Ensuring sterility in cell- and tissue-based products presents unique challenges due to inherent product variability, limited sample sizes, and the extensive manual handling involved in their production. As the need for expedited product release continues to grow, alternative sterility testing methods are being explored. However, these methods introduce additional challenges, as they must undergo rigorous validation and gain regulatory approval.
Regulatory bodies such as the FDA and EMA are increasingly open to alternative methods, provided they are supported by robust validation data.
Anthony Thatcher, Senior Director of Manufacturing Operations at Sumitomo Pharma America, and Prethib Arumugam, Associate Director of Quality Control, shared insights on this topic. Below is a summary of their discussion.
Challenges of sterility testing in cell- and tissue-based products
Sterility testing for these products is more complex than for traditional aseptic therapies due to several key factors. The scarcity of product material restricts the amount available for sterility testing. Many cell- and tissue-based therapies have a limited window for testing before they must be administered. Manual and intricate processing increases the potential for contamination. The presence of cellular components and biological matrices can interfere with sterility detection methods.
When selecting a sterility test method, factors such as the required speed of product release, the presence of cellular debris, and the need for antimicrobial neutralization must be considered.
Alternative sterility testing methods
Any alternative sterility test must be proven to perform comparably to traditional compendial methods. One challenge in developing new testing technologies is that faster detection methods may have lower sensitivity for detecting a broad range of contaminants or those present in very low concentrations.
While some alternatives may not serve as direct replacements for compendial sterility tests, they can still be valuable as supplemental methods to support interim batch release. Examples of alternative methods include:
- Growth-based detection methods: Utilize ATP bioluminescence or CO2 production to detect microbial presence.
- Non-growth-based methods: PCR-based techniques enable rapid detection of microbial contaminants without requiring growth cultures.
Regulatory perspectives on alternative sterility testing
Regulatory agencies, including the FDA and EMA, recognize the need for faster sterility testing for cell- and tissue-based products. While regulatory acceptance of alternative methods is increasing, companies must provide comprehensive validation data to justify their use. Alternative methods must demonstrate performance comparable to or exceeding that of traditional compendial tests.
A risk-based approach to sterility testing may allow for the incorporation of alternative methods alongside traditional compendial methods. In some cases, alternative methods may support interim product release while compendial testing is performed in parallel.
Balancing sterility assurance with product viability
One of the greatest challenges in sterility testing is ensuring that rigorous sterility standards are met while preserving product viability and function. Excessive sterility testing can deplete valuable therapeutic material, whereas insufficient testing may fail to guarantee safety.
A strategic approach to addressing this challenge includes:
- Testing surrogate samples: Instead of testing the final therapeutic product, sterility assessments can be performed on spent media or other surrogate materials.
- Implementing in-process testing: Conducting sterility tests at multiple time points, including early stages, improves contamination detection while conserving product material.
- Developing a risk-based strategy: Tailoring sterility testing and release strategies ensures compliance with regulatory and safety requirements without unnecessary product loss.
By employing these strategies, manufacturers can ensure sterility while preserving the integrity and effectiveness of cell- and tissue-based therapies.
Bron: Bioprocess Online