The challenge to designing a Microbial Challenge Study
Samantha Chang, Group Leader, Microbiology Department, Eurofins BioPharma Product Testing
Steve was recently diagnosed with bladder cancer. He is treated with an antibody-drug conjugate IV bag infusion solution. The drug is reconstituted before being prepared at a specific concentration in an IV bag. The reconstituted vial is multi-use and can be used to prepare multiple IV bags. The hospital staff will hold reconstituted vials per the product insert and only prepare the IV bag infusion solution before each individual patient’s treatment.
When Steve arrived at the hospital for his treatment, the staff who prepared the reconstituted drug product 6 hours before his arrival were not wearing gloves and contaminated the reconstituted vial. The contamination introduced during reconstitution proliferated during those 6 hours, and Steve contracted a hospital acquired Staph infection. If the microbial growth potential of the reconstituted drug product had been assessed by the drug manufacturer, the product insert would have instructed the hospital not to hold the reconstituted vial for more than “X” hours before patient safety was at risk.
Adapted from USP Chapter <51>, microbial challenge studies are non-compendial studies that evaluate the microbial growth potential of a product. These studies are often performed on sterile, non-preserved drug products that are prepared and/or penetrated for the purpose of final product preparation and are often held for a period of time before administration to the patient. To perform a microbial challenge study, a low level of organism is inoculated into the product to simulate contamination during preparation of a patient’s dose. Throughout the study, the inoculated product is removed from the specified storage condition and plated to determine the number of microorganisms present at that time point. At the conclusion of the study, the microbial growth potential of the product is defined as not more than 0.5 log10 increase from the inoculum control concentration. Ideal candidates for microbial challenge studies include lyophilized powders that are reconstituted with a diluent or admixtures of liquid products.
Microbial challenge studies can provide information on how long drug products can be held before patient safety is at risk, the effectiveness of preservatives and/or preservative ingredients, optimum storage conditions, and ultimately, if the drug product formulation can withstand low level contamination. If microorganisms can grow in the final drug product during the holding period, then the intended hold time, product formulation, or storage conditions should be re-evaluated.
When designing a microbial challenge study, multiple factors should be considered. This includes, but is not limited to, the inherent characteristics of the drug product formulation, the storage condition(s) of the drug product, target organisms (i.e., organisms prevalent in a hospital setting), diluents, and testing time points dictated by intended hold time. The challenge organisms should include the panel of organisms provided in USP<51>, as well as typical skin microflora and nosocomial organisms. The determination of time points should exceed 2-3 times the maximum hold time in the proposed drug product label.
The Microbiologists at Eurofins have the breadth of expertise required to assist in the design and execution of microbial challenge studies, as well as to analyze and interpret the results.