In this Q&A session, John Litz, Business Development Manager at ILC Dover, explores the importance of speed and flexibility in the biopharmaceutical supply chain and the advantages of single-use liquid bags in bioprocessing. He discusses their role in scalability, contamination risk reduction, and process efficiency compared to traditional glass and stainless steel alternatives.
John also highlights key quality assurance measures and emerging industry trends, including the rise of large-scale single-use bioreactor bags and the demand for smaller volumes in autologous cell therapies. This discussion offers insights into the evolving bioprocessing landscape and ILC Dover’s commitment to innovative solutions.
Watch the video or explore the transcript below to learn more.
Transcript
[Question] 0:05 – What trends have you observed regarding the adoption and acceptance of single-use liquid bags in cGMP processes? Are there particular challenges or opportunities associated with this shift?
[John Litz] 0:12 – Yeah, so some of the trends that you might see in bioprocess now—one of the bigger ones is size. People are scaling up to larger batches, and one of the things that we’ve noticed is some of our larger-sized bags, like our 100-liter and 200-liter bags, are very commonly used in areas where people are doing these large-scale UPS.
So, this isn’t necessarily just going to be for bags—this is going to be for a lot of different process equipment, which we can use for our liquid bags and for our bag assemblies, or as we like to call them, our FTAs (Fluid Transfer Assemblies).
Size is one, and then, of course, there are other different challenges regarding adoption and acceptance. Occasionally, you might see issues with bottles. One of the things I really like to say is you can’t knock over a bag. I’ve seen operators knock over open bottles under hoods and lose product. When it comes to the therapeutic itself, it’s a very valuable fluid, and with that being said, containment measures need to be taken to ensure that you’re not losing any of that product, given its high value.
Some of the other things that we’ve been doing that have been helping adoption—we do various pressure tests on the bags, we do various hanging tests, weight tests, leak and burst testing, just to ensure that the bags are going to be working in process as needed. This ensures that end users aren’t having challenges with tubing falling off, bags leaking, or poor seals where ports might be.
Of course, other challenges that might be seen in the industry are material choices, right? Material can play a big part in the overall process. If people are having challenges with chemical compatibility, they might want to use a polyethylene bag instead of something that’s more of a legacy product, like ethyl vinyl acetate, or EVA.
[Question] 2:23 – How crucial is customization in meeting the diverse needs of users in the biotherapeutics and gene therapy fields?
[John Litz] 2:26 – That’s going to be extremely important, right? While a lot of practice can be done with standard items, when you’re actually getting into your commercialized process, you look at things like your footprint and your layout in your lab or clean rooms where you’re doing the manufacturing.
Having the customization aspect is huge because whether it’s tubing lengths coming off the bag, different connectors to be used to maintain a sterile closed process, or even certain things like bag shape—these can be customized to maximize product recovery as you move through the bioprocess.
Because again, as I mentioned previously, you want to make sure that when you’re doing your customization of your bag, you’re optimizing your process for maximum yield, maximum product recovery, and essentially just making sure that those cells stay safe and happy.
That being said, the customization option is something that we really look to do here at ILC Dover, and it’s something that we believe is incredibly important in the industry—not just to provide a potential partner with something off the shelf that might work. We prefer to move forward with full customization to ensure that the end user is getting exactly what they need for their process so that it can be optimized and streamlined for the best possible outcomes.
[Question] 4:05 – How do industry standards such as USP impact the design and manufacturing of liquid bags, and how does this contribute to overall compliance in cGMP?
[John Litz] 4:14 – So, when it comes to the quality of the bags and the regulatory requirements needed in the industry, this all goes into the thought process when designing the films and the product contact parts of the bag, right?
For us, we use the Renet 9101—it’s a polyethylene film. One of the reasons why we wanted to use that film, and why so many others in the marketplace use that film, is because it has a great test profile for these different regulations, whether it’s USP, FDA, or ISO. There are many standards that go into the development of these materials because they are product contact materials.
These regulations, as well as other tests like BPOG, USP 665 extractables, are very important to ensure that when you’re using these materials—especially in single-use applications where we use a lot of plastics, silicone, and similar materials—there are tests in place to ensure that the materials are biocompatible with human cell lines or animal cell lines.
Of course, we also want to make sure there won’t be any product leaching or extraction into the therapeutic product because that can affect the overall viability of the therapeutic itself, particularly if there are issues with material compatibility.
These types of considerations are extremely important in bioprocessing to ensure that you have pure materials that are inert when interacting with different types of cells, buffers, and media.
[Question] 6:00 – What are the common challenges that pharmaceutical professionals face when selecting and using liquid bags, and how does ILC Dover address them?
[John Litz] 6:10 – One of the main challenges is ensuring that you’re going to have a custom product to fit your bioprocess. That’s one thing we always work with customers and potential partners on—making sure that challenges they might be facing with tubing length or connector types on standard bags are addressed through our customization process. Our ability to customize really helps when it comes to overcoming these common challenges.
Also, for different applications, we have a great team here that can help end users streamline their process. Whether it’s for tangential flow filtration, general pump transfer applications, or other processes, we can help end users spec in the necessary parts to optimize their process at whatever stage of bioprocessing they’re working through.
Of course, another challenge is material compatibility. If you’re working with different acids, bases, buffers, or media, you might occasionally run into chemical compatibility issues. That’s why it’s incredibly important to know your material—what it’s interacting with and what you’ll be running through the tubing and bag. That way, we at ILC Dover can select the proper material for that specific application. Whether that means polyethylene or another material, we always ensure we have all the information needed to make the right recommendation.
And lastly, regulatory compliance. Not all bags are created equal from a regulatory compliance standpoint. It’s extremely important for customers to ensure that the bag they choose has all the necessary regulatory certifications for their specific application.
In most cases, you’ll need animal-free certification, USP Class VI compliance—these are fairly standard in the industry, but not all materials automatically meet them. If regulatory compliance is a requirement, that needs to be addressed early in the selection process.
One of the things we’ve done to ensure this doesn’t become an issue is proactively conducting these tests and securing the necessary regulatory certifications prior to launching our 2D liquid bags.
[Question] 8:46 – How important is speed and flexibility in the supply chain for companies engaged in biotherapeutics and cell and gene therapy?
[John Litz] 8:53 – So, speed and flexibility is one of the most important things, if not the most important thing, when it comes to selecting a supplier. At times, of course, quality and regulatory are very important, but ultimately, when it comes down to it, speed and flexibility are going to be key to ensuring that you have a consistent manufacturing process and you’re not having any shutdowns.
Flexibility, as well, is one that’s incredibly important to customers and users because when you do have the flexibility—whether it’s to make an order quickly or to change parts on the fly because the design has changed or something along those lines—having that speed to react and having the flexibility to accomplish the end-user need is going to be pretty critical when it comes to the overall design and consistency in your bioprocess.
[Question] 9:54 – Can you elaborate on the specific advantages of single-use liquid bags at various stages of bioprocessing?
[John Litz] 9:56 – So, of course, we all know that there are different stages of bioprocessing. You have, generally, your upstream and your downstream, and that can be broken into different things like medium buffer preparation, cell culture, harvest, and purification, etc.
One of the great things about the bags that we have is you have the flexibility to scale up. When you’re starting with very small volumes upstream and you might be doing your cell line development, inoculation, or things along those lines, we have a bag that’s 50 mL, so you can start very small. There are other manufacturers that even have bags smaller than that for things like sampling or initial cell line development and inoculation.
And then, of course, as you move through upstream and you develop higher volumes, as you’re getting into the purification or downstream phase, you have the ability to move from that 50 mL bag or 100 mL bag all the way up to the 100 L for any type of bulk therapeutic substance. So, the scale-up with the bags is very simple in comparison to things like bottles.
Especially with bottles, when you’re looking at different areas of the process, of course, you can scale up, but once you get into those larger liquid volumes, you might have issues moving the product from area to area if your upstream and downstream are in separate manufacturing suites. Generally, bottles are going to be a little bit more difficult to move just because of the way they’re shaped and the way they fit on totes or rollers.
The bags generally offer that flexibility to sit in totes, and they can be frozen a little bit easier. They store better than bottles, mainly because you can stack them one on top of another, whereas bottles sit flat and next to each other. The bags give you a little more flexibility from a storage perspective, too.
Now, another thing with single-use bags, in comparison to glass bioreactors or stainless steel, is if you want to use a single-use bioreactor, the changeover time is much easier with single-use liquid bags than it is with glass or stainless steel vessels.
That being said, you also don’t have to do any type of sterilization for these single-use items because, in most cases, they’re being pre-sterilized by your manufacturer via gamma radiation, X-ray, or sometimes EtO sterilization.
One final point that just popped into my head is the reduced risk of contamination. I mentioned cleaning of glass bioreactors or stainless steel tanks—the amount of energy that goes into cleaning is very high, especially when you look into things like water for injection that needs to be turned into steam to clean stainless steel piping, vessels, or tanks.
With single-use items, you’re using one per batch. That’s one of the great things about single-use liquid bags—you really can use them once per batch and then dispose of them without having to worry about autoclaving or generating water for injection to do steam-in-place or clean-in-place.
So, those are some of the advantages that might not be specific to just one area of bioprocessing but instead cross over into a lot of different branches in the chain, from upstream to final fill and finish.
[Question] 12:50 – How do manufacturers ensure the integrity and safety of liquid bags?
[John Litz] 12:53 – The way that we ensure the integrity and safety of our liquid bags is, first, when we’re manufacturing the bags, we inspect all of them over a lightbox to ensure there are no visible particulates.
That helps us make sure there are no, as I like to call them, “little nasties” in your therapeutic product. Quality assurance is a key factor in ensuring the integrity and safety of the bags.
Another thing we do is a variety of tests, whether those are hang tests to ensure the bags can carry the weight of the full fill and volume of the liquid being stored in them, burst testing, pressure testing, or pressure decay.
There are a lot of different tests we perform to ensure that the seals on the bags and the ports are going to stand up to various bioprocessing conditions, where you might see different factors affecting the performance of those bags.
[Question] 15:02 – Where do you see the future of liquid bags for fluid storage and transfer in CGMP heading? Are there emerging trends or technologies to watch?
[John Litz] 15:04 – One of the biggest emerging trends I’ve seen is larger-scale manufacturing. Some great companies out there are coming out with single-use bioreactor bags anywhere from 2,000 to 6,000 L.
That’s quite a large batch size. Whereas previously, those volumes would have been handled in large stainless steel tanks, now more and more companies are offering the option to do single-use biomanufacturing bags for those larger volumes.
Also, with the advent of certain cell therapies, we’re seeing a trend toward smaller volumes as well. You might see small 10 mL sampling bags used in autologous cell and gene therapies, which are highly individualized and require very small batches. This is in contrast to allogeneic therapies, which come from separate donors and can be used for multiple patients. Autologous therapies use very small batches because they take the cells of one patient, genetically modify those cells to become the therapeutic itself, and help attack whatever ailment that patient might have.
