The how, why and when of comparability exercises for ATMPs
Process changes are an inevitable part of most drug development programs, and this is particularly the case for cell and gene therapy products due to their complex manufacturing needs. Whether it is a move from a CellSTACK culture (Corning’s cell culture product) to a bioreactor, a process scale up, or a move to a new manufacturing site, a substantial process change warrants a comparability exercise as assurance that the product manufactured with the new process is as similar as possible to the one manufactured by the original process.
As noted by the European Medicines Agency in its ICH Q5E Guideline for Comparability of Biotechnological/Biological Products, “The goal of the comparability exercise is to ensure the quality, safety and efficacy of drug product produced by a changed manufacturing process, through collection and evaluation of the relevant data to determine whether there might be any adverse impact on the drug product due to the manufacturing process changes”. The ATMPs are not within the scope of the ICH Q5E Guideline, but, as stated in the EMA’s “Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP)”, the general principles of comparability outlined in the ICH Q5E guideline can be applied to ATMPs.
The Process
An appropriate way to approach product comparability should encompass in a three-staged approach. The first stage would involve conducting a thorough risk assessment, which would identify the critical quality attributes (CQAs) likely to be affected by the introduced process changes, and the critical process parameters (CPPs) that control these CQAs.
The second stage would devise an analytical testing plan to assess these CQAs in the pre- and post-change material. Such a plan would define analytical methods chosen for the investigation of comparability, as well as specify criteria for its acceptance.
It is important to note that for a comprehensive assessment of comparability, passing release tests will generally not be sufficient. In fact, a comparability study does not need to include all release tests but should instead include a selection of relevant tests to specifically evaluate those CQAs that have been identified to most likely be affected by the process changes. This selection would usually comprise release tests and additional tests, such as extended characterization and in-process-control methods.
The methods selected for comparability should ideally be qualified against the relevant parameters, including sensitivity for methods evaluating impurities, specificity for tests of identity confirmation, accuracy for the dose-informing tests, and precision as an overarching requirement for all methods since the goal of the comparability exercise is to compare products manufactured using two different versions of the manufacturing process.
Similarly, demonstrating product comparability should involve more than simply passing release test specifications. To conclusively demonstrate that the new process yields material that can be considered comparable to the material produced with the original process, acceptance criteria for comparability will often need to go beyond existing release specifications, particularly in cases where in the early phases of development specifications for some tests may still be wider than representing actual product variability or even “report result”. Acceptance criteria for comparability should be pre-defined using a suitable statistical method, such as equivalence testing, the 95% confidence interval method, or potentially the T-test. For small data sets, Bayesian statistics may be employed.
Finally, the third stage would involve conducting the analytical testing as set out in the plan, ideally as side-by-side testing of pre- and post-change material with subsequent evaluation of comparability according to acceptance criteria defined in the protocol. If no pre-change material is available, it may be possible to use historical data, provided that the material was from a process representative of the clinical (or pre-clinical) process, and that it was subjected to the same tests as set out in the protocol.
It is worth noting that failure to pass the pre-defined comparability acceptance criteria should be treated as “flags” triggering further investigations for possible non-comparability, rather than directly concluding comparability failure. Such events should be further assessed, taking into consideration analytical method precision and/or potential failed testing (if indicated by system suitability criteria). Observed variations should be evaluated with respect to the actual impact on the product quality, safety and efficacy. If analytical comparability cannot be concluded, non-clinical studies may provide further indications as to whether the observed differences should be considered significant with respect to safety and the therapeutic efficacy.
What the regulators expect
When assessing process changes detailed in regulatory submissions, regulators will expect the developers to provide sufficient analytical evidence of product comparability, particularly if pre-clinical data from pre-change batches have been used to set the clinical dose, and especially if clinical studies with pre-change material are already underway or even completed.
Introducing process changes during or after pivotal studies is not recommended, since the requirement for comparability will then reach maximum stringency and could result in a negative outcome on the acceptability of the clinical data. Any regulatory challenge to comparability results can lead to a clinical hold or other significant delays if additional studies are requested. For this reason, it is strongly recommended that when planning to implement major process changes, especially during the clinical stage, developers seek feedback on their planned comparability exercise from the regulators before setting out to conduct such activities. Feedback on comparability exercise protocols can be sought at Scientific Advice meetings in Europe and the UK, and at Type C meetings with the FDA in the US.
About the author:
Elena Trude is a regulatory CMC consultant at Biopharma Excellence. She provides support on regulatory CMC issues to developers of cell and gene therapies, specialising in analytical strategy, including biological potency assays and product comparability.
