The changing environment in pyrogen and endotoxin testing

Recently published articles have shown similar specifi city for bacterial endotoxins as LAL.² Furthermore, rFC has been shown to minimise false positive results and improve assay specifi city (eg, insensitive to beta glucan). As a consequence, the use of rFC is a robust method for the replacement of LAL and can be validated for the detection of bacterial endotoxins in a variety of pharmaceutical products.³

Pyrogenic substances beyond endotoxin

Taken together, alternative methods allow modernisation of the quality control environment of parenteral drug manufacture by eliminating animal-based tests. First, the application of the MAT may be an excellent method to replace the rabbit pyrogen test for detection of potential pyrogenic substances beyond endotoxin. Second, the rFC test is a sustainable method to replace the LAL test for highly sensitive detection of bacterial endotoxin.

Thus, rFC and MAT are valuable methods and complement one another. Last, but not least, these methods support the European Directive (2010/63/EU) for the protection of animals used for scientifi c purposes.

In addition to the progress in alternative methods for endotoxin testing outlined above, a team of PDA member volunteers has worked for the past two years to develop a comprehensive overview of the phenomenon of low endotoxin recovery (LER). The purpose was to support the ongoing practice of endotoxin testing for product safety and patient well-being.

The technical report is now near to completion and aims to fulfi ll four main goals to aid the biopharmaceutical industry. Those are:

1. Describe the underlying mechanisms and contributing factors of LER

2. Summarise the potential clinical impact of the LER phenomenon

3. Present guidelines for developing LER hold-time study designs

4. Provide strategies for product-based mitigation of LER.

The authoring team included members from more than a dozen pharmaceutical companies, several service and supply company representatives, and a number of academic and regulatory agency contributors. More information on this technical report and endotoxin testing will be given at PDA’s Pharmaceutical Microbiology Conference this coming October, taking place simultaneously in Berlin, Germany and Bethesda, USA. Check PDA’s website for more details: www.pda.org.

References

1. Montag et al., 2011, Hartung et al., 2013

2. Bolden et al., 2017; Takaoka et al., 2017

3. Bolden et al., 2017

Biography

MARSHA STEED, Senior Consultant with Concordia Valsource, has over 20 years of experience in the pharmaceutical, biopharmaceutical, cell therapy / gene therapy and medical device industries with extensive experience in quality and microbiology. Her leadership experience includes global experience at manufacturing locations in North and South America, Europe and Asia. Marsha is actively involved in the PDA and is a member of the Scientific Advisory Board (SAB), the Education Advisory Board (EAB), the Annual Microbiology Meeting planning committee as well as numerous task forces.

JOHANNES REICH works in Endotoxin Testing with Microcoat. He has held previous positions as doktorand at Universität Regensburg, Germany. He studied at the Marcoule Institute for Separative Chemistry, France.

JOSH EATON is Senior Project Manager, Parenteral Drug Association (PDA). Josh works with PDA members to facilitate the production of technical reports and assists in the organisation and coordination of scientific and regulatory affairs activities and strategic goals.