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Review of 'Measures to minimize cross-contamination risks in Advanced Therapy Medicinal Product manufacturing'

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Overall, it is an interesting review, however, a few items would still need to be addressed.
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Measures to minimize cross-contamination risks in Advanced Therapy Medicinal Product manufacturing

 Livia Roseti (corresponding) ,  Marta Serra,  Brunella Grigolo (2014)
Current European regulations define in vitro expanded cells for clinical purposes as substantially manipulated and include them in the class of Advanced Therapy Medicinal Products to be manufactured in compliance with current Good Manufacturing Practice. These quality requirements are generally thought to be elaborate and costly. However they ensure three main product characteristics: safety, consistency and absence of cross-contamination. The term cross-contamination is used to indicate misidentification of one cell line or culture by another. The Good Manufacturing Practice Guidelines suggest some recommendations in order to prevent cross-contaminations and require a demonstration that the implemented actions are effective. Here we report some practical examples useful both to minimize cross-contamination risks in an Advanced Therapy Medicinal Product production process and to evaluate the efficacy of the adopted measures.
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    Review information

    10.14293/S2199-1006.1.SOR-LIFE.AEJRV9.v1.RWLBDF

    This work has been published open access under Creative Commons Attribution License CC BY 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com.

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    Review text

    This paper discusses methods to avoid cross contamination used in GMP manufacturing facilities for advanced therapy medicinal products, such as cellular therapies. Overall, it is an interesting and relevant review, however, a few items would still need to be addressed.

    1. Environment: The GMP facility should not only be designed to provide properly treated air for the specified room classification, it should also be designed so cross contamination of products is minimized. One way personnel, product and waste flow, for instance, prevents cross contamination of incoming products with outgoing products. If a multi-room facility is planned, manufacturing rooms should also be separated from each other in such a way that multiple products can be manufactured simultaneously without interfering with each other; the rooms should not communicate with each other. If only cellular products are manufactured that are contained in culture vessels, and no aerosolization occurs, these manufacturing rooms can be positively pressurized in respect to their ante-rooms, which prevents air-borne contaminants to enter. An interlock system should be provided, so only one door at one time can be opened, preventing cross contamination by air turbulences and pressurization interruption.

    2. Personnel: It is suggested that personnel gown in sterile gowns. Although this suggestion is well meant, the sterile gown will not remain sterile for long, since a GMP facility is not a sterile, but only a clean environment. It seems much better to rather use a fresh, clean but not sterile gown, and then employ sterile sleeves and gloves over the gown if work is being performed inside a biosafety cabinet. This saves resources and a good amount of money in the long run, as gowns could be re-used after laundering, and inexpensive disposable sterile sleeves and gloves could be used, providing the sterile work environment inside the biosafety cabinet.

    3. How to prove the absence of cross-contamination: In this article it is suggested to test the absence of cross contamination after the fact; recipients of cellular products should be tested for DNA fingerprints of the infused product. In order for this method to detect cross-contamination, it needed to occur already in a patient, which is not desired. Rather, the manufacturing process and the manufacturing rooms should be tested preemptively for the absence of cross contamination. This could be done by validation of a surrogate test. Tests for the absence of bacterial and fungal contamination can be used as such a surrogates, as these tests certify the absence of detectable microbiological organisms. If, in several validation runs, carried out with cellular material and subsequent change over cleaning procedures, it can be demonstrated that the changeover cleaning procedures are sufficient, and no DNA from the cellular product and no bacterial / fungal traces can be found, the changeover cleaning procedures are validated and the bacterial and fungal test can be used on its own as a surrogate test.

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