Findings published in Cells have emphasised the need for faster microbial tests to address contamination concerns for these incredible therapies
A revealing study has been published in the first half of 2023, shining a light upon some of the issues with contamination and microbial monitoring of ATMPs. Hot Water Tank Supply Lines
Szabłowska-Gadomska et al. laid out shocking findings that showed a 40% contamination rate of the examined advanced therapy.
One of the greatest challenges with ATMP production is the short-shelf life of the product. The study explains that this characteristic means that the therapy is often administered to the patients before sterility can be confirmed due to microbiological analysis time frames.
In addition, there is the biological nature of the product. Subcutaneous adipose tissue is an excellent source of mesenchymal stem cells (ADSCs), which can be used in cell therapies as an active substance in advanced therapy medicinal products (ATMPs). Because the tissue used for cell isolation is not sterilised to maintain cell viability, controlling and ensuring microbiological purity at all stages of production is crucial.
Both these factors mean that ensuring product sterility can be an uphill battle for these incredible products.
The study, published in Cells, monitored contamination incidence during ADSC-based ATMP manufacturing over two years.
The cells themselves were harvested during standard liposuction from 100 adult patients, the lipoaspirates were then checked at five different stages for microbial contamination. Whilst the cleanroom environment was also monitored.
To the best of our knowledge, this is the first study presenting such an observation
The results found that more than 40% of lipoaspirates were contaminated with thirteen different microorganisms, which were identified as being physiological flora from human skin.
The most commonly isolated bacteria of these were Staphylococcus epidermidis (40%), Propionibacterium acnes (13%), Staphylococcus capitis (9%), and Bacillus spp. (9%).
"To the best of our knowledge, this is the first study presenting such an observation," the authors stated.
Regarding the built surroundings, ATMP manufacturing takes place in cleanrooms of grades A, B, C and D. The study conducted concurrent environmental monitoring to control for contamination sources. For this, three methods were used to monitor the microbiological safety of the manufacturing environment: active air sampling (volumetric sampling), passive air sampling (settle plates), and surface sampling (contact plates).
From these assessments, most microbial contamination was found to be owing to the cleanroom windows and door handles.
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These revealed "incidental bacterial or fungal growth, which did not result in any product contamination and was reduced thanks to an effective quality assurance system."
In fact, the authors propose that "since all of the identified microorganisms are part of the physiological flora of human skin, the contamination is apparently related to the tissue donor site." This lead them to the conclusion that the starting material for ADSC-based ATMPs should be considered contaminated even if it is harvested under the strictest regimen. "Therefore, decontamination steps must be routinely implemented."
The study also looked at the implementation of improved procedures, and found the clinic brought down contaminated sample rates from 44.6% to 36.4% in the trial's second year. This could be owing to the increased proficiency of the cleanroom team carrying out the process.
Currently available RMMs which shorten the test from the classical 14 days to 7 days are still too long
Since exact preparation steps can vary in success based on the type of tissue and its common contaminants, the authors also state that each cell lab should develop its own strategy regarding "use of antibiotics-antimycotics at various stages of manufacturing based on the optimisation of the type, dosage and duration of exposure".
But the main takeaway the authors want to emphasise is, regardless of the specifics for varying cells, there is an urgent need for the further development of rapid microbiological testing methods (RMMs).
Handmade Cleanroom Panel "Faster, reliable microbial tests would be highly desirable, as they would significantly improve the safety of the patients receiving ATMPs," the authors conclude. "Given the development of cell-containing products with a short shelf life, there has been an intensive development of rapid microbiological methods accepted by regulatory bodies as so-called “alternative methods”. However, for the products with shelf lives of a few hours, currently available RMMs which shorten the test from the classical 14 days to 7 days are still too long."