Comparability Studies Are Inevitable, Here's How To Make Them More Efficient
By Christopher Shaw, Bioanalytical Sciences, Global Technical Operations, AstraZeneca
Comparability studies are an integral part of the life cycle management of marketed pharmaceutical products. Market authorization holders are expected to demonstrate that pharmaceutical products that have undergone changes to their manufacturing process are comparable to the material produced from the pre-change process. The similarity of the pre- and post-change product is established in part through the supporting analytical comparability package. Designing an appropriate yet simplified analytical comparability package can reduce the burden on the analytical labs and improve the efficiency of the work necessary to support the life cycle management of a marketed product.
Regulatory Expectations For Comparability Studies
In order to design an appropriate analytical package, we should first discuss the regulatory expectations for comparability studies. ICH Q5E Comparability of Biotechnological/Biological Products provides a thorough resource on the expectations for comparability studies. The major point of interest in Q5E is the understanding that the comparability study is designed to show that pre-and post-change materials are highly similar. This is a major factor: they are expected to be highly similar, but they are not expected to be identical. For the characterization expectations of Q5E, the study sponsor should demonstrate that the higher order structure – be it secondary, tertiary, or quaternary – is maintained.
The FDA guidance Demonstration of Comparability of Human Biological Products provides another resource for understanding the expectations for comparability studies. The main point in the guidance is that a well-composed data package can be used to demonstrate the similarity of the pre- and post-change material. The analytical data package should comprise the tests used as part of lot release and the additional tests used to characterize the product structure for market approval. This indicates that the company should repeat the testing that is performed as part of the elucidation of the structure of the product. While a number of those tests are appropriate for elucidating the protein structure of the product, that does not mean they are appropriate to detect the more subtle changes expected during a comparability study. Those characterization tests should be chosen based on the expected impact on product quality attributes for the proposed manufacturing changes.
Design Of The Comparability Study
A typical design for a comparability study will often compare three pre-change lots to three post-change lots for a late-stage or authorized product. The tests on specification are going to provide the most in-depth comparison and compose the majority of testing. The stability portion of the comparability study is often performed side-by-side, typically with three pre-change lots versus three post-change lots.
Characterization testing can be simple to extensive. If the expectation is to provide confirmation of similar primary, secondary, and tertiary structures, or maybe even quaternary structure, a number of different tests would be utilized to demonstrate the similarity of the product using pre- and post-change materials. Ideally, the same three lots from both pre-change and post-change are chosen for lot release and stability.
Figure 1 provides an example of what a typical comparability study might look like: testing for specification lot release tests, stability, and then characterization. For the stability portion, a typical design might use two conditions for the side-by-side stability portion of the comparability study. In the example in Figure 1, the specification lot release testing for the pre-change lots is listed; however, the pre-change lots may not be specifically retested for the purpose of comparing those results to the post-change lot release results. However, when performing a side-by-side stability study, the pre-change lots may need to be retested to establish a new T=0 for the purpose of determining the degradation rate. For characterization testing, a method list might be chosen to represent all possible characterization tests performed for the product for market authorization, and those are to be performed side-by-side. Many of these sorts of tests are not routine and can require extensive expertise to perform the data comparison, like mass spectrometry, for example.
Figure 1: Typical Study Design, Drug Substance
In an optimized study as displayed in Figure 2, the lot release and stability portions can be satisfied by the testing that is scheduled to be performed for the post-change lots and then comparing it to the existing data for the pre-change lots. This strategy can be used for both late-stage development changes and post-marketing changes. Often, many manufacturing changes that warrant a comparability study will also have the post-change batches placed on stability, so the market authorization holder will usually be performing these activities as part of their business as usual. Acceptance criteria utilized for a comparability study can be set using all existing lots manufactured up to the point that the acceptance criteria were calculated. Then the post-change lots can be compared against the totality of existing lots to assess comparability. This is to compare the post-change lots to the whole experience of the pre-change process, rather than just compare against three lots that might have been cherry picked or only represent a small portion of the current product history. For the stability acceptance criteria as well, the degradation rates of the post-change lots can be compared to the average degradation rates of all pre-change lots that had been put on stability at the time of the study.
Figure 2: Optimized Study Design, Drug Substance
In the optimized study design, there will be minimal changes to the extensive characterization testing design for how the testing plan is constructed since it is usually essential to compare the pre-and post-change material side-by-side. However, the tests selected for the extensive characterization aspect of the comparability study can be optimized as the next opportunity to reduce any unnecessary testing.
Extra care should be taken to choose characterization methods that have been shown to be fit-for-purpose. Can the method reliably monitor the differences in the molecule that might be expected from the proposed manufacturing changes? This is something that should be determined based on the method qualification results. The key factor in deciding which tests to choose for the comparability study centers around the expected changes to the product, based on process and product characterization studies. If your product understanding demonstrates that certain quality attributes are not affected by particular process changes, it may not be necessary to perform the characterization tests to monitor that quality attribute. For example, the characterization performed at market authorization for a biological product may contain far UV CD (or FTIR), a disulfide map, free thiol, analytical ultracentrifugation, along with other popular assays such as differential scanning calorimetry (DSC), peptide mapping, oligosaccharide profiling, and intact mass. However, in a comparability study, only DSC, near UV CD, peptide mapping, oligosaccharide profiling, and intact mass may be chosen based on fit-for-purpose qualification studies. Since many of these characterization tests are not high throughput, care should be taken in only selecting tests that are able to detect the changes to the molecule expected to be seen in a process change.
Challenges With Reducing Testing
The major challenge a sponsor may face when designing a comparability study with a reduced testing burden is that it does not meet regulatory expectations. A poorly designed comparability study could delay the release of a new facility or a much-needed process update. Conducting a thorough investigation can be more challenging if the testing results from the optimized study design generate a result that is inconclusive regarding comparability. However, there is a strategy that can help to mitigate these risks.
A Post-Approval Change Management Protocol (PACMP) can be utilized to get a study design approved by regulatory authorities prior to the execution of a comparability study. A regulatory authority can provide feedback on the comparability study design prior to its initiation, greatly reducing the risk involved with the smaller testing load. Another advantage of using a change management protocol approved by regulatory authorities is reduced response time from the regulatory authorities when the final comparability package is submitted. Meeting all the predefined criteria in the protocol could allow the market authorization holder to implement the post-marketing change immediately after notifying the regulatory authority instead of waiting for the full review of the study as part of a traditional supplement to a license application.
Conclusion
Market holders should understand that a comparability study is commonly needed during the life cycle support of a biological product. Managing a comparability study as part of life cycle management of a product should not be a daunting task and can typically be performed by leveraging as much routine testing as possible. For most studies, the only testing required outside of already established lot release and stability testing will be the characterization testing of the pre-and post-change materials. Using a PACMP will greatly reduce the risk of the comparability study’s design, while also enabling quicker review of the summarized results. Early discussions with regulatory agencies to discuss the proposed comparability study plan and criteria can allow the market holder to truly optimize the efficiency of their comparability studies.
About The Author:
Christopher Shaw has been a member of AstraZeneca’s MS&T and Global Technical Operations group since 2013. During that time, he has been designing and executing validation and transfer studies required for release and stability methods performed in the quality control laboratory. He has extensive knowledge in working with forensic spectroscopy techniques to assist in manufacturing and drug product investigations and has been responsible for implementing higher-order structure analysis to support post-marketing comparability studies. As the process owner for post-marketing comparability strategy for large molecule products, Shaw has worked to implement a lean testing strategy for comparability studies at AstraZeneca.