(M1230-08-43) A Survey of Biological License Application of Monoclonal Antibodies – Part II: Comparability Approaches for Manufacturing Changes

Purpose: Manufacturing changes have the potential to impact safety and efficacy of therapeutic proteins [1] and comparability assessments are highly recommended or required to support the change [2]. The comparability approach has been reported to be determined on a case-by-case basis because of the diversity in the types and timing of changes [3]. Based on the Purple Book published by FDA, as of December 31, 2021, FDA approved 85 mAbs in 351(a) biological license applications (BLAs), i.e., non-biosimilars. We reported the survey results on the manufacturing changes contained in submission package of these mAb BLAs in a separate abstract - Part (1). Here we report Part II of our survey regarding the comparability approaches used to support manufacturing changes.

Methods: We surveyed the regulatory submission packages of 85 mAbs in the FDA’s database for the comparability approaches (or types of data) supporting their manufacturing changes. For all 506 manufacturing changes reported in Part I, we identified the data that supported the post-change product and grouped the comparability approaches by the supporting data types including analytical comparability studies with physicochemical, functional, and stability attributes, clinical pharmacokinetics (PK) comparability studies, and other clinical studies (such as efficacy/safety studies) using the post-change product.

Results: Analytical comparability is the foundation of comparability strategy and were conducted to support almost all 506 manufacturing changes. Based on other supporting data we grouped the approaches into the following 4 main groups (Figure 1):

Approach 1: No clinical study data (analytical comparability study only); accounting for about 6.3% of all changes. These changes happened in early stages between pre-clinical phase and early clinical phase. In addition, some minor changes in cell line or process happened in late stage were also solely bridged with comprehensive analytical comparability study since analytical comparability data were adequate to demonstrate the post- and pre-change products are comparable.

Approach 2: Clinical PK comparability study; this accounts for about 1.6% of all changes. The PK comparability studies generally applied the statistical criteria for bioequivalence to evaluate the PK data. Presentation changes (from prefilled syringe to autoinjector) that happened post-pivotal study were mainly bridged with this approach.

Approach 3: Clinical experience with post-change product; accounting for about 70.1% of all changes. For process changes happened in the early stage, the post-change products are used in pivotal clinical study. There was no clinical bridging study with a head-to-head comparison of two products.

Approach 4: A combination of the two clinical approaches above, i.e., the post-change product is supported by both clinical PK comparability and other clinical experience, accounting for about 17.3% of all changes. This approach has been seen in late-stage cell bank changes, big scale-up process changes, late-stage formulation change for subcutaneously administered mAbs, etc. In some cases, clinical experience with the post-change products was provided in addition to a clinical PK comparability study that failed to pass the bioequivalence criteria.

Other comparability approaches have been used. For example, nonclinical PK comparability studies have been used occasionally to support changes (4.8%), though most of them were followed up with further clinical PK comparability studies or clinical experience of post-change products.

Conclusion: Comparability assessments are necessary to ensure that the post-change products have comparable quality and clinical performance as the pre-change products. Our survey results showed that four main approaches composed of bioanalytical comparability, PK comparability, clinical experience, and a combination of clinical experience and PK comparability taken to bridge the pre- and post-change products. The comparability approaches have been customized considering the complexity of manufacturing changes and the special characteristics of each drug and its manufacture procedure.

References: 1. Putnam, W.S., et al., Pharmacokinetic, pharmacodynamic and immunogenicity comparability assessment strategies for monoclonal antibodies. Trends Biotechnol, 2010. 28(10): p. 509-16.
2. Food and H.H.S. Drug Administration, International Conference on Harmonisation; guidance on Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process; availability. Notice. Fed Regist, 2005. 70(125): p. 37861-2.
3. Lee, J.F., J.B. Litten, and G. Grampp, Comparability and biosimilarity: considerations for the healthcare provider. Curr Med Res Opin, 2012. 28(6): p. 1053-8.

Acknowledgements:This project is funded by The Oak Ridge Institute for Science and Education (ORISE). We acknowledge Drs. Leopold Kang and Haoheng Yan for their valuable input to this project.

Disclaimer: The findings and conclusions in this abstract reflect the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1 Summary of comparability approaches by the type of manufacturing changes.