Advancing Revolutionary Therapies
Advancing Revolutionary Therapies
Apples to Apples: Playing the Comparability Game in Biotherapeutics Development
Comparability studies are a significant issue for those working in biotherapeutics development, as undetected product changes are considered high risk. Listen as Kevin Hennegan, Lisa Erickson and Sarah Roemer take us through several considerations when Playing the Comparability Game in Biotherapeutics Development.
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Speaker 2:Hello and welcome to Art Podcasts, advancing Revolutionary Therapies, a podcast series presented by the Centers of Excellence at Barat. My name is Kevin Hennigan, director of North American Regulatory Affairs. I'm delighted to continue season three, a dedicated series of regulatory podcasts on topics that cover everything from smart regulatory strategies, maintaining continued regulatory compliance, the influence of health authorities on clinical trials and more. Today I am joined by Lisa Erickson and Sarah Roamer, two of our regulatory C M C strategists here at Veristat to discuss today's topic. Apples to Apples playing the Comparability Game in Biotherapeutics Development.
Speaker 3:Hi, Kevin. Great to be
Speaker 4:Here. Yes, thanks for having us.
Speaker 2:We work with a lot of biotherapeutic products here at rista, and one of the issues that comes up frequently is assessment of comparability after a process change. Sarah, why are comparability studies required and why is this such a significant issue for Biotherapeutics development as compared to small molecule development?
Speaker 4:Biotherapeutics are extremely complex macromolecules, and it can be difficult to predict the functional impact of small manufacturing changes to the product using analytical techniques alone. Health authorities expect that a change in the manufacturing process will result in product changes that may not be detected using established release analytical methods. Undetected product changes are considered high risk because they can and have resulted in significant changes to the PK p d or immunogenicity profile, and therefore the clinical safety and or efficacy profile of Biotherapeutics. The biotherapeutic mantra is the process is the product. However, changes in manufacturing such as an increase in scale in process optimization are required as part of development. Additionally, availability of raw materials and I manufacturer's schedule and capacity can also force changes in manufacturing. If it cannot be demonstrated that a product is clinically equivalent to product produced from the previous process, a sponsor can no longer rely on completed animal and clinical studies. Therefore, to minimize repeating nonclinical and clinical studies needed to support process changes, one must plan for and implement a robust comparability plan.
Speaker 2:Lisa, from your perspective, what are the key aspects of a comparability assessment?
Speaker 3:Well, Kevin, first you need to start by assessing the change or the changes being made. I can give a few common examples of these types of changes. First, there's site manufacturing site or facility change. You can have cell culture changes or upstream changes, purification changes or changes to the unit operations in the downstream. Also, formulation changes and final presentation changes. For example, a lot of times sponsors wish to change the final presentation from a vial to a prefilled syringe. Oftentimes during development, there may be multiple changes that occur at the same time, which adds another level of complexity to assessing the changes. In planning for the comparability assessment using a hierarchical approach, you start with assessing the pre and post change material with analytical testing to ensure product quality followed by biological characterization. Determining whether additional in vivo comparability studies are needed can be assessed based upon the extent of differences seen in the analytical and biological characterization testing and the timing during clinical development of when changes are made. If you thoroughly assess the potential risks associated with the changes and have solid product process knowledge, analytical testing alone can often suffice to successfully demonstrate comparability. However, the tricky part is if your analytical testing shows some or slight differences, then you would need to consult with, and there's great guidance out there. I C H Q five E. It's the guideline on comparability of biotech products subject to changes in their manufacturing process, and it provides further detail around when quality analytical data alone may be insufficient and additional nonclinical or clinical evidence to demonstrate comparability might be warranted.
Speaker 2:What types of changes are usually considered low risk versus high risk? With respect to comparability study requirements,
Speaker 4:A risk assessment based on the type of change and the potential impact on the product is a critical element of comparability studies. FDA's guidance document on comparability protocols for post-approval changes to C M C is a good source for rules of thumb on assessing the risk of different types of changes. For example, like for like changes in reagents or process equipment are generally considered lower risk and do not typically require comparability studies. What should be assessed for potential risk. At the other end of the spectrum, changes in the master cell bank purification modalities or changes in manufacturing sites are usually considered to be high risk few types of changes, merit special mentioned, changes to product contact materials are usually considered high risk changes to manufacturing steps that are important to virus. Inact activation or removal will usually trigger a need to repeat viral clearance studies in addition to product comparability evaluation. Finally, for manufacturing site changes, F D A will expect a thorough G M P risk assessment of the new site and not just reliance on the comparability data.
Speaker 2:Lisa, knowing that comparability is an issue that is likely to come up at some point during development, whether due to scale up or facility changes or some of these other potential issues that we've already talked about, what can sponsors do to plan ahead for comparability studies?
Speaker 3:I think it's important that sponsors place an equivalent emphasis early on with their C M C or manufacturing development plans as they do their clinical development plans in early development. Drafting a manufacturing development plan is prudent. The manufacturing plan is not a required component of an I N D submission, but it will help you anticipate comparability needs and it may be a useful tool to facilitate discussions with F D A during development meetings. This planning is absolutely the critical element here. You need to carefully plan out the projected analytical and clinical needs for each stage of development to ensure that enough material can be produced to meet those needs, plus the addition of product retains as required. For example, almost every sponsor will scale up their manufacturing process during the course of development and scale up inevitably means changes to, at a minimum, your process equipment, you will need more retain material than projected based on prospectively planned development activity. Sponsors we have worked with have had to make changes to manufacturing processes during the course of development to account for unexpected product quality issues such as aggregation, undesirable endotoxin levels, and interruptions in supply of critical reagents. Additionally, once you consider if retained storage at low temperatures is needed to extend sample shelf life for comparability testing conducted beyond the long-term storage shelf life, what
Speaker 2:Are the potential ramifications of failing to plan ahead for comparability
Speaker 4:Potentially severe? In the worst case where there are insufficient data on the old product and no remaining material that could be used for additional testing, a sponsor could have to effectively restart development product beginning with nonclinical toxicology studies and carrying through into additional clinical trials. The financial and timeline impacts of such requirement would kill most development projects less severe consequence, but one that we have seen more frequently is a requirement for additional clinical data such as an additional clinical efficacy study or increased sample size for an ongoing study.
Speaker 3:I have an example from a program that I worked on where we made some very minor process changes as part of a site change and process optimization. During phase three, we provided the analytical comparability data alone to F D A demonstrating comparability between the pre and post change material. However, due to a slight increase in a damated species in the post change material, F D A did not agree that we had demonstrated comparability. This was an orphan drug and a new first in class biologic regulating platelet production. Due to the complexity of the P K P D interaction of the drug, F D A needed to have further evidence that the minor difference inuation was not clinically significant. We ended up working closely with F FDA A on a PK P D comparability study in 20 patients along with a commitment to further gather supporting safety and efficacy data in an open-label study. The drug did end up being first cycle approved, however, we did incur a six month delay in our initial filing date in order to include that clinical PK p d comparability study.
Speaker 2:How does the phase of development impact comparability requirements?
Speaker 4:Comparability expectations increase as the product advances through development lifecycle in early development phase one or sometimes phase two. A modest in vitro comparability studies sometimes supplemented with non-clinical tox data is often sufficient to enable development to proceed in late stage development. A more robust analytical package is needed in some amount of clinical comparability is usually expected. The F D A actively discourages sponsors from making process changes in between the completion of pivotal clinical trials and submission of a marketing application and that situation. Most companies may be better served by proposing the desired change in a post-approval supplement to the marketing application for anticipated post-approval changes. It is often helpful to include a proposed comparability protocol in your b L a's submission. If F FDA concurs with the design, it can allow for a reduced reporting category, for example, changing from a prior approval supplement to A C B E 30 submission and therefore reduce the timeline impact for post-approval changes
Speaker 2:Using something like monoclonal antibodies as an example product class. What types of analytical parameters need to be evaluated in a comparability study?
Speaker 3:This is a great question, Kevin, but it's important to note that even when we limit it to a single product subclass, the range of analytical tests that may be required or informative is quite broad. That said, we can start with the potency assay for the product, which is always required for comparability studies as this in theory should directly correlate to the clinical efficacy of the product. Other assessments of antibody functions such as antigen binding and FC effector function should be assessed even if not part of the official potency evaluation for the product. Next, you should look at techniques that that evaluate antibody integrity and potential product related impurities. Attributes such as charge extensive glycosylation and aggregation are all critical to antibody function, E K P D or pharmacokinetics and pharmacodynamics and immunogenicity. Analytical techniques such as size exclusion, chromatography reducing and non-ed, reducing capillary electropheresis and isoelectric focusing are a few of the common methods used post translational modifications should be assessed. Although some differences in these parameters may be tolerable if functional parameters of the product are unaffected. One example is with charge heterogeneity. There can be a range of heterogeneities for a given monoclonal antibody or therapeutic protein. A change in charge heterogeneity could alter the drug's PK and tissue distribution. However, there are some differences that may not be clinically relevant and are well-documented in the literature. One example is C terminal lysine residues on an IgG one heavy chain of a monoclonal antibody, which is delivered intravenously since the bloodstream contains carboxypeptidase enzymes which quickly remove lysine residues. Variation in this attribute is not clinically relevant. The point here being is that comparability risk needs to be assessed holistically, taking into account the clinical indication, the mode of administration of the drug and mechanism of action. Finally, analytical tests that may be relevant to the specifics process change such as tests for process related impurities may be necessary.
Speaker 2:How comparable is comparable? What they usually mean is what limits do you need to set and need in your analytical studies in order to successfully declare that you've established comparability between pre and post change material?
Speaker 4:This is a very difficult question to answer as demonstrated by Lisa's earlier example. Without diving into the details of a specific product and proposed change, the I C H Q five E guideline lays out some general principles. The key point relevant to this question is that BRI change and post change products do not need to be identical, but should be similar enough that any differences will have no adverse impact on either the safety or efficacy of the drug. Quantifying that level is similarity into criteria for a comparability study requires a risk assessment that is parameter and product specific. Some differences such as significant loss of target binding potential are clearly very problematic while others, such as elimination of a product related impurity may be clinically meaningless or even beneficial. In cases where there is insufficient information to predict whether a given magnitude, a shift in quality attributes will have an adverse effect on product performance, you may need to further evaluate the impact in either nonclinical or clinical studies.
Speaker 2:So I did want to wrap up or or touch on one last topic before we wrap up today, and that's stability studies. With respect to stability studies in a comparability program, what types of conditions need to be evaluated and over what period of time?
Speaker 4:Accelerated in stress conditions are often considered the most informative for stability comparisons, finding that pre and post change products have equivalent degradation profile supports a comparability determination. However, even when degradation profiles are similar, real time, real temperature studies are still needed to fully evaluate the post change product. In terms of study duration, three to six months of real time data in combination with accelerated condition data can be sufficient to allow the post change product to be introduced into clinical trials, particularly if the product is still an early development in later stage development, or for commercial product long duration stability data may be needed of a year or even more, and that's gonna be dependent on your risk analysis.
Speaker 2:Well, on that very stable foundation. We'll wrap up for today. I wanna thank our C M C strategists, Lisa Erickson and Sarah Roamer for joining me today and contributing their insights and expertise to the podcast. If you have questions about the information you've heard today or about any aspect of pharmaceutical product development, you can reach out to us through the links available on the veristat website. Also, be sure to subscribe to the Art podcast on your favorite player so you can get notified when new episodes become available. Thank you for listening. Until next time,
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