Hi, everyone, and welcome. My name is Veronica Feinberg and I will serve as your moderator today. Thank you for joining us for today's webinar. Our journey worth taking an easier path to process change management as your moderator. It's my role to ensure that we make the most of your time with us. I'm here today with John, Meet Anant and Pascal Richard. John Meet Anant has been providing regulatory consulting for biopharmaceutical manufacturers for more than 10 years. Johnny has a Global Regulatory Affairs certification, a Bachelor's of Science and Chemistry and APHD in Pharmacology, Pascal Richard provides regulatory and validation expertise to biopharma customers with a focus on sterilizing filtration systems. Validation For more than 25 years, she has helped drug manufacturers demonstrate that their filtration systems contribute to safe drug manufacturing. She's a member of PDA and holds Master's degree in Biochemistry and microbiology. 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My name is Jen Mead and I'll be presenting the first part of this presentation and then Pascal will pick up the second part. So today we'd like to share information with you about a journey worth taking and our focus here is on manufacturing process change management. We will be looking mainly at sterilizing grade filtration and different applications as as they're used through the process. So for today's agenda, I'll be presenting part one and Part 2 on why are these change changes and change controls, why are they needed for drug manufacturing. The second part I'll be discussing which will seem like a mindset shift on some common myths and how quality risk management approaches can help in the change management process making a little bit more efficient. Then I'll pass over to Pascal who will go over some specific case studies and sharing our knowledge and experience on how we manage those case studies. And then finally how can suppliers help support you to accelerate and simplify this manufacturing change process. So I'll start with the 1st section, which is why change controls are needed. And what we'll do first is we'll start with the poll question. OK, everyone should now notice their first poll question on the screen. And if your company is thinking of making a change in processing equipment for an approved drug product, was this due to supply constraints or for other process changes? A. No, not aware of any post approval changes made. B yes, changes made due to supply challenges, C yes, changes made due to process changes or D yes, changes made for other reasons. We'll give you a few moments to answer and we can see live how many people are submitting here. So please participate and we can we'll look at the results after this. Jon, me. I'll let you close it out when you'd like and move it over to the next slide. Yeah, thanks. Thanks for those who are participating and I will move this forward. So thanks for this. This is very, very interesting and and we'll cover a lot of this during our presentation today. So for the change management, you know what you need to think about and what, why are they, why are these changes made? So I've kind of grouped them in a simple way in three areas. So there could be supply changes and in that supply there also could be new products that come up and maybe there's some that have actually been rationalized or discontinued, some more innovative products and they're also can be in that supply. And with those raw materials some changes and you know one of these could occur or all of these could occur. So these are some of the things that we'll be highlighting today in terms of you know some of the changes that could be impacted in this way and So what are the main drivers for change and we'll cover that here. And and our focus is really on what we think is the worst case which is once you have a commercialized product, how do you make changes to that authorized products of post approval changes. So some of our raw material or some of our manufacturing equipment availability issues addressing any quality issues that could have an impact. And so this is one of the major reasons for change, especially when there's a huge cost of goods or there's a huge quality issue. And the other, I would say one of the bigger impacts is a regulatory change. So then you're really required to do it based on getting your continuing to have your commercial product approved and that can be for various reasons, whether it's a specific compendial change or an environmental impact, expansion of your existing facilities. So scaling up processes, I think there are some that are looking at putting in improvements, maybe there's optimization and that could also link to cost, but improvements of modernization of the manufacturing facility and that also links into addressing aging facilities and equipment. OK. So for this section, I'm gonna go over some of the common myths and how quality, risk management and those approaches can help. So one of the things that I'm highlighting here is a basic approach that's been communicated by regulatory agencies around the world and that has been also tied together with ICHQ 12 is a risk categorization level. And along with that risk categorization level, there is a notification and approval level requirements. So for a major risk level change, it is known as tell and wait. So that means notify and wait for approval. So before moving forward and implementing a change, you have to wait for that approval. And that has various terms in, in other countries. In the US, it's called a prior approval supplement for a major change. And in the EU it's called a variation and it's labeled as a Type 2 variation for moderate and minor changes, which the regulatory agencies have said should be the majority of manufacturing changes. Which is actually one of the myths is that if you do change your application, it's automatically a major change. But that's not the case. If you change your filing or application, there's a need to notify the agency and that also the level of notification and the requirement for approval would depend on the risk level. So for moderate and minor risk category, virtually all of the agencies around the world do not require no approval, they just require notification. In the moderate one, you tell them first you notify 1st and you typically wait around 30 days and that's I've seen that in various countries. And if you don't hear back then you just go ahead and implement and then for a minor change you can actually implement the change first and notify the agency later like during the annual report. The key thing to remember that these all of these changes can be downgraded using different tools, but also having the right support and documentation. And the key thing is making sure that the drug substance or drug product meets the same specifications and quality requirements. And that has a lot to do with manufacturing expertise and the experience that you have. So what's the evidence that the regulatory agencies are open to more, more freedom of operation while our industry is more restricted in terms of their risk averseness. So what we see here is that the industry typically sees these and I've seen numbers like greater than 60%. And in biologics, sometimes 80 or 90% of all changes are major changes. And the FDA and other agencies have said that a majority of the changes should be moderate or minor. And in this case, they've published this in 2014 to say that they are just overwhelmed. Their resources are limited. And when they evaluated all of these prior approval supplements, they have to review which are major changes. They determined that many of those changes are actually a low risk to the quality of the product and do not need to be submitted in supplements. So basically saying we don't need to approve these, you can just go ahead and implement them and all we need is a notification. And for this case they you can implement it first and just let us know during the annual report. This is all on the foundation that you would have to make a change to your filing. So when we look at the guidance, what we notice here is that for filters and manufacturing equipment, this is, this is the things that they look at. So one of it is the design and operating principle. And in one extreme, something that has the same design and operating principle would be, for example, a normal flow filtration. If you're changing from a normal flow to maybe a tangential flow filtration, that may be a different operating principle. Or on an extreme, if you're changing from a centrifugation to filtration, that would be a different operating principle. The other thing that you want to really look at is the filtration process parameters. What are changing and how well do you know those process parameters and what may impact the function of those filters? Then finally, a change from a qualified sterilization chamber to another is something that's considered a lower risk and doesn't need approval, especially where that is following the sterilization standard. So I'll go through some examples from another guidance. I just highlighted FDA, but from The Who guidance where they have a little bit more detail on some of these changes and they have two guidances. This is from Annex 3, but they have a comparable 1, which is Annex 4 for vaccines. This is for bio therapeutics, which typically cover recombinant proteins. What you can see here is that the highest reporting category is moderate, which is different operating principles and different product contact material. Anytime you change the operating principles, there's a focus on re performing the process validation. So a revalidation anytime you change the product contact material, there'll be an emphasis on performing extractables and leachables. Of course that level of studies will depend on the risk to patient safety. Please keep in mind that a lot of these studies and comparisons, especially batch comparisons, can use relevant small scale models or historical testing data. And then if we move toward same operating principles then you can see that there's no process validation or revalidation required. You would just need to do one commercial batch comparison. When we look at the same product contact material, then you don't need that extractable leechable comparison. And then what's termed as equivalent here is always a minor risk and the equivalent definition is the same operating principles and the same product contact material. So that's just to give you an idea of kind of the categories here and some of the descriptions on manufacturing equipment changes. And what I'll do here is that there's a lot of guidance and the PPQRI guideline really looks into sterile products and sterile filters and some of the key change factors that you want to look at when you do your risk assessment. So a pore size change is listed and that is considered I think one of the most critical, especially where the pore size change may impact the functionality and sterilizing grade filter for the final drug product is the key thing that you want to keep that the same material changes listed there bacterial retention, compromise, pressure flow, solvents, compatibility. And that really depends on if you're you know in typical aqueous solvents versus maybe some extremes that only one one type of filter may manage or you're on the boundary of compatibility. So that's something you would may want to look at. Usually not a big issue for biologics. Time of use and temperature range of use and stability. OK, so here we have our second poll. OK, so everybody, here's your next poll question. Would you consider a post approval change if the change offered benefits process or economic to your process? A change means too much work and unlikely to make B have considered a post approval change management protocol PACMP but never used it, or C have used APACMP successfully. We'll give you a few moments to answer. We're. Almost at 50. OK. I'll give it back to you John, whenever you'd like to close it out and go to the results slide. Thanks everyone. Yeah, thanks everyone for submitting the answers and yes, thank you. Thanks for the the information. OK. So one of the key things that I mentioned earlier was process understanding. So ICHQ 12 terms uses a term called knowledge management. So the knowledge management is could be within your own organization or it could be outside of the organization. So I've seen a lot of drug manufacturers use industry publications, industry knowledge from, you know, different things that are publicly available. You can use your own internal knowledge like what changes have you done before, How well do you understand the the the process? Has it has? Have there been comparable processes that you've used before that have gone through changes? How did you manage those then? And also you can access this information from collaborations if you have ACMO, if you have a supplier who really understands their manufacturing equipment or raw materials and can help or has you know information on the the comparability of those. So, so yeah, so this is just to kind of show you some of the approaches to to manage change based on knowledge. So the more knowledge you have, the more efficient you can make the changes. And if the knowledge really helps you to find that you're not changing your drug substance or drug product quality or safety, then it's easier to set a risk category that may be lower than what you initially thought. So in general, this slide will show some of the scenarios of a final fill sterile filter and what may require more effort. So I haven't put the risk category here because that like I said depends on process understanding and some of the other input but and other conditions to be fulfilled. But here you can see some of the highest effort changes would be a change in the filter membrane, because a filter membrane is the key one that manages the bacterial retention and the sterility. And then on the other end, like format changes or sterility changes, as long as there's some standard approaches, those are typically a lower level of effort or data needed. And then from there we'll be covering some other cases with supplier changes and changes in filter housing. And some of the information you need will be dependent on a change of material, like I said, extractable leechables or some of the other data and validation that may be required with the change in operating principles. And from here I'll pass it on to Pascal. Thank you, Janet. For the regulatory insight of the change management. I'm going to present you 3 case studies on what can be learned from our experience. So the first case studies about supply chain or business to benefit our customers by implementing our source within in our membrane manufacturing. In this case, the change is a supplier in use change of the membrane within without that change of material of construction of the membrane. And this change allowed us to expand our fitter manufacturing sites. And when we talk about change link to a fitter membrane, it could be often considered as high risk, especially if a critical sterilizing way the fitter is impacted. So before making this change, we've performed the qualification studies and comparability studies. First, on the membrane itself. Many physical tests were done to verify that the new resin provide the same membrane characteristics and are within the same membrane specification. So tests such as the bubble point or the ability of the membrane or evaluating the tanseed and elongation of the membrane. Also, membrane thickness and membrane surface chemistry were verified by SEM and compared to the previous freezing. And finally, microbial tests such as the microbial retention and endotoxin were conducted. All those results were compared to the previous resin results and it showed equivalency. In conclusion, we've demonstrated the consistent performance of the membrane made of either resins. So the the next step was done to perform qualification and the comparability studies on the filter device itself. The testing verified that a filter device made with the new within as the same filter characteristics and now within the same specification. So testing such as integrity testing, hydrological stress, thermal resistance, stress factor retention on the toxin extractable fiber and particle with release. And last but not the least historical comparison of the filter key attributes between the qualification lots with the new within versus our world of many years of historical lot data was done. And here we've demonstrated the equivalent feature device performance and claims for the new within. So before implementation of the change your filter supplier should provide you with define documentation. So first notification letters well in advance of the change and you will find information such as the change type, Is it the whole material change, is it product specific specification change or is it that change Link to the product claim. You will find also information of what fit our catalog number are affected, the description of the change, why the reason of the change. Also our information on data package availability, for instance qualification reports and the implementation detects when this change is is occurring and the impact assessments regarding the product specific validation. So secondly, you will also get summary reports. So those are summaries of your filter or supplier qualification reports where you will be finding conformance to the specification, historical equivalence with larger historical load data, manufacturing process assessments and also conclusion. Thirdly, your supplier will provide you support to reply to any of your questions and also provide you availability of Peter samples should you need to perform any additional testing at your end. So how does this information from your supplier impact your manufacturing process and product? Related to the documentation, so one of the things to assess is the impact of search change on your product specific validation. So usually your filter supplier has a validation service lab offering such capability. So let's see what those filter validations are. So the membrane bacteria retention. This test demonstrates that the stylizing weight filter, when loaded with challenge bacteria produces a sterile effluent, the membrane and device compatibility. This test demonstrates that the process read and conditions do not impact the structure of the filter. The Product Specific Integrity Test specifications. So what is an integrity test? It is a non destructive test which confirms the fitter retention. So here are products specific integrity test specification and determines the specification with your product instead of a standard. Read such water for example for aerophyllic filters, extractables and leachevers and patient safety. So those studies are identified, quantify and assess the impact on patient safety of compounds that can migrate from the feature or from the single use assembly to the process streams. So going back to our previous question, how does this change from your supplier impact your manufacturing process and product related documentation? So there was no change in the material of construction. Your filter supplier has demonstrated the same and consistent feature performance with the membrane made of either within. So therefore there is no impact on the former product specific validation and this conclusion is also included in your supplier or notification letter. Finally, from our collaborations with our big pharmaceutical companies, these types of change have been reported as minor changes. So now let's move to the second case study here. It deals with another change linked to filter innovation and increase the benefits for our customers. Why not changing to a new filter which brings more and better functionality? A filter optimizing your final situation step and reducing risk of contamination and reducing patient safety risk with safer material of construction. So in this case it is a new filter improving the former filter version. It has the same material of construction for the membrane, but different material of construction for the housing. So in this case your filter supplier will provide you with different documentation and services. So first the new filter documentation, such as the brochures technical information with dimensions of the filter, for instance the list of method of construction, biological, physical and chemical information as well. You will have also user guides available, example of certificate of quality and also chemical compatibility charts. Of course what will be available also is a future qualification including the feature performance claims as well as the extractable for full profiles. And of course your feature supplier provides you with with support on on the feature consumables and also services such as validation services offering for your product specific validation. So the question to to address before implementing this this new filter in new product manufacturing line is how to assess the impact of this change to the situation validation. So here is a generic overview on how to proceed. So first look to all the material of construction and these differences and look to which filter path it's corresponds. Is it a membrane? Is it the filter housing? Is it the band? Secondly, when you know the affected future parts, you can then list all the effects is the product specific validation report and I will detail in the next slide this part in #3 gather available documentation on your filter supplier such as the compatibility chart, extractable profiles and here the the collaboration with your feature supplier is is key. And finally, perform gap analysis and if needed updates the feature validation with appropriate rationale in order to complement the validation Dosia. So to come back to our case 32, a few thousand change. Here is a detailed view of how to assess the impact of the change to the situation validation. So with the same membrane, same situation area, same intensity test specification, so no evaluation is is needed when it comes to bacterial retention test, intensity test, binding of practical shading studies. Here with the change in housing vans material of construction regarding the compatibility and extractable, you can repair to available data so coming from your supplier or data that you may have in house and then confirm compatibility and as well as the patient safety. So now this is the last case study and case study 3A filter membrane change. Here is a detailed view of how to assess the impact of this change to the situation validation. So here there are different membrane, certainly a different integrity test specification and also a different situation area. Here we have different material of construction and only the the housing remains the same in terms of validation needs of your feedback style retention test regarding integrity test. So you can refer to the certificate of quality for standard freed or if you wish request the product specific integrity test. You will need to assess binding studies and also compatibility and extractable for patient safety evaluation. So here for those two you can refer to available data and ask your support from your filter or supplier. So now it's time for the search poll question. Thanks, Pascal. So you'll now notice your last poll question on the screen. Are you planning any changes in your sterilizing grade filters? A no changes are planned. BA change to a different filter from the same supplier, CA change to a different filter from a second supplier or D multiple changes, sterilizing grade filters and other process related changes at the same time? Again, we'll give you a few moments to answer. Any more submissions, Pascal? I'll hand it back over to you to decide when you want to close it out. Thank you for those. Who submitted? Thanks so much for your for your inputs. The results are interesting and provide a good overview of our audience change plan. So how a supplier can simplify and accelerate the process. So as we've seen previously with the different case studies, changes can be coming from your future supplier or changes can be coming from your manufacturing process changes with AT that we your product composition or changes to your situation parameters such as patch volume, time pressure, temperature for for example. So all changes need an impact assessment to formal product specific validation. So as an inner world senior news and the future or validation service team can help you in in this assessment. So our experience technical experts review the nature of the changes and the possible impact to your validation report. So here there are different scenarios. So first if there is no impact, it is mentioned in the notification letter provided by your excel supplier. But we can also provide you with the generic letter or letter specific to your product and situation process. Second scenario, if there are impacts on the validation results then letters with updated results can be provided for your product and if there is an an impact to the validation then our validation services team can perform a new test. So here are disabled details the difference of filter changes which can occur versus the validation need. And as mentioned before, not all changes for your new test and updated validation letters are sufficient, as highlighted in the yellow boxes. For instance, changes in the situation area requires only a documentation exercise with updated results. This where was a change in Fitzer Membrane would require new additional tests. So here this table details the different changes which can occur in your manufacturing process versus the validation need on. So here I again some changes. The triggers add additional validation test only if some parameters are exceeded as shown in the tan boxes. So for instance, changes in the standardization condition would trigger a new test only if the new conditions exceed those mentioned in the former validation report. This table details the default changes which can occur in your product versus the validation need. Changes in the product formulation obviously would be full of validation, whereas a change in product podiology requires only an updated patient safety or documentation. So the take away message here is that we as your filter supplier can help you through your your change process. We leverage our knowledge to help our customers who shift focus on innovation and continuous improvement even if it triggers for stuff well challenging. And you can benefit from our years of experience in units operation and situation, chromatography, viral clearance and in collaboration with our customers defining critical process parameters associated with risk. And our labs also use a small scale models to support risk assessments approved by regulatory body. So we've also went through many changes in our unit operations from process optimization and continuous improvements and providing our customers with validation data and documentation package. So how to reach us to benefit from our experience? So who your local service representative of technical service or also who your local senior use and feature validation service land and of course on our website. Thank you for your attention and we can now start the Q&A session. Thank you, Pascal and Jenny for this great presentation. Now it's time to answer a few questions that have come in from our audience. But before we do, I'd like to remind you it's not too late to send us your questions now using the Q&A widget. This also applies to on demand webinar viewers. We'll try to get through all of them, but if we run out of time, we'll respond to you individually. And as a reminder, this webinar will be available on our website soon and all participants will receive an e-mail notification when it's available for viewing. OK, so now we can start answering questions that have come in. So we have a question here. How do you assess which validation report is impacted by a change? Pascal, do you want to take that question? Yeah yeah thank you. So in fact firstly you you need to check what this change is is about, what is different. If the challenge is related to the filter housing, then mostly compatibility and it's profitable. Each other patient safety have to be accessed and all validation link to the membrane performance are valid and if the challenge is related to the membrane than mostly validation linked to the membrane need to be assessed back there with tension is the most obvious as it assesses the with tension performance and then all studies linked to patient safety evaluation to be reassessed to be able to conclude on on patient safety and also studies such as integrity test binding and particle shading studies need to be accessed as well. OK, thank you. OK, So you mentioned you mentioned a product specific letter versus a validation. What's the content and does this documentation replace a new validation? Yeah, I will, I will take this one too. So it's it is a documentation exercise and it assesses the impact of the change for validation performed with specific products and also specific manufacturing process. So this documents justifies that a new test is not necessary and you will find the reference of the former validation report and also a comparison of the the validated conditions versus the new conditions. What is, what has been changed? What is the change about? And then a section on on the impact also of of this change with the appropriate justification when formal reports are are still valid. Or it can be also a letter with with updated results, for instance extractable amounts recalculated when there is a situation that we are increasing. And finally in the conclusion that all the other information in the former or reports contents remains valid. Thank you, Pascal. Another question, do you help customers decide if a particular change would be considered minor, moderate or major? Yes, thanks for that. Thanks for that question. So I think that's where a lot of our industry and a lot of the drug manufacturers, you know they're a little bit hesitant to to categorize a change as other than a major change. And So what we've seen from the regulatory guidance, you know in the end it's actually the drug manufacturer sponsor's decision on how they want to categorize the risk. But we have guided customers a lot on this. So what's really clear from the regulations is that major changes to manufacturing are quite limited, a master cell bank change. And this has also been in different publications. A good one is John Geigert on the challenge of CMC changes for for biopharmaceuticals. And he also lists that that like a master cell bank change would be considered a major risk. Some of the container closure, drug product, container closure changes could be considered a major risk based on certain conditions. But a majority of everything else is considered at highest a moderate risk even for vaccines and there's a lot that's major. So what the Regulatory agency has said before when they look at the overall industry is that 60 to 80% of all the manufacturing changes should be minor to moderate risks. So that just to give you an idea how the Regulatory agency looks at it based on the industry and the how risk averse we are. And So what I can tell you is that when we do help certain customers or drug manufacturers in selecting a certain risk category, out of maybe a handful of customers, only a few will agree with us and they're actually successful in that. So why actually wait for approval when you can get it through with just a notification. So I hope that makes sense. But also what we've seen is some of the big pharmaceutical companies for filter membrane changes have submitted this in the US as an annual report, so as a minor change. So we've also experienced that, just to give you an idea. Thank you, Johnny. OK. So we do have a question, another one about what is the ICH guidance for managing process changes and difference between pre and post commercial? Yeah, no, thanks for this question too. It's, it's, it's something that I you know to start out with. There is only ICH guidance on changes in authorized products and that was also from The Who is changes in post approval changes, so post commercial not pre marketing changes or changes during clinical trials. So that's number one. However, the same reference from John Geigert and others go through some of the changes during the development process. So earlier you have more freedom to operate in terms of the change and of course the more process understanding you have, the more freedom you have to operate. Now remember a lot of these changes that we're talking about from a regulatory standpoint is in the filing. So if there's no change in the filing, you manage those changes in your own quality management system and they may be re reviewed by regulatory agencies during an inspection. The Regulatory agency on a new drug product. And if it's a new company that hasn't produced anything before, they will not inspect the manufacturing site, especially in the US Now Europe has some different rules until you come close to approval, it's called a pre approval inspection. But for the filing or CMC changes, if you're doing it before talk studies or early and talk studies, there's a lot of freedom to operate in those process changes. As you transition to 1st in human studies, you have to make sure that your safety profile of your product has not changed. Usually people use the same GMP batch for their talk studies as their first in human studies. In early clinical studies during manufacturing, there's a lot of changes happening anyway and developing of analytical methods, developing a process, understanding it's still early. The level of comparability testing is generally not that extensive. Studies are usually referred to by regulators as adequate. So again the main focus is patient safety. You don't need extension extensive studies there. And then as you move forward, especially as you get to phase three, then those are usually change changes that are comparability studies are much more comprehensive and thorough and it gets closer to what's required for a post approval change. So I hope that's what the the audience member was asking about, but I I tried to cover a few things there. Thank you. Thanks for that question and John me for your answer. The next question we have is what is the highest motivation for customers to change their process? Yeah. So that's a good question. I think there's a few really major motivators. I think the highest one would be linked to regulatory. So if your quality of your product, your quality safety or efficacy is what do you call it is altered to a degree that it won't, you won't be able to gain regulatory approval for release of that product. Like for example, it doesn't meet your specs and there's a recurring problem then change has to be made, right. So that's number one and it could also be compendial changes that need to be met. It could also be some regulatory restrictions that we need to we need to meet now. So that would be the highest motivations for customers. I think the second one would be if there's, if there's a clear and large, the larger the cost change like if you could if you could minimize the cost of something dramatically then there's a drive especially based on the business management to move. But I would say the highest is always related to kind of you know that regulatory quality, safety and efficacy aspect. Thank you. OK, I think that's all the time we have actually for questions. I didn't realize we're coming up at the hour. If we didn't get to your question, please feel free to e-mail our our presenters directly and to register for future webinars or to access our archived webinar library, you can visit our website. And I'd like to thank John, me and Pascal for today's presentation and thanks to our audience for joining us. Thanks everyone. Have a good day. Bye. Thank you. Bye, bye. _1732519825953

 
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