterministic methods that I mentioned before, and then secondly, to take more of what's called a product lifecycle approach to container closure. And this means that before you actually get to the manufacturing stage, you should already be generating data to show and demonstrate that your container, or primary packaging system, actually has and can maintain good container closure integrity.
So this means that in development studies, for example packaging development, you're looking at the containers that you're going to use and already doing studies and generating data to show that these containers have good closure. Also perhaps in certain storage conditions that might need to be used for your particular product. And so stressing this product lifecycle approach means that you're not just doing testing in manufacturing or on actual product, but that you're actually doing scientific studies beforehand to demonstrate and improve good container closure. And so another thing that these new guidances, regulatory guidances, are asking for is to take a more holistic approach. So it's also not just testing those containers themself, but making sure that the process that you're using to assemble those containers and seal them, that these processes are consistent and robust. And so you not only need to test the container, but you also need to test the process. And that's a holistic product lifecycle approach, which I believe is what the regulators believe should be the future.
Andrea Corona: So have innovative therapies that require extreme storage and transport temperatures added extra considerations for container closure testing?
Derek Duncan: Right, and that's a good example of a very specific type of product that requires some extra attention. So I think during the pandemic, everybody became aware of these COVID vaccines that needed to be stored at very low temperatures, minus 80 degrees Celsius. And studies have shown actually that the traditional packages or containers that the pharmaceutical industry uses were actually not designed for those very low temperatures. And so as an example, these COVID vaccines that were produced during the pandemic, actually quite a lot of data had to be generated in a very short amount of time to really show that these containers that were being stored and transported at these very low temperatures were able to maintain good container closure integrity. And scientific studies have shown that there is extra risk at these temperatures that when you go down to these very low temperatures, the container can lose container closure and be open during this cold temperature storage. And when you take them out of this ultra cold temperature storage, they warm back up and actually reseal themselves. So it's very difficult to actually detect these failures.
The technology that we focus on at Lighthouse Instruments, headspace analysis, actually is able to detect these types of failures because we measure the changes in the gas composition of the containers. And when gas comes in during this cold storage, even if that vial reseals itself afterwards, you can still measure that the headspace inside these containers have changed. And that's a good indication, or that is an indication, that that vial failed at these low temperatures. So that's an example of a very particular type of pharmaceutical product which can lose its container closure in certain conditions. And so as a pharmaceutical manufacturer, you need to be aware of this, and again, make sure you take this product lifecycle approach, do the studies that you need to do to prove that your container and your product is actually working properly so that when you get to manufacturing, you already have this knowledge in hand and you know what to test for and how to test for it.
Andrea Corona: You just answered some of my next question as well with that, but I'll ask it again just in case. Given all these changes, what type of approach should pharma manufacturers take towards assuring good container closure?
Derek Duncan: Right. And I think that question, the answer to that is kind of a summary of what we've talked about, because number one, I think you want to make sure that you have the right tools in your toolbox to generate good container closure integrity data. And as we mentioned at the beginning of this talk, that means moving or adding these deterministic methods described in USP 1207 so that you have more than just the microbial ingress test or the blue dye ingress test to do all these studies that you should be doing in development. So that's the second point. Make sure you start early with generating data on your container closure integrity so that you have a good understanding of it before you get to manufacturing. And once you get to manufacturing, implement this holistic approach where you're also looking at your process, making sure, for example, in the stoppered vial case that you're capping and crimping process has been robustly tested and qualified to produce good container closure, so that in addition to the testing that you do in manufacturing, you're also monitoring the process and making sure that the process is working well. So that's kind of a summary I think, of what we talked about, and those are the things I think to pay attention to as a manufacturer of sterile pharmaceutical product when it comes to container closure integrity.
Andrea Corona: Thank you so much for joining me and for all your insights, and we really appreciate your time.
Derek Duncan: All right. Thank you.
Andrea Corona: To our audience, this is Andrea Corona, and you've been listening to a special edition of Off-Script, a Pharma Manufacturing Podcast. Stay healthy and stay informed. Thank you for tuning in.
