Many sterile drug products require reconstitution or dilution prior to use which requires breaching the container closure system. Once a drug product’s container is breached, it is assumed that microbial contamination of the contents may have occurred. Manufacturers of non-preserved drugs, that will not be immediately administered to a patient, must demonstrate that the product will not support microbial growth during the labeled storage period under the stated storage conditions.
ICH Guideline Q8 (R2) Pharmaceutical Development states: “Where relevant, microbial challenge testing under testing conditions that, as far as possible, simulate patient use should be performed during development. Additionally, ICH Guideline Q1A (R2) Stability Testing of New Drug Substances and Products provides the following instruction: “Stability testing of the drug product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the formal stability studies at initial and final time points”
LexaMed performs Microbial Stability Studies (MSS) to evaluate the microbiological stability of drug products under specified storage conditions following reconstitution and/or dilution with specified diluents to demonstrate the product does not support microbial growth throughout storage in its end-use condition.
Working closely with the study sponsor a LexaMed project manager will attain an understanding of the drug, diluents for preparation, storage conditions and storage time post reconstitution or dilution. Using this information, a protocol specific to the drug product will be generated. The study sponsor will be asked to review and approve the protocol prior to study initiation.
Test articles are reconstituted and/or diluted with diluents specified in the product labeling and then inoculated with ≤ 100 CFU/mL of the challenge organisms. Challenge organisms include strains listed in USP <51> and typical skin flora associated with nosocomial infection. The inoculated test articles are then stored at the storage conditions (temperature and duration) specified in the proposed label. A positive control prepared in the diluent solutions and a product negative control (without inoculation) are also included.
Test articles are stored for a period exceeding 2-3 times that of the maximum holding time in the proposed label with samples tested at periodic intermediate timepoints during storage to demonstrate that the diluted product does not support microbial growth for at least the maximum storage period under the specified storage conditions. At each sampling timepoint surviving viable microorganisms are enumerated using a qualified neutralization method. The change in log10 values of the microbial concentration at each timepoint are calculated and compared to the initial positive control concentration and expressed in terms of log10 change. A test article is considered to have microbial growth if the population is increased by more than 0.5 log10 units compared to the initial value measured.
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