Aisling Greene (Host):
Thank you very much for dialing in everyone. You're welcome to the next in our series of webinars from the Medicine Accelerator. For those of you who aren't familiar, the Medicine Accelerator is a dual effort and partnership made up of APC and VLE in which APC manages the research and process development arm and VLE manages the GMP manufacturing arm allowing us to collectively see through the full product lifecycle. This is bridge by our digital knowledge platform I achieved that. We'll introduce during the presentation as an introduction. My name is Aisling Greene. I'm a project manager here at apc and our speakers today are both from the Medicine Accelerator coming from VLE on our GMP manufacturing side. I'll be moderating the webinar this afternoon and I am delighted to welcome my colleagues Michael Ó Gailín and Elaine Hiney. Michael is the manufacturing cell lead and Elaine is the senior process engineer, both coming from VLE Therapeutics. We're really looking forward to this presentation. We can go through any questions you might have at the end of the webinar and without much further ado, I'll hand over to Elaine.
Elaine Hiney (Speaker 1):
Thanks million Aisling for that introduction. Hello to everyone who has joined us today. I'm Elaine Heney. I have around 15 years in the pharmaceutical industry and have been involved in many tech transfers over those years, both good and bad.
So what is technology transfer? The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, the control strategy, the process validation approach, and ongoing continual improvements. So depending on what point the product is in the CMC lifecycle, the level of process knowledge is different at the beginning.
Product design and understanding is key and is the focus. Once the product is understood, you move into process design and understanding. After that, you put the controls around the manufacturing process, which forms the control strategy and as you move into commercial manufacturing, it's process monitoring and continuous verification. Tech transfer can happen at any of these stages and as when the manufacturer of a product is moved from one manufacturing suite or facility into another throughout the CMC lifecycle. Key ICH documents that need to be understood and followed are ICH Q8, Q9, and Q10. These documents provide structured guidance on defining, defining product critical quality attributes and determining the critical process parameters that can impact the product quality. These all help to define the product control strategy.
So there are many challenges that can be encountered to during a standard to tech transfer process. Many of these challenges come from the disconnect between development and GMP manufacturing teams on either end of the transfer spectrum. These challenges affect the efficiency of the transfer process, which ultimately affects timelines and costs. Some typical challenges include process development priorities are not aligned with JMP needs.
For example, what are the key documents or reports that need to be generated during PD that can help the tech transfer later? Sometimes formal reports or documents are not included in the PD scope and this might be due to cost or timelines. However, key document identification early can help speed up the transfer later process operability is not always considered. This is an interesting one. Sometimes during the PD phase, the equipment set or the bespoke design s u t has a long lead time and so PD may decide to go with a more manual process or a material that is not GMP suitaVLE to keep the process moving.
And while you're speeding up the development process here, it causes a bigger delay during the tech transfer part of the process into GMP manufacturing and that's not where the knowledge is. So the process is not easily peaceful, which it needs to be for GMP manufacturer. Another challenge is sme. Tacit knowledge can get lost. Typically during PD work, the process scientist grows with the process and develops a really in-depth understanding of how the product behaves during that unit process. If this is not documented or GMP personnel are not involved early, this task knowledge is lost and manufacturing a repeataVLE process that GMP takes a lot more time and that GMP phase, it is much more expensive. The implications of these challenges are time delays, which may result in missing the clinic scheduled slot. Also, cost implications where rework is required in the GMP suite, for example, which is hugely more costly than in a developmental laboratory knowledge loss, which could result in batch failure. It is so important to have a GMP lens on the process development strategy from the start, identifying key deliveraVLEs or documents together as a team all contribute to a smooth later stage tech transfer.
It's also important to understand the regulatory expectations depending on the phase in the product life cycle you are at. If these are not known, this can lead to additional PD work at a later date, again, impacting timelines and costs. So what is cmc? It stands for chemistry, manufacturing and Control. It involves understanding the product and the specifications that must be met to ensure product safety and consistency between batches. CMC begins immediately at the start of r and d and continues through age, the product development lifecycle right into commercial manufacturing. Depending on the product lifecycle phase, the product is at the level of knowledge investment and activity changes. For example, if the product is at pre-clinical phase product understanding and identification of the cqs, that's key. What are the cqs that need to be met within defined specifications to ensure that a product has the desired safety and efficacy in a patient? C QAs are typically selected through risk assessment following I c HQ nine, whereas if the product is a phase three clinical, for example, the impact of process and material variability must be known and understood With cqs, PPS and process design spaces clearly defined, these all feed into the process and analytical control strategy for the product.
This slide here just provides a visual representation of the phase appropriate activities that are required. As you can see from the graphic above there, you're not considering process validation at the r and d phase or into preclinical. That's something that comes when you understand your process and you're putting the controls around your process. In phase three, as you move into commercial fire burden and endotoxin controls need to be known and un understood right throughout the phases of of the clinical supply equipment is calibrated at the start and you're moving towards qualified equipment. As you move towards the CNC lifecycle, methods are qualified and you're moving towards validated analytical methods as you come towards phase three and commercial in the CMC product lifecycle. I'm now gonna hand you over to my colleague Michael.
Michael Ó Gailín (Speaker 2):
Thanks Elaine. So as as said at the start my name is Michael and I am the manufacturing lead at VLE and today I am going to discuss how we at the Madison Accelerator have improved our internal tech transfer processes, capturing a lot, a lot of what lean has highlighted as improvements and indeed the different pitfalls that you want to avoid. Previously I worked on the process development side and in the past clients have experienced difficulties and frustrations during the transition from process development to tech transfer and subsequent GMP manufacturing as a means to improve this process.
APC who are involved in the process development side of, of the product lifecycle have brought the full tech transfer process in-house under one roof, extending the value chain from process development to GMP manufacturing by establishing VLE Therapeutics together. This strategy is called the medicine accelerator and I will discuss how this has helped tackle the different obstacles and to facilitate tech transfer without the jet lag. A key part of the medicine accelerator is the, the strong planning and clear process development output with open communication and strong collaboration between process development and GMP teams during the tech transfer process to really help us strive towards that seamless submission. And we ultimately achieve this using the help of our digital platform I achieve, which I will also discuss at a later point.
As part of the medicine accelerator strategy, a multi-functional team of scientists, engineers, supply chain specialists, CMC experts and quality and regulatory affair professionals work together to consider all aspects of the tech transfer process. From a very early stage, this ensures that these considerations are taken into account and it allows us to develop a robust process that can then be rapidly transferred to the manufacturing phase. I'll now discuss how APC and vle managed to apply these improvements to the transfer strategy all under one roof. So recently AP C and VLE applied the strategy for the design development and scale up of and transfer of an atmp process.
APC initially de developed this process from a bench top scale, characterize it, and then scaled it right occupied scale. This allowed the team to assess the different types of equipment that was required for the process. From a very early stage, they were aVLE to see what, what equipment was suitaVLE, the types of single use technology assemblies that were required to run the equipment and all these requirements in considerations were thought about from a very early stage. The important part of this is that with single use technology demands impacting global lead times and the the stress that has been put on the supply chain process for through identification and procurement, it is critical that we have this oversight to help forecast and manage procurement and industry and and inventory. Also, awareness of single use technology requirements allow the process development teams to design bespoke or process specific solutions that are tailored for your process, but also compliant and suitaVLE for manufacturing requirements.
Equipment selection is also very critical, as Elaine alluded to earlier, sometimes equipment that fulfills process development requirements is not necessarily appropriate or indeed operational within a GMP cleanroom environment. And without these considered tech trans transfer considerations at nearly stage you run that risk of having to revisit process design and this results in significant rework, increase in cost to your overall program and it ultimately delays the delivery of your molecule to the clinical trial and to supply it for the patients. In addition to the process design and equipment or material selection benefits, there are many other parts of having this, this process in-house and with the under one roof that encourage and such as that encourages the strong collaboration between both process development teams and the GMP professionals. Here we have a few pictures of our pilot plant which is a non GMP pilot plant where the process development teams initially scaled up the process.
The GMP manufacturing team were then aVLE to engage with the PD SMEs at a very early stage, learn the process steps and to become familiar with the equipment sets. Bear in mind, the process development team have nurtured this process from very early stages. They have characterized heavily and they know they have an indi intricate understanding of the process nuances and we can then transfer that task of knowledge which is critical to the GMP teams. An al bonus is that the GMP team can start to redline documentation such as MBRs and SOPs to help reduce the documentation lag. That can always delay a transfer.
The manufacturing team can also assess the different single use technology assemblies that are being used. The different equipment that has been operated during these pilot runs to ensure that any GMP or clean room gaps that might not have been considered are captured at an nearly stage and we can then adapt them to make sure that they're clean room compatiVLE. More often than not, tech transfers can span continents, countries and time zones. Teams are separated and very disjointed, which can result in poor communication, delays in knowledge transfer and this ultimately impacts key decision making. Tech transfers can result in a lot of back and forth traveling, leading to increasing expenses, a lot of time wasted, and also the complexities in building relationships across a large distance. So when you think about it, not only is there a metaphorical jet lag, but there's also an actual personnel jet lag. What APC and VLE have achieved is a tech transfer that spans a corridor, not a notion, and this helps them with that jet lag.
So at this point I want to draw your attention to a tool that we have developed within APC and VLE called I H E I H E is a first in class digital CMC platform designed to create and contextualize all CMC decisions in the development journey of your medicine. It was actually originally designed to assist in early, early answering questions around the scientific rationale behind why certain developmental decisions were made. But it has proven an invaluaVLE tool in assist in tech transfer, whether that transfer is between a P C and V or indeed between APC and a third party manufacturer. Essentially it makes tech transfer much easier because it provides a central resource for all the key information related to key process parameters which inform the scale up and GMP manufacturer of your at m p.
Previously, this information may have been dispersed across a lot of different stakeholders and within a lot of different information repositories. This dispersion makes it next to impossiVLE to undertake a smooth and efficient tech transfer. So what I achieve does is it removes this proVLEm by aggregating and curating all this information and making communication and information transfer between development and manufacturing scientists much easier and much smoother. So here we have the process that was originally designed and developed in APC, scaled up to a pilot plant and then transferred to our VLE cleaning facility right across the corridor. Here are a few pictures of our GMP team performing an engineering run in the clean room facility. And the beauty of this process is that we are heavily supported by our process development SMEs. We're using light for like equipment and tailor-made s u t assemblies and we've perfected the process documentation throughout the pilot runs and the transfer process, which gives us control over a full knowledge and skill transfer with additional point of view support and guidance. This support offers us the confidence that we can progress to GMP clinical supply manufacturing and ultimately reduce timelines and remove tech transferral blocks.
So to achieve tech transfer without jet lag is important that we have full CMC oversight to make sure the correct strategy is in place at the process development stages to help make the smart choices and to meet clinical trial timelines. Material and equipment selection and process design where possiVLE will significantly speed up that transfer process. Striving for that like for like transfer and ultimately a seamless submission improving the interaction and engagement between process development, tech transfer and manufacturing teams across the different stages and phases of a project ensures that full knowledge transfer and capturing key task skills and understanding the GMP teams have also experienced important training opportunities in a more relaxed space, such as a pilot plant without the stringencies or constraints or clean rooms so that they can really get to grips with the equipment and the complex at m p process steps. So improving document transfer, reducing or indeed removing the need for process development rework, reducing the risk to GMP batches will ultimately prevent the program delay and the delay of delivering critical medicine to the patient. So thanks all for your time today and I'll pass you back to Ashley for any questions.
Thank you so much Elaine and Michael for a brilliant presentation. We really hope everyone enjoyed it and found us informative. So we're just starting to get some questions in and we have a few minutes left. I can read some of the questions out and we'll go through them until we run out of time.
So I have a question here that has been sent in from Eric. The question is, do you take transfer to other sites other than really?
Michael Ó Gailín (Speaker 2):
Yeah. Thanks Eric. That's a good question. So the beauty of the transfer process is that it's not designed or restricted to any one modality or, or any one type of medicine really. It's a framework that we can apply to any type of process and also go to multiple sites. So it's not just internal, but I presented today as an example of internal transfer, but we're aVLE to take that framework and apply it so that although you might not have the face-to-face interaction of different third party manufacturers and the APC transfer side, we have that transfer team who can, who can make sure that all the information is effectively transferred.
Great, thanks a million. Michael, we have another question in from Joanna. Joanna is asking, you mentioned early exercises that should be performed to facilitate a smooth tech transfer. Can you give an example of an early stage exercise you've performed to help with this?
Elaine Hiney (Speaker 1):
Yeah so I suppose it depends on what point in the CMC cycle we are at, but it should always start with a meeting of the key stakeholders from both sides, both G and P and process development. So firstly, determine where in the CMC cycle the product is at and what is absolutely required to meet expectations at that point in the CMC lifecycle. So if it's a phase one clinical batch, for example, one of the most important things you need to look at is a C Q A risk assessments. So identifying the critical quality attribute from the start and monitoring them throughout all of the activities. The QT PPP needs to be supplied from the product owner and this should include, and that's a regulatory requirement. They should include product description, clinical application dosage, and then those cqs that that look after the safety of the product and the efficacy of the product.
The process flow diagram is another key document that you'd want to be tracking and developing throughout the process development part and, and through into GMP manufacturer. And that process flow should have all of the inputs, all of the outputs, the in process testing and specifications, so all the key information that that needs to be known. And then identifying the study in process development that we you might want to use for comparability when you go into GMP. So that particular study in process development should have a really, really good protocol and report because then that can be used, you know, in the regulatory aspect of the, of the application. I hope that answers your question.
Thanks Elaine. We have another question coming in from Daniel. Daniel is asking, you mentioned tacit knowledge learned during early stage process development engagement by the GMP team. Can you give an example of how you learned this specific knowledge? How did you extract it?
Michael Ó Gailín (Speaker 2):
Yeah, I can probably take this from the operations side. So whenever we were running the, you know, the, the at p process in our, in our APC pilot plant during the scale up activities some of our team on the operations side on the GMP side we're aVLE to go in and, and perform, you know, batch observations alongside the process development SMEs. And you have to remember that, that the PD team, you know, have that, that strong strong knowledge of what every step should look like, simple things like the characteristics or colors of different intermediate pools. And what we were aVLE to do was they were aVLE to highlight, you know, key things to look out for that key task knowledge. We were aVLE to photograph those different steps and see what was, what was important, what we had to, you know, be aware of.
And then we used our, our digital platform iAchieve to be aVLE to, you know, go back and review those different, those different pools and that that documentation of, of photographs so that then whenever we were in manufacturing phase, if we observed something that we weren't entirely comfortaVLE with, we were aVLE to, you know, go back and review that. And that really gave us confidence that for the first time executing the process, you don't have multiple runs. So it really, we had that, that background and that context to be aVLE to, you know, be confident that what we were doing in the GMP space for the first time was like for like, for what the pilot plant achieved, if that, that makes sense.
Thank you Michael. Okay. I'm just conscious of time. I think we are unfortunately just up to time now and we wanna ensure everyone can get back to your busy days. And so unfortunately we don't have any time for further questions, but any questions that have come in through the chat that we haven't addressed, we'll be sure to follow up with via email. We'll also be providing a recording of this session to everyone who attended. And if anyone is interested in having a virtual tour of our APC and VLE facilities, please do feel free to get in touch with us. We'll be very happy to schedule that with you. So thank you very much everyone for dial in and attending this afternoon. And a huge thanks again to Elaine and Michael for a brilliant presentation. We hope you enjoy the rest of your day.