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Fill-Finish Podcast 5 – “Temperature Sensitive Biologics and BFS”

Participants

  • Guest: Philip Leslie, Acting Head of Manufacturing, ApiJect
  • Hosted by: Rizwan Chaudhrey

Rizwan Chaudhrey: Hi everybody, this is Rizwan Chaudhrey, and you are listening to the Fill-Finish Podcast sponsored by ApiJect. The show that has expertise in all aspects of injectables, vaccines and aseptic fill-finish, and today we are speaking with Philip Leslie, the acting head of manufacturing at ApiJect. And today’s topic is temperature sensitive biologics and BFS. So, thanks for joining me, Philip. Before we start why don’t you tell us a little bit about yourself?

Philip Leslie: Currently I’m working with ApiJect as a consultant, with the manufacturing side of the process. I’ve worked for over 30 years in the pharmaceutical business mostly with blow-fill-seal, for various pharmaceutical companies around the world and I’ve really enjoyed you the use of blow-fill-seal and the opportunities it provides for pharmaceuticals for the world.

Rizwan Chaudhrey: Can you tell us about ApiJect itself, and their experience within Blow-Fill-Seal?

 Philip Leslie: So ApiJect is a device technology company and it’s very much in the startup phase and we’re looking to develop a range of devices that enhance the delivery of pharmaceuticals to patients, using the blow-fill-seal technology which has a number of advantages over conventional processes.

Rizwan Chaudhrey: I understand you lead a team that launched the first commercial vaccine into blow-fill-seal. So, before we talk about how that came about, for those people who are listening, who are not familiar with BFS and blow-fill-seal, can you describe what BFS actually is?

Philip Leslie: Yeah, sure so blow-fill-seal is innovative packaging process and where, as the name suggests, it blow molds polymer into a bottle. And after the bottle is formed the filling process and the needles come down and fill the product into the preformed bottle and then the needles retract, and the final seal process seals the bottle into an automatically sealed product. This process is relatively quick all done within a few seconds and done very well in terms of its aseptic quality.

Rizwan Chaudhrey: Going back to that launch of the first commercial vaccine, into blow-fill-seal, how did that come about?

Philip Leslie: So I was working for a previous company before ApiJect, we were mostly making respiratory products. We were looking at a business plan to move into more of a higher value products like vaccines, which would be more challenging to make and more value adding than a commodity product like of the respiratory product. And we were fortunate that the vaccine division of the company was also having some challenges with a product they wanted to change the packaging process and also have the packaging that would also be the delivery device as well. The challenge, of course, with blow-fill-seal was the fact that people were cautious that hot polymer would possibly degrade the vaccine, and this is why it hadn’t really been challenged before.

Rizwan Chaudhrey: So, how did you go about solving that particular problem with filling a temperature sensitive product and BFS?

Philip Leslie: There are lots of advantages of blow-fill-seal, these include the reduced supply chain, and you know with our only two inputs, there’s the polymer and the vaccine and it’s a much more economical way to do it, then traditional glass and things like that. So, we were keen to try and show that the vaccine wouldn’t be degraded by the temperature profile, but being a production facility, didn’t have an R&D facility, but we had a very strong relationship with a local university who had some researchers and produced some bench top tests for us. The other thing we knew was the temperature profile of the polymer as it goes through the process, so we mapped that out. And what we asked the researchers to do was to simply set up a water bath with the polymer in that water bath at the temperature we knew would be the temperature when the product is dosed into it. So, we dosed some water into it had some thermal couples into the water and mapped the temperature profile as it cooled down and this showed that the temperature of the product didn’t get anywhere near as hot as people expected and that was really promising for us.

Rizwan Chaudhrey: Right, and so what happened next, and after you solved that particular problem?

Philip Leslie: So, we presented that to the vaccine team and showed that there was a real possibility that we could fill the product into blow-fill-seal without degrading it. And, they were quite excited, and were interested in doing a real trial with some vaccine. We needed to do quite a bit of work for us to be able to do that. We had a pilot blow-fill-seal machine at the site, and we then set about working on how best to set that machine up to ensure that we control the temperature into the profile that we believe would be that. The next steps for us were to run a sort of design of experiments, because we knew that there were a huge range of parameters of blow-fill-seal machine, like any machines that you can adjust temperatures and you know extrusion rates and profiles and things like that. We tried to control some and vary the others and there’s a standard experimental design, where you put this into a software process and randomize the trials to show and to understand which parameters are really influencing the final temperature.

The temperature of the product was our control. And we did this on the machine, initially with some water and we built a special way of measuring the temperature with some thermal couples on the fill needles and things like that. That was quite extensive thermal trial and it came back that there were a couple of key things that we needed to control. One of which was the wall thickness of the bottle and the other was the temperature for liquid that we fill into it. It’s not surprising that wall thickness was a key factor, because it’s rather like a bottle. That this is the polymer that has the heat and it’s delivering the temperature to the product, so if you can make the wall thickness as thin as possible. You’re reducing the heat capacity of the container it can transfer it. And then, of course, there is obviously a step up with the temperature of the product and If you can put the product in it and low temperature say two to six degrees, then when it goes up say 10-15-20 degrees it’s still well within room temperature type things. So, they were the two things that we learned out of that experiment, and we then went to set about to make sure we could control that and modify the machine to give us those parameters.

Rizwan Chaudhrey: Did you then fill the vaccine right away for the trial?

Philip Leslie:The next step, of course, was bringing the vaccine onto the site, and in the pharmaceutical industry, a lot of challenges with dealing with live viral vaccines. So, we had to go through a big risk assessment, talking with the regulators and our Quality people, to ensure that we didn’t contaminate the whole site with the vaccine. That was quite a large piece of work. With the disposal and training of staff and things like that. So that went through quite a bit of work and then, of course, the documentation, both training documents and validation documents, and control documents. So, we had to write, which comes with the pharmaceutical industry to get this right. So that was the setup and then, finally, we ran the trial, which was all over in a day after several weeks of planning and the trial went very well. We felt hopeful that that the product was done as best we could. So, we had to send it back to Belgium, and for them to do the assaying and check that the vaccine survived the process and the waiting started at that point.

Rizwan Chaudhrey: What processes are involved, would you carry out a trial with a vaccine with a bloke who sold container? It’s obviously this extractable each of us, you have to test for another things as well, I’m sure. What else do you have to do when you’re doing a trial like that, with the vaccine.

Philip Leslie: Well, of course, the vaccine group weren’t able to provide us with very much in terms of volume, we had two or three liters of product to trial. So we had to modify a way of putting this into a sort of disposable bag that came aseptically from the manufacturer and connect that to the machine aseptically and keep that cold. So, we had a little portable fridge that did that, and so that was the control of the temperature of the product, and then we did some fancy work around changing the fill head, so that we control the cooling process, so we made sure that we could suck the heat out the polymer as quickly as possible. We had that cooling water, right down to a very low temperature to suck the heat out of the process. One of the other things we found was, of course. the vaccine was Quite viscus and we set a very slick liquid, and when we cool it right down to 2 to , it became almost like golden syrup. So, filling it, we’d never filled anything that viscus before so we had to build some new fill needles that we could push out the dose that we wanted, in the time that we needed. There were many trials with them just placebos as well as finally with the product itself.

Rizwan Chaudhrey: Right. You mentioned obviously you ship the vaccine back to Belgium to ensure that did it survived its trip back. What were the next steps?

Philip Leslie: Yes, it was handled very carefully in a special little box, with its own temperature controller, flown back to Belgium, and they then tested it in the normal way because they were the experts in testing the product. And yes, it did it showed there was very little degradation of the temperature of the products potency, but this was the first time we had to wait for several months to get sort of several other timepoints to ensure that there wasn’t something lurking that, then it would suddenly start to die, but it didn’t. It matched the normal process that was being used for filling into other containers. We were very happy, then, that we felt the blow-fill-seal could fill vaccines into blow-fill-seal effectively and not affect their potency.

Rizwan Chaudhrey: And then from that point on, what were the next steps to get to the commercial stage?

Philip Leslie: Yeah so we you know really jerry rigged it in the factory with the various gaffer tapes and different small things, and processes to make sure that we could do it, but then do it commercially we were obviously changing for a couple liters up to 600 liters. And we had to develop a process of how we cool that process and raise a capital project to do the permanent changes and also to the air conditioning, to make sure we have more confined processes in terms of controlling the airflow to make sure that we didn’t contaminate cross contaminate. We had to build a packaging line. And we had to look at lead testing and other processes that were aligned to that process. Of course, along with this was the initial requirement of the vaccine team they wanted to develop a new container that would also be the delivery device. They didn’t want is typically you would have say you’d have a glass container or something that you would draw it into the container into a device that you would dose the patient with. They wanted to use the container and the advantages of the soft low-density polyethylene to squeeze it and deliver it to the patient in one go.

So, we designed the device and the shape of the bottle and made sure that we were actually delivering the dose that they wanted. And they had to do a number of human factor studies, with different healthcare professionals and instructions on how to use it. And then went through various design cycles, as we changed the mold slightly to improve its performance and that ran in parallel with the building and the fit-out  of the facility that we were doing at the site, and then we were pretty well ready to go and we had our first batch came out and filled out and yeah we did three batches in a row, to do the traditional three batch validation process and then they went on to stability as well. It was quite a big project in terms of getting us into the point of being able to make commercial supply.

Rizwan Chaudhrey: How long did this process actually take then?

Philip Leslie: The best part of a year or so from the approval of the project to go ahead to when we were ready to make a product and, of course, that didn’t include the time because they wanted, three and six months stability data and I had to write the registration dossier and submit that to the European Union and auditing by both the TGI local authority here in Australia, as well as you know WHO wanted approval and various other local internal things. There was quite a bit of paperwork done after the facility was finished.

Rizwan Chaudhrey: So, from your perspective, what do you think the key learnings are from doing that particular project?

Philip Leslie: Well, I think the key thing for us was to assemble the right team. Fortunately, we’d been making blow-fill-seal and doing some development work for a number of years. So we had a team of experts who knew the quality side of that plumbing and the processes inside and the control of the machine and how we ran it. And that team really was the key part of that. Also, a key process around problem solving. If you have a problem doing the root cause and trying to find what the root cause of it was so it didn’t happen again and using a good scientific method in that process. So, we documented that and finally really trying to write very good procedures because, really, creating training modules and people who were experienced and knew which knobs made the big difference and what to do when things started to change so we could control the process in a very good way. So, they were the key things that we learned. And, of course, you know the whole real belief that we could do it and nobody’s done it before in a big scale, and it was exciting and it was a great support from the whole site. We were a relatively small team of 10 or 15 people in the time, but yes, it was an exciting time when you do something like that, for the first time.

Rizwan Chaudhrey: Listening to you talk about the trial itself when you first did it with small sample of vaccine, it struck me how you had to be very adaptable and obviously as you said, creating a new needle so that you could inject and things like that. It tells you were using different materials that perhaps you weren’t expecting to.

Philip Leslie: Yes, absolutely. I mean the interesting thing with a needle was of course, If the machine stopped the temperature of the liquid increased and the viscosity reduced so when you started up instead of getting a couple of million, but you know 15 mil, and went all over the floor and everything you had to adjust. That was the learning of how to control the machine if you stopped it or you started it or what to do with the different parts of it. And having people able to understand the process itself. To have a deep understanding of the process was key to the success of it. Teamwork is always the way.

Rizwan Chaudhrey: As they say, teamwork makes the dream work, doesn’t it?

Philip Leslie: Yes, absolutely yes.

Rizwan Chaudhrey: So, what do you think about the future of filling temperature sensitive products into BFS?

Philip Leslie: Well, I think we’ve just scratched the surface. I know I’m biased, but I think there’s a huge opportunity here. I think we have seen paradigm shifts in many things in the past decade, and I think there’s going to be a paradigm shift away from traditional glass bottles into blow-fill-seal because it’s a better aseptic process. Particles are almost nonexistent in it. And it’s faster it’s cheaper, it is a better-quality process. So, I think the ability to use the blow-fill-seal container as a delivery device. Whether you want to put a needle on it, or whether you want to be able to squirt it into the mouth of a patient or squirt it on to the skin and spread it around or do that sort of thing, mix it up in a dual chamber. You know, ApiJect is really looking at a range of different devices that could enhance the delivery and the efficacy of products going forward, so I think there’s a great opportunity for us in the industry to convert to blow-fill-seal.

Rizwan Chaudhrey: Philip, As always, it’s always a pleasure speaking to you, and I always learn something new when I get to talk to you. So, appreciate you taking time out to talk to me today. There you go, listeners. If you’d like to know more, you can find out more about ApiJect and what they do and the different solutions they offer at www.apiject.com. Philip, Thank you very much for your time. It’s lovely speaking to you, and hopefully we can catch up again soon. Listeners, thank you for listening. I hope you enjoyed that and until next time, goodbye.

 

 


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