Rational arguments for regulatory acceptance of consistency testing: benefits of non-animal testing over in vivo release testing of vaccines

ABSTRACT

Introduction

There are rational arguments to replace existing in vivo potency and safety assays for batch release testing of vaccines with more advanced non-animal techniques to measure critical quality attributes. However, the introduction of in vitro alternatives to replace in vivo release assays of authorized vaccines is challenging.

Areas covered

This report describes the hurdles encountered in substituting in vivo assays and ways to overcome these and provides arguments why more advanced in vitro alternatives are superior, not only as a tool to monitor the quality of vaccines but also from a practical, economical, and ethical point of view. The rational arguments provided for regulatory acceptance can support a strategy to replace/substitute any in vivo batch release test if an appropriate non-animal testing strategy is available.

Expert opinion

For several vaccines, in vivo release assays have been replaced leading to an optimized control strategy. For other vaccines, new assays are being developed that can expect to be introduced within 5–10 years. From a scientific, logistical, and animal welfare perspective, it would be beneficial to substitute all existing in vivo batch release assays for vaccines. Given the challenges related to development, validation, and acceptance of new methods, and considering the relatively low prices of some legacy vaccines, this cannot be done without government incentives and supportive regulatory authorities from all regions.

KEYWORDS:

• 3R
• assay variability
• consistency approach
• in vivo assays
• potency testing
• batch release testing
• reverse characterization
• vaccines

Article highlights

• Replacement of in vivo QC (Quality Control) assays is rational and driven by better science, not just (valid) ethical concerns, and should be encouraged by regulatory authorities.

• In vitro tests are superior to in vivo assays for quality control of vaccines. Due to their inherent large variability and poor discriminative power, in vivo batch release assays are less suited to monitor process consistency. Furthermore, they are costly, and the lead time for in vivo testing is often several months with practical implications.

• For vaccines initially authorized with an in vivo potency assay for batch release, there should be a commitment to replace this with an in vitro method in due time.

• Due to the challenges and considerable effort involved substitution of long existing in vivo assays for legacy vaccines, this cannot be done without government incentives and supportive regulatory authorities.

• Despite the many practical and regulatory hurdles, for several existing vaccines, in vivo assays have been successfully substituted with in vitro assays, leading to an optimized control strategy.

Acknowledgments

This publication benefited from the discussions held in the frame of Work Package 6 (WP6: Promotion to regulatory acceptance of consistency testing) of the VAC2VAC consortium. We wish to thank all participants in WP6 for their most valuable input.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors have substantially contributed to the conception and design of the review article and interpreting the relevant literature, and have been involved in writing the review article or revised it for intellectual content.

Additional information

Funding

This manuscript was funded by the VAC2VAC project. The VAC2VAC project received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement N-115924. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.