August 7, 2025

By: List Labs

Live Biotherapeutic Products (LBPs) are emerging as powerful tools in the fight against chronic illness, infections, and even cancer. These living microbial therapeutics hold immense promise—but their very nature presents unique challenges, particularly when it comes to quality control. Standard microbiological examination methods, designed for non-living products, often fall short when applied to LBPs. In this blog, we explore the evolving regulatory landscape and real-world strategies that CDMOs use to develop tailored testing protocols throughout the LBP lifecycle.

The Role of Quality Control Across the LBP Lifecycle

Quality control (QC) for LBPs ensures that products are safe, potent, and free of harmful contaminants. At List Labs, rigorous analytical methods and QC tests are integrated throughout the entire manufacturing process—from strain cultivation and fermentation to lyophilization and encapsulation. Testing at every stage helps mitigate risk and ensures product integrity. Quality control testing can include evaluation of product appearance, potency, identity, water activity, pH, and microbial contamination assessments.

Microbiological Testing: Why One Size Doesn’t Fit All for LBPs

USP <61> and <62> govern microbial enumeration and detection of objectionable organisms in non-sterile pharmaceutical products. However, their traditional applications often falter when used for products densely populated with live bacteria. In LBPs, the therapeutic organism can interfere with detection of contaminants or overwhelm test systems, especially when using membrane filtration or spread/pour plating techniques.

Rather than relying on standard protocols, microbiological testing must be adapted based on product type, strain characteristics, and interfering compounds. Early-stage collaboration with CDMO partners allows for this kind of customization.

Regulatory Flexibility and the EP Framework

Regulatory bodies recognize the limits of one-size-fits-all methods. The European Pharmacopoeia (EP) provides valuable guidance for developers. EP Monograph 3053 and chapters 2.6.36 and 2.6.38 offer decision trees and modification strategies like pH adjustments, custom media, and alternative challenge organisms. These resources support a case-by-case approach—encouraging developers to adapt tests based on risk level and organism behavior.

Practical Customization: A Case Study in Bacillus

Consider a product containing Bacillus spores. Instead of using standard enrichment and plating to detect contaminants, a developer may choose Tryptic Soy Broth (TSB) combined with selective media like MYP or Chromogenic Agar. Adjustments to pH and incubation time, based on the known growth curve of Bacillus, can significantly improve contaminant detection.

This type of customized approach requires collaboration between QC experts and formulation scientists to ensure compatibility between product requirements and testing conditions.

Choosing the Right Alternative Methods for Testing LBPs

When USP or EP methods prove inadequate, alternative culture-based techniques may offer better specificity and sensitivity. For example:

• Fermentation tests using phenol red or purple broth for metabolic profiling
• Nitrate reduction tests to target enzyme expression
• Selective media or antibiotics that suppress the product organism

These methods are particularly useful when the LBP is not easily differentiated from the contaminant in traditional culture methods, as they offer additional layers of differentiation.

Working with CDMOs to Validate Custom Methods

Developing non-standard tests requires thorough validation. Key parameters include:

• Specificity: Differentiation between LBP and contaminants
• Repeatability: Delivers consistent results
• Robustness: Holds up under varying conditions
• LOD and LOQ: Align with administration route and regulatory requirements

Experienced CDMOs like List Labs can help ensure these parameters are met, even with limited product availability in early clinical phases.

Conclusion: Building a Lifecycle Testing Strategy

LBPs demand more than routine microbiological testing. From early development to clinical trial support, QC strategies must evolve to reflect the realities of living drug products. Regulatory guidance is moving in the right direction, but successful implementation depends on the ability to adapt methods to each unique product.

List Labs provides full-spectrum CDMO services, combining deep microbial expertise with customized quality control solutions. We help innovators navigate this complexity with confidence, safety, and scientific rigor.

Contact us today to start your project!