Thermo Fisher Scientific Inc. (TMO) Earnings Call Transcript & Summary

Hello, and thank you for joining us today for this webinar, Mastering Analytical Methods for Failsafe PPQ, which is brought to you by Script and sponsored by Thermo Fisher Scientific. My name is Andrew Warmington. I'm the manufacturing Editor at Sightline, and I'll be your moderator today. Before we jump into the presentation, let's first go over some housekeeping items. [Operator Instructions] Because we know you want to listen to this webinar again, the session is being recorded and will be available to view on demand in about 48 hours' time. I'd now like to introduce our speakers for today's session. First, Christy Eatmon is the Global Subject Matter Expert for Sterile Drug Products at Patheon, which is part of Thermo Fisher Scientific. Christy supports the global sales and businesses development teams in providing technical support, designing strategies and supporting new business opportunities for Thermo Fisher Sterile Manufacturing business. She has more than 14 years of experience in the pharmaceutical industry with an emphasis on process engineering, product development, aseptic manufacturing and filling. She also has working knowledge of all phases from drug discovery to sterile product commercial manufacturing with expertise in the sterile formulation of small and large molecules. Previously, Christy supported the site at Greenville, North Carolina as a senior principal scientist in the pharmaceutical development services area. Secondly, Nolan Dean is the R&D and Manufacturing Scientist at Thermo Fisher Scientific. Nolan is a Staff Scientist for BioAnalytical Development Group at the site in Greenville. He has 6 years of experience with Thermo Fisher and 15 years of experience in pharmaceutical method development and validation with a focus on chromatography for large and smaller molecules. We also have Dr. Katherine Hanson, Associate Director for GMP Laboratory Services at PPD, which is also part of Thermo Fisher Scientific. Katherine has more than 10 years of experience in the CMC space, with an emphasis on method development and validation. She's worked on products from early formulation studies to commercial registration. Katherine earned a BSC in Biochemistry from Michigan State University and a PhD in Biochemistry from the University of Wisconsin-Madison with a focus on protein engineering and X-ray crystallography. She currently oversees a team of more than 115 people in performing analytical method development and routine testing on a variety of small molecule and biologic products. Previously, she oversaw a team dedicated to development and validation of analytical methods for biologics and cell and gene therapy products. Ryan Uding finally is Manager of Analytical and Formulation Scientist at Thermo Fisher Scientific. Ryan is an Analytical Development Subject Matter Expert with 15 years of industry experience. He received his Master's Degree in Chemistry from the University of Missouri at St. Louis and has a strong background in passion for mathematics and statistics. Beginning his career in method development, he utilized QbD tools for over a decade to develop robust and rugged methods to support early to late phase processes. In his current role, he drives the approaches used for method development, phase appropriate validation and method transfer as well as supported process developments and characterization. And with that, I'd like to hand things over to Christy, Nolan, Katherine and Ryan, the floor is yours.

Great. Thank you so much, Andrew, and thanks, everyone, for joining our webinar today. This is our third webinar in a series of preparing for PPQ and executing PPQ. So we already discussed late-stage planning. We discussed execution of PPQ from an operation standpoint and a regulatory standpoint, both for large molecule drug substance and aseptic sterile drug product. And today, for the third and final webinar, we'll be having an analytical focus as we were brainstorming about what to discuss in these webinars. We thought, well, it might be good to focus on analytical for one of the webinars as sometimes those are [indiscernible] from an operations background or from a CMC perspective, we often take analytical for granted or just expect analytical to be there for us when we need them. And the truth is that this team is working diligently behind the scenes to ensure that they're not the bottleneck to ensure that their methods are up to snuff and meet all the regulatory requirements and really the analytical necessity for us in the operations space to understand that we have robust processes that we can repeat our processes that everything is in control and that we can validate our processes and our production. So today, we'll discuss analytical for specifically biologic drug products and drug substances and discuss what we need to do to ensure that we execute PPQ flawlessly. So to get us started, I'll pick on Ryan. So Ryan, can you just get us started with some background on how we identify what analytical method should be in our panel of assays for release testing and IPCs and maybe a little bit about specifically what analytical tests are performed on a large molecule biologics.

Sure, happy to. There are generally understood specifications supplied in most biologics and categories for these are outlined in ICH Q6. These include characteristics such as appearance, concentration, pH and osmolality. We have identity methods, typically done by peptide mapping by late stage. Then there are product purity assays, which are comprised of a variety of techniques. These include charge variance by [ indiscernible] Ion Exchange, assays which measure purity and product-related impurity such as size exclusion for aggregates and capillary electrophoresis for fragmentation. Next, we have process-related impurities including HCP and residual protein A. These are done by [indiscernible] residual cDNA by qPCR. Finally, we have product-related potency, activity methods as well as cell-based assays. We also regularly encounter test for excipients, stability, microbial testing, particulates and container closure-related assays to name a few others. Identifying the assays in the appropriate analytical methods can be related back to the process development stage. Critical and quality attributes for the product are identified through process development activities with prior knowledge, for degradation and stability studies as well as processes and product characterization. These CQAs are the physical, chemical and biological characteristics, which must be maintained within defined limits to ensure the desired quality is achieved. From CQA, we define the analytical target profile, which includes the intended purpose and required performance criteria such as specificity, precision and accuracy. And the ATP is used to select the appropriate technique and lays a foundation for method development and validation.

Great. Thanks so much, Ryan, for that introduction. Katherine, over to you, can you help us understand how we prepare these methods for PPQ and when we need to have commercial-ready methods?

Sure. So ideally, the methods are commercial ready, meaning that they've been fully validated prior to the PPQ testing. And this ensures that data can be trended and compared between the PPQ batches and any future commercial batches.

Great. Thanks. Let's move on to talk a little bit about validation strategy. So over to Nolan. Nolan, can you help us understand how we demonstrate that analytical methods are suitable and what parameters need to be assessed?

Yes. As Ryan indicated, analytical methods are developed in alignment with the anticipated batch quality assessment. So working off of that analytical target profile, the method first goes through an evaluation to make sure we'll meet the design criteria. Once that basic method has been developed, it goes through next up, optimization to identify the best operating conditions. Now this optimization can include modifications to the equipment and instrument, the materials used, including the capillary or columns as well as the preparation and extraction steps. Once the optimized method has been developed, it goes through a robustness study just to confirm that the optimization worked. Now once you've got a well-operating method, you move on to your phase appropriate validation. So if your qualitative methods, these are your ID methods like as Ryan mentioned, peptide mapping and also CIF and others, you typically look at specificity and robustness, if you didn't perform robustness during development. And then again, you might do precision depending upon if the method has a source of variability in the sample prep or measurement that should be assessed as part of the validation. Your quantitative methods, these are your assays and purity methods against CIF, CGE, UV, others, need to go through a much more robust full validation for specificity, linearity, accuracy and precision and robustness. And these methods should also include the analytical methods for your solubilizers and stabilizers and other additives that might go into your bulk drug substance. It should be noted that stability indicating methods, these are the ones that assess the purity and [ degradation ] in the material. Those should also go through a Forced Degradation Specificity Study as well as an LOQ and LOD assessment as part of validation. And for these stability-indicating methods, it's best to include either a degraded or spike sample for the precision and robustness studies to ensure that you're able to indicate or -- sorry, to measure those impurities during true sample testing. Ryan, do you have anything you'd like to add?

Yes. A little bit more about optimization and development. So as you mentioned, with the goal of a robust and rugged method, we begin to pursue as early as method development by employing analytical quality by design approaches. Typically, these include screening designs aimed at identifying critical variables and main effects as well as multivariate use, partial factorials and response designs, all which helped to identify the presence and understand the importance of interactions between variables. These approaches enable method developers to make statistically based decisions and are often more efficient by obtaining a lot of information about being data dense. These types of studies help link the ranges of instrument operating parameters, sample preparation conditions and chromatography settings to variations observed in method performance, ultimately creating a model that can predict the performance over a range of conditions also known as the method design space. They can also provide the basis for setting appropriate system suitability criteria to ensure proper method control and indicate when the method is performing outside this design space. Another example of the tools used is the Monte Carlo simulation or other forecasting models. These use the expected variability of key factors that can affect method performance to understand the probability of future outcomes such as invalid rates or assess the method's ability to support predetermined performance criteria.

Great. Thanks, guys, for those insights. Moving a little bit to regulations. Katherine, maybe you can start us off in talking about how regulations have changed recently and how those regulations provide better risk mitigation in the development process?

So to me, the biggest change is ICH Q14, which is anticipated to come out later this year. ICH Q14 provides a great framework for developing robust, well-characterized methods through analytical quality by design, particularly by leveraging risk-based assessments combined with the design of experiments or DOE. So these tools allow for very efficient evaluation of multiple factors with minimal experimental work and allows you to detect factors which influence each other, which you cannot do in a more traditional one factor at a time of evaluation. In addition, companies who opt to all this enhanced approach, gain additional flexibility in certain modifications to their commercial methods. Thermo Fisher has prepared for this change by ensuring we have SOPs in place around this guidance as well as the software and the personnel with expertise necessary to execute on enhancement development.

Nolan, do you have anything in addition to add to this?

Yes. The new ICH Q14 guidance doesn't just focus on the QbD aspect of development, but it also includes the need to monitor and continually improve your methods. Now this is going to require all the pharmaceutical companies out there to develop new SOPs and new procedures for how they're going to do this. The first speaking, how are they going to monitor their method? So how are you going to track its performance over the lifespan of the product being out on the market? How are you going to track the rate of the system, suitability failures, the rate of true and false, OS results as well as the impact to your company through column and capillary lifetime? Is your method of doing undue stress on the materials used to perform the test? So after you've got that procedure, you need your procedure for life cycle risk assessment. So looking at the data you're collecting on your method as well as the development and validation you previously performed, how often is your company going to need to redevelop or reevaluate or revalidate portions of that analytical method. And the last one is going to be an improvement to your technique and instrument modification procedures. How often are you going to look on the market and refurbish the equipment you're using for testing? How often are you going to look out on the market for different types of detection modes, a new detector here, a new detector there? And lastly, how often are you going to go back to your analytical method and look out there for orthogonal techniques that could be used to enhance the data you're generating on your sample. I think the ICH is including this because in the past, in the pharmaceutical industry, it was tend to be a plan to, once you validate your methods, analytical work is essentially done. You just go forward in your QC environment. And they don't like that approach because it doesn't force its clients to modernize and discover more information about their product as time goes on.

And Nolan, just real quick to jump in there. You talked a lot about needing to revamp your methods. Again, the ICH Q14, if you follow the enhanced approach allows you a more flexible ability to modify those methods in the future without potentially going through a complete revalidation, saving companies a lot of time and money.

I do agree. The more time you put in earlier into your methods, the less often you will need to reevaluate it and revalidate those methods because you will have optimized them with the best possible equipment and analytics at the beginning. Another change recently in the regulatory guidance is the issue of Revision 2 to ICH Q2. So this guidance has been published or will be published soon, but it hasn't significantly changed the validation requirements. Those are essentially staying the same, but there are some important additional information that's been out of the session to clarify the expectation of these method validation studies. So some changes worth mentioning are risk assessments for methods and how often they'll need revalidation. So again, that goes back to what we just talked about previously. Additionally, several studies have had different potential study designs presented to help the person drafting the validation protocol. They could use different types of experiments depending upon their method and they'll still be considered ICH compliant. The last significant change is that robustness and system suitability are mostly removed from Q2 because those assessments have been added to Q14 and robustness as well as the definition of system suitability and the ongoing monitoring of that has been moved to Q14.

Great. Thanks, Nolan, that's really descriptive and helps us understand the guidelines which I know sometimes are the difficult part for me to understand, right? I can understand the methods of how we run instruments and how they work, but understanding all the ins and outs of the regulatory landscape can be quite a challenge. Can you also help us understand what actually changes as we get closer to commercialization, right? We've established that in previous webinars we've established, we need methods, commercial ready by Phase III. But what actually changes as we go forward to commercialization?

Sure. So I'm going to kind of reference this back to what we've been talking about. But the previous way we went forward from early phase to commercial was not a great deal of effort was put into analytical methods in early phase. There'd be a rough development, maybe a small optimization and then you go forward into your early phase validation. And then you step up that evaluation and validation as you went through future phases, basically, each new phase would be a stock gate to revalidate the method or supplementally validated to add additional studies. Now the downside of that approach is that method issues are not discovered at the beginning of it, but later during project transitions, which means as you step up to maybe Phase III or commercial, you could find a significant flow with your method that were required you to go back and start over, redevelop and optimize, which is not something you want to do when you get to the late stage which is why the new ICH Q14 style was so much better. You put a lot of effort in early phase because you know exactly the profile of the material you're looking to test. So you know exactly how the method should perform. The more effort you put in earlier, you can basically go through each of those stages, knowing your method had already passed them before you get to them.

Great. Thanks for that. And I know we have folks here from DS and DP. I'm a DP person. Nolan, can you maybe describe some of the differences, what methods would be specific for DP compared to DS? And maybe a little bit about why we can always just transfer methods as they are from DS and DP. I know that's a question that we get a lot from customers and really not understanding why we have to revalidate for drug product if we've already validated for drug substance.

Sure. So most analytical method is for identification, assay and purity and impurities, are transferable to drug product, maybe with some minor modifications. So typically, when moving from one site to another, you're going to have different instruments, different procedures. And so the more effort you put into the robustness of the ICH Q14 guidance, the easier those transfers are going to be because you will have already done a lot of assessment of that method and now it's fairly transferable. Now drug product methods, they have to take into account a different container closure system than the drug substance. Typically, drug substance is packaged to bulk. And as we know, drug products were put into prefilled syringes and vials of various types and sizes. So you have to look at the different degradation as well as extractables and leachables that can come from those different container closures. Now methods are usually also evaluated for drug products at slightly higher storage conditions than drug substance. Drug substances that are biologic are typically stored frozen, and maybe they evaluate 2 to 8, but out on the market, the products have to be stable at refrigerated conditions as well as [ refrigerated ] in some climates at an accelerated or higher room temperature setting. So we have to do those additional stability studies, and therefore, the methods have to be shown to be robust for those types of samples being tested at late stage and higher storage conditions. Another thing is that as part of the product moving forward in phase and going on to commercialization is that the drug product needs to be stable during administration and dosing. So your analytical methods will need to be assessed to verify that as the product is dosed into the patient either directly into the patient through the syringe and needle or administered through an infusion or IV bag, the product needs to be stable in that administration medium and the administration materials to show that the product can then make its way into the patient without being degraded by the process itself. Ryan, do you have anything you want to add to that one?

Yes. And just as you mentioned, considerations for the drug substance and drug products. For drug substance, we have other things that probably are more related to the process. So protein, residual protein A, DNA. These types of methods, you'll find those on drug specifications and release, but of course, moving to drug product, depending on the process in there, you will see those absence. So just another few differences between the two DS and DP sites and expectations for analytical methods.