Innovating quality control mechanisms in aseptic drug manufacturing by means of isothermal microcalorimetry and tunable diode laser absorption spectroscopy

摘要

Aseptic manufacturing refers to bringing the sterile drug solution into decontaminated containers in a way that product sterility and therapeutic effectiveness is maintained. At this stage the produced drug has a significant value, reflecting relatively large financial risk in case of failure during manufacturing procedures. Therefore, environmental monitoring activities strictly control production surroundings to ensure that no accidental product contamination occurs.ududMedia fills are part of environmental monitoring activities and imitate the aseptic (free from pathogenic microorganisms) filling procedure with microbial growth medium instead of the liquid drug product. After filling, media fills are inspected visually on turbidity, which represents the control on filling line asepticity. Such inspection is time-consuming, manually performed and therefore considered for potential automation. A laser-based technology was used (called tunable diode laser absorption spectroscopy) abbreviated as TDLAS to determine CO2 and O2 variations in media fill headspaces as related to metabolic activity of growing microorganisms. The study results demonstrated that TDLAS can automate the visual media fill inspection reliably (inspection rate of 100 containers per minute) allowing a roughly 90% faster inspection than achieved by the manual visual inspection on turbidity. TDLAS was further assessed on its potential in simplifying conventional measurement techniques in the field of calorespirometry. Calorespirometry deals with the simultaneous analysis of O2 consumption, CO2 production and heat emission by living systems such as tissues or organism cultures. TDLAS is a well-performing and convenient way to evaluate non-invasively the rates of O2 consumption, CO2 production during mentioned studies.ududIn aseptic manufacturing the sterility assessment is the last control of product sterility before an entire batch is released to the market. The assessment usually consists of a final visual inspection on turbidity 14 days after drug preparation. Isothermal microcalorimetry (IMC) is a methodology measuring small amounts of emitted heat and can thereby detect growing microorganisms. It is more sensitive than the visual inspection on turbidity and was therefore applied as alternative test for microbial growth to sterility assessments. IMC appears to have a large potential to improve the sterility assessment as all tested microorganisms were earlier detected by IMC as by the visual inspection.ududPerformed projects demonstrate that IMC and TDLAS can improve quality control mechanism by designing those more efficiently. Therefore, ongoing IMC and TDLAS based research is recommended to exploit the full potential of the aforementioned technologies.