Apples to Apples: Playing the Comparability Game in Biotherapeutics Development

ART PODCAST | SEASON 3 | EPISODE 8

In this episode of Advancing Revolutionary Therapies, Kevin Hennegan, Director of North American Regulatory Affairs at Veristat, speaks to Lisa Erickson and Sarah Roemer, both Regulatory CMC Strategists also at Veristat, about why comparability studies pose a significant issue for those working in biotherapeutics development, as undetected product changes are considered high risk.

Check out the full episode or read the summary below.

The Importance of Comparability Studies for Biologics

Kevin: Why are comparability studies required and why is this such a significant issue for biotherapeutics development as compared to small molecule development?

Sarah Roemer: Biotherapeutics are extremely complex macromolecules, and it can be difficult to predict the functional impact of small manufacturing changes on 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, PD, or immunogenicity profile, and therefore the clinical safety and/or efficacy profile of biotherapeutics.

The biotherapeutics mantra is “the process is the product.” However, changes in manufacturing such as increases in scale and process optimization are required as part of development. Additionally, the availability of raw materials and a manufacturer’s schedule and capacity can also force changes in manufacturing. If it cannot be demonstrated that a product is clinically equivalent to the 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.

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Assessing Comparability

Kevin: What are the key aspects of a comparability assessment?

Lisa Erickson: First, you start by assessing the change or changes being made. There are several types of changes that are very common in biotherapeutics development:

Site or Manufacturing Facility Changes
Cell Culture Changes (Upstream)
Purification Changes (Downstream)
Formulation Changes
Final Presentation Changes (i.e., changing the final look from a vial to a pre-filled syringe)

Oftentimes during development, there may be multiple changes that occur at the same time which adds another level of complexity to assessing changes and planning for 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 on the extent of differences seen in the analytical and biological characterization testing and the timing during clinical development of when the 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.

Refer to ICH Q5E, the guideline on the comparability of biotech products subject to changes in the manufacturing process, for further detail around when quality and analytical data alone may be insufficient and additional nonclinical or clinical evidence to demonstrate comparability might be warranted.

Kevin: What types of changes are usually considered low-risk vs. high-risk with respect to comparability study requirements?

Sarah Roemer: 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 CMC” is a good source for rules of thumb on assessing the risk of different types of changes.

Low-Risk Changes: “Like for like” changes in reagents or process equipment are generally considered lower risk, and do not typically require comparability studies, but should be assessed for potential risk.
High-Risk Changes: Changes to the master cell bank, purification modalities, or manufacturing site are usually considered to be high-risk.

A few types of changes merit special mention:

Changes to product contact materials are usually considered high risk.
Changes to manufacturing steps that are important to virus inactivation or removal will usually trigger a need to repeat viral clearance studies in addition to product comparability evaluation.
Finally, for manufacturing site changes FDA will expect a thorough GMP risk assessment of the new site and not just reliance on the comparability data.

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Set Yourself Up for Success: Planning Your Clinical and CMC Manufacturing Development Plans

Kevin: Knowing that comparability is an issue that is likely to come up at some point during development, what can sponsors do to prepare for comparability studies?

Lisa Erickson: I think it is important that sponsors place an equivalent emphasis early on with their CMC 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 IND submission, but it will help you anticipate comparability needs, and it may be a useful tool to facilitate discussions with FDA during development meetings.

This “planning” is absolutely the critical element here. You need to carefully map 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 process equipment at a minimum.

And 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 development to account for unexpected product quality issues such as aggregation, undesirable endotoxin levels, and interruptions in the supply of critical reagents. Additionally, one should consider if retaining storage at low temperatures is needed to extend sample shelf life for comparability testing conducted beyond the long-term storage shelf life.

Kevin: What are the potential ramifications of failing to plan ahead for comparability?

Sarah Roemer: 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 the development of the product, beginning with nonclinical toxicology studies and carrying through into additional clinical trials. The financial and timeline impacts of such requirements would kill most development projects.

A less severe consequence, but one 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.

Scenario

Veristat supported a Sponsor in developing an orphan drug and a new first-in-class biologic regulating platelet production. We made minor process changes as part of a site change and process optimization during Phase 3 and provided the analytical comparability data alone to FDA demonstrating comparability between the pre-and post-change material. However, due to a slight increase in a deamidated species in the post-change material, FDA did not agree that we had demonstrated comparability. Due to the complexity of the PK/PD interaction, FDA needed to have further evidence that the minor difference in deamidation was not clinically significant. Our teams worked closely with FDA on a PK/PD comparability study in 20 patients along with the commitment to further gather supporting safety and efficacy data in an open-label study. Although the project incurred a 6-month delay in the initial filing date in order to include the PK/PD comparability study, the drug was first-cycle approved.

Kevin: How does the phase of development impact comparability requirements?

Sarah Roemer: Comparability expectations increase as a product advances through the development life cycle. In early development, Phase 1 or sometimes Phase 2, a modest in vitro comparability study, sometimes supplemented with nonclinical toxicology data, is often sufficient to enable development to proceed. In late-stage development, a more robust analytical package is needed, and some amount of clinical comparability is usually expected.

The FDA actively discourages sponsors from making process changes between the completion of pivotal clinical trials and the submission of a marketing application. In 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 BLA submission. If FDA concurs with the design, this can allow for a reduced reporting category (i.e., changing from a Prior Approval Supplement to a CBE-30 submission), and therefore reduce timeline impact for post-approval changes.

Determining Analytical and Stability Parameters When Measuring Comparability

Kevin: Using monoclonal antibodies as an example product class, what types of analytical parameters need to be evaluated in a comparability study?

Lisa Erickson: This is a great question, but it’s important to note that even when we limit it to a single product sub-class, the range of analytical tests that may be required or informative is quite broad. That said, we’ll 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 function, 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 evaluate antibody integrity and potential product-related impurities. Attributes such as charge, the extent of glycosylation, and aggregation are all critical to antibody function, PK/PD or pharmacokinetics and pharmacodynamics, and immunogenicity. Analytical techniques such as size exclusion chromatography, reducing and non-reducing capillary electrophoresis, and iso-electric 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 the functional parameters of the product are unaffected.

Example: Changes in Charge Heterogeneity

There can be a range of heterogeneity for a given monoclonal antibody or therapeutic protein. A change in charge heterogeneity could alter the drug’s PK and tissue distribution. However, some differences may not be clinically relevant and are well documented in the literature. One example is C-terminal lysine residues on the IgG1 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 is that comparability risk needs to be assessed holistically taking into account the clinical indication, mode of administration, and mechanism of action.

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Kevin: How comparable is comparable? What limits do you need to meet or set in your analytical studies to successfully declare comparability has been met?

Sarah Roemer: 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 ICH Q5E guideline lays out some general principles.

A key point relevant to this question is that pre-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 the safety or efficacy of the drug. Quantifying that level of similarity into criteria for a comparability study requires a risk assessment that is parameter and product specific. Some differences, such as a significant loss of target binding potential, are clearly problematic, while others, such as the 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 of the shift in quality attributes will have an adverse effect on product performance, you may need to further evaluate the impact in nonclinical or clinical studies.

A Deeper Look into Stability Studies

Kevin: With respect to stability studies in a comparability program, what types of conditions need to be evaluated, and over what period?

Sarah Roemer: Accelerated and stress conditions are often considered the most informative for stability comparisons. Finding that pre- and post-change product have equivalent degradation profiles supports a comparability determination. However, even when the degradation profiles are similar, real-time/real-temperature studies are still needed to fully evaluate the post-change product.

In terms of study duration, 3-6 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 in early development. In late-stage development or for a commercial product, longer-duration stability data may be needed (1 year or more), depending on your risk analysis.