Staying On Top Of Microbes: Smarter Testing Technology For Labs Of The Future
By Foster T. Jordan, Corporate Senior Vice President, Endotoxin & Microbial Detection, Charles River Laboratories
Over the past decade, drug and medical device manufacturers have become leaner and more stream-lined. Given the current market pressures, companies are looking for more ways to improve their bottom-line. However, with product safety of paramount concern, cutting back on drug safety testing can’t be an option. What is feasible, however, is making the process of detecting, quantifying, and identifying microorganisms in products and facilities more rapidly, objectively, and efficiently than the traditional method of growing microorganisms in culture media. Under the more traditional system, it takes weeks to complete and interpret results compared to the days and even hours it takes using rapid tests.
Clinical microbiology labs and food manufacturers have been using various rapid microbiological methods for over 20 years to rapidly diagnose problems. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency have been trying to motivate the pharmaceutical sector to improve the production process with quality-by-design, risk-based approaches. Since 2002, the two agencies have embraced a Process Analytical Technology (PAT) initiative that joins modern analytical technology with information management and analysis to identify and control conditions that affect the manufacturing process.
For cultural and historical reasons, the pharmaceutical industry has been slow to implement these newer technologies, but with the science evolving and expanding, the industry is moving more toward implementing some of these practices for in-process testing, bioburden assessment, sterility testing, microbial limit testing, and other areas.
Recent Strides
The most significant changes have occurred in the field of endotoxin testing. In the 50 years since scientists discovered Limulus Amoebocyte Lysate — a clotting response to bacterial toxins found in the blood of horseshoe crabs — the LAL test used to detect bacterial endotoxins in parenteral drugs and medical devices has gone from a basic gel clot assay and kinetic colorimetric assay to self-enclosed or disposable cartridges and, most recently, fully automated, robotic systems for high volume endotoxin testing. These changes have helped reduce the risk of using endotoxin-contaminated water, raw materials, and products, while making the process faster and more efficient.
The area of bioburden testing is evolving as well. There are now rapid technology platforms that offer faster, more efficient, and more accurate bioburden testing of nonsterile drug substances, excipient material, and drug products. These platforms include instruments that use solid-phase fluorescence cytometry and modular components to efficiently and rapidly detect viable microorganisms in multiple samples simultaneously.
Microbial identification platforms that support environmental monitoring are also getting faster, too, with cellular-based technologies, such as matrix-assisted desorption ionized-time of flight (MALDI-TOF) mass spectrometry and sequencing of microbial DNA using PCR, that analyze the genetic makeup of microorganisms.
The big hurdle right now is developing processes and procedures that support real- time assessment and decision-making, rather than the traditional and episodically driven conditions that still persist. Aside from rapid, point-of-use, and on-line technologies for environmental monitoring and in-process testing, it is essential that we develop software programs that can effectively manage a decentralized quality-control testing environment. Joining technologies that provide rapid, accurate (quantifiable) results with data management solutions that allow confident decisions to be made will help companies meet the goals of PAT.
Being Proactive
Fortunately, there is incentive for companies to invest in quality by design in the manufacturing process and in process controls and to rely less on the final batch release testing alone. Making large batches of advanced therapeutics gets expensive, and implementing engineering controls, clean room design, continuous monitoring, and rapid in process testing at critical steps provides early detection of contamination events that could result in batch release failures later on. Early detection allows manufacturers to stop production and reduce unnecessary waste.
It can also provide a window into the root causes of the failure and mitigate the chances the problem will reoccur. While the regulatory changes pertaining to control of microbiological contamination have remained fairly constant over the last decade, the number of warning letters related to this topic has increased steadily. In fact, whether it is medical devices, pharmaceuticals, or biologics, contamination is among the top areas of risk to public safety. The headlines are dominated by stories like the highly publicized 2012 FDA inspection of New England Compounding Center (NECC), where mold was discovered growing in steroid vials supposedly tested for sterility. Inspections also revealed mold growing in the “clean rooms” where drug vials were filled. More recently, specialized endoscopes used to treat disorders of the digestive tract have been found to be the cause of widespread infection with the “super bug” bacteria CRE (carbapenem-resistant enterobacteriaceae) that can kill up to 40 percent of the people it infects. As the result of this event, the FDA has stated that they may require hospitals to verify sterilization of these devices with bacterial testing.
Following FDA regulations effectively is a great challenge for manufacturers of the world’s most critical health care products today. Every aspect of production is at continual risk of being a vector for microbial contamination of product as depicted below:
As a result, advances in aseptic controls, clean room technology, environmental monitoring, sterilization methodology, cleaning validation, in process testing, and final product release testing are greatly needed by an industry that continues to grow exponentially. Advanced therapeutics in the field of biotechnology, where terminal sterilization is not possible, is rendering many conventional microbial tests obsolete. In line with the FDA’s PAT initiative, the expedited development of new rapid microbial methods have become essential in ensuring the most critical new therapeutics can be safely distributed to the public.
About Author:
Foster Jordan joined Charles River Laboratories via the acquisition of Endosafe in 1994. Mr. Jordan joined Endosafe as R&D Director in 1991 and was responsible for the development of Charles River’s FDA-licensed in vitro endotoxin detection test kits. Mr. Jordan became Director of Technical Operations in 1994, and in 1997, he became General Manager of Charles River Endosafe and assumed responsibility for global In Vitro operations. He became Executive Director in 2001, Corporate Vice President in 2006, and Corporate Senior Vice President of Endotoxin & Microbial Detection in 2008.
Mr. Jordan received his B.S. degree in chemistry from Wofford College, attended graduate school at Clemson University, and completed Duke University’s Executive Education Program.