Variability, Limits, and Other Considerations for the Next Generation of Pyrogen and Endotoxin Testing

The Limulus Amebocyte Lysate (LAL) test has been the “gold standard” test for endotoxins since the 1980s. In 2023, we will find ourselves at an exciting crossroads. We are thinking “outside the box” with respect to using recombinant and cellular based technologies that promise to make improvements to the existing lysate-based methods. But as technology evolves, should we also be evolving in our thinking regarding assay capability and variability? Given the clear benefits of the LAL test in process control and the statistically irrelevant final sample size for drug product testing, should we consider parametric release? How do we think about setting appropriate endotoxin limits for complex or combination drugs or drugs used in infusions? Is 20 EU/device an appropriate limit for all medical devices? Given ongoing research into microorganism adaptation and the microbiome, what is the appropriate role of the current purified E. coli calibration standard?

Can we be content with 2023 technologies that are mired in 1980s thinking? This webinar describes the events and thinking that got us here and poses some food for thought moving forward.

Presented by Karen Zink McCullough, Owner and Principal Consultant at MMI Associates

Karen Zink McCullough is the principal consultant at MMI Associates, a firm focusing on GMP and microbiology in the drug, biologics, cell therapy, and medical device industries, with a speciality in the Bacterial Endotoxins Test (BET). Ms. McCullough was the first to publish on the use of the BET as a replacement for the rabbit pyrogen test for small-volume parenterals. She has published over 50 articles and book chapters and is the editor of the book “The Bacterial Endotoxins Test: A Practical Guide.”  She is a well-respected international speaker on GMP and BET. Ms. McCullough is chairperson of the LAL Users’ Group, is a United States Representative to Working Group 2, TC 209 for the revision of ISO 14698, and is a member of the United States Pharmacopeia Expert Committee on Microbiological General Chapters. She holds a bachelor’s degree in bacteriology from Rutgers University and a master’s degree in molecular biology from the University of Oregon.

Kevin L. Williams, Microbiological Test Development at BioMérieux

Kevin studied microbiology at Texas A&M University and has worked in the pharmaceutical field for 35 years. The bulk of his career was spent at Eli Lilly & Company (30 years) developing QC tests for microbial and endotoxin detection. Kevin‘s current role at BioMérieux as a senior scientist focuses on endotoxin science, including low-endotoxin recovery method development. Kevin has also helped set up a dedicated endotoxin service laboratory in the USA for hold-time studies, LER root cause analysis, and endotoxin demasking protocol development. He is the author of Endotoxins 2nd Edition (Marcel Dekker, 2001), Microbial Contamination Control in Parenteral Manufacturing (CRC Press, 2004), and Endotoxins 3rd Edition (Informa Healthcare, 2007).

Nicola Reid, Associate Director, Product Management, Endotoxin Products at Charles River Laboratories

Nicola has over 20 years of experience with bacterial endotoxin testing and pharmaceutical microbiology. She has been involved in all aspects of the endotoxin assay, including the design and development of BET-specific instrumentation and software. Her work has led her to direct workshops and training courses, as well as lecturing internationally on a variety of BET-related topics, including LAL methodologies, product validations, 21 CFR Part 11, and BET regulatory affairs.

Veronika Wills, Manager, Technical Services at Associates of Cape Cod, Inc

Veronika Wills manages the Technical Services group at Associates of Cape Cod, Inc. She joined the team in 2007 and, thanks to her strong knowledge of biochemistry, microbiology, and immunology, brings an expertise that is vital to ACC customers when it comes to the technical support of testing complex samples, low endotoxin recovery matrixes, and troubleshooting of the Bacterial Endotoxins Test at all levels. Veronika speaks frequently at scientific conferences and seminars globally and is an established expert on endotoxin testing. Veronika holds a Master’s Degree in Biochemical Engineering from the Institute of Chemical Technology in Prague, Czech Republic.

Allen L. Burgenson, Global Subject Matter Expert, Testing Solutions Lonza, Walkersville, USA

Allen L. Burgenson has over 35 years of experience in industries regulated by the FDA, including foods, drugs, biologics, medical devices, and cosmetics. He has worked in R&D, QC, QA, regulatory affairs, and now marketing as an SME for endotoxin detection. Allen is involved in several scientific organizations, including the immediate past chair of the Horseshoe Crab Advisory Panel for the Atlantic States Marine Fisheries Commission (ASMFC) and the immediate past president of the Capital Area Chapter of the Parenteral Drug Association (PDA). He was chair of the 2004 PDA Annual Meeting.  He is a co-author of three PDA technical reports, including TR-50 and 51 regarding mycoplasma detection and filtration and TR-82 regarding low endotoxin recovery (LER). Allen also contributed to USP Informational Chapter <1228.5> on Endotoxin Indicators. Allen has a BA in Microbiology from Rutgers University and an MS in Biotechnology Management from the University of Maryland

Sponsored by BioMérieux, Charles River, Associates of Cape Cod, Inc., and Lonza

About BioMérieux
With more than 50 years of pioneering diagnostics, the people at bioMérieux understand the challenges you face when it comes to ensuring product quality and are proud to offer the most comprehensive portfolio of solutions for microbiology quality control of biopharmaceuticals and ATMPs.  Choosing the right microbiology diagnostic can boost efficiency with in-process testing, and automation simplifies the testing process, reduces human error, and helps ensure data integrity. Rapid, simple, at-line testing of key parameters allows in-process tests to be performed closer to the production environment and provides certainty that your manufacturing process is secure.

About Charles River

The Microbial Solutions portfolio from Charles River brings you progressive products and services that deliver accurate, relevant, and reliable data to fuel confident decisions on product quality and contamination control. Our unique combination of Endosafe^® endotoxin testing, Celsis^® rapid microbial detection, and Accugenix^® microbial identification and strain typing keeps your manufacturing operations running efficiently and smoothly, lowers your cost to manufacture, and protects your reputation.

About Associates of Cape Cod, Inc

YOUR ENDOTOXIN EXPERTS!

Specializing in chromogenic and turbidimetric reagent technologies, Associates of Cape Cod, Inc. (ACC) has been a global leader in endotoxin and (1→3)-ß-D-glucan detection products and services for more than 45 years. ACC pioneered the LAL testing methodology and was the first FDA-licensed company to manufacture LAL reagents. ACC has grown to be an internationally recognized leader in endotoxin detection. Our worldwide headquarters are located in East Falmouth, Massachusetts. With a dedication to quality, ACC is certified to I.S. EN ISO 13485:2016 and ISO 13485:2016. We are FDA-inspected and operate DEA-licensed and CLIA-certified laboratories. Our endotoxin detection reagents, instruments, and software are used within the pharmaceutical, medical device, biotechnology, compounding pharmacy, and dialysis industries for quality control, product release, and research. Our reagents are FDA-licensed and can be used for testing in compliance with USP, EP, and JP bacterial endotoxin test chapters, and our software is 21 CFR Part 11 compliant. ACC also operates a Contract Test Services (CTS) Laboratory, which has specialized in testing for endotoxin and glucan contamination for over 30 years. Our CTS laboratory is GMP-compliant, ISO-registered, and DEA-licensed and is capable of handling all controlled drug substances except those included in Schedule 1. All testing services can be performed according to FDA, USP, EP, and/or JP regulatory guidelines. In addition to routine testing, our CTS Laboratory will customize endotoxin testing, troubleshoot difficult samples, develop and/or transfer LAL test methods, design and produce custom depyrogenation controls for oven validation, and perform Low Endotoxin Recovery (LER) studies and protocols.

About Lonza

Lonza is the preferred global partner for the pharmaceutical, biotech, and nutrition markets. We focus on enabling treatments that prevent illness and support healthier lifestyles. We optimize scientific innovation and manufacturing technology to enable our customers to serve their patients and consumers. Our comprehensive range of testing solutions supports your efforts in pyrogen and endotoxin testing of raw materials, in-process samples, and manufactured products. No matter where you are in your process, Lonza’s testing products optimized with our world-class software and hardware solutions and supported by our experts will help streamline your workflows and meet regulatory requirements for injectable drugs and implantable medical devices, including for new modalities used in modern vaccines and biologics. We can help answer your questions about endotoxin testing, whether you use qualitative gel clot, quantitative turbidimetric, or quantitative chromogenic LAL-based assays, or want sustainable recombinant factor C endotoxin testing or sustainable pyrogen testing. Our BioScience Division provides a large portfolio of testing solutions to support the pharmaceutical and medical device industries, including classical LAL assays (Pyrogent® gel clot, Pyrogent-5000® kinetic turbidimetric, and KineticQCL® kinetic chromogenic assays) and sustainable recombinant Factor C (PyroGene®) assays for endotoxin detection.  We provide monocyte activation assays to detect pyrogenic substances as a sustainable alternative to the rabbit pyrogen test.  We also supply the industry-leading MODA software for laboratory data that eliminates paper from the process, as well as the PyroTec^TM PRO Automated Endotoxin Testing solution, which is the industry leader in automated endotoxin detection.