Outsourcing
Assessing contamination using mycoplasma testing is a regulatory necessity for CGT products.
quality control testing may not be sufficient to fully characterise the complex nature of cell and gene therapies, or are not adapted at all to provide results faster,” says Montero-Julian. “Typically, sterility testing takes 14 days, but the use of new rapid microbiological methods has allowed us to release products in just seven days.” The complexity of the raw materials involved makes the quality control more challenging, and as they are uniquely tied to one single patient, it is essential to ensure full traceability of the entire process and have the right IT and digital systems in place to guarantee data integrity for each batch. “Also, because one donor is one batch, the analytical methods used for the quality control should allow the scalability of the process and respond to the patient demands in terms of volume, throughput and automation,” Montero- Julian explains. “The manufacture of cell and gene therapies involves the use of living cells in culture with media, and these products are prone to contamination if they are not handled appropriately. So, it is important to implement measures to avoid contamination.”
“There is no rapid test for adventitious virus yet. Nevertheless, methods are being introduced to validate the sterility tests, and regulators understand the urgency to get patients infused.”
Félix Montero-Julian, healthcare scientific director
Compliance, contamination and quality control
Regulatory standards tend to be conservative, though they are constantly developing to reflect the challenges of this innovative field of research. There are rigorous standards for sterility testing, and it is widely
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recognised that the current growth-based sterility test described in the United States Pharmacopeia (USP) and European Pharmacopoeia with an incubation period of at least 14 days is not suitable for products with a short shelf life such as CGTs. To accelerate the testing and release of CGTs, the European Pharmacopoeia has published a new chapter on microbiological examination of cell-based preparations, and the USP is working on a similar approach to allow manufacturers to use automated growth-based methods that are more suitable for the release of cell therapy products after just seven days of incubation. Mycoplasma testing is a mandatory part of quality control for CGTs, as bacteria can contaminate cell cultures and impact the safety and efficacy of the final product. It can be performed using cell culture-based methods, which are extremely arduous, require high levels of technical expertise and need 28 days to get a result. “This is absolutely not compatible with the product-release schedule of a CGT,” says Montero-Julian. “Alternatively, the indicator cell culture approach requires elevated technical expertise and even then it takes five to eight days, but the limit of detection of mycoplasma with this technique is extremely high. The nucleic acid testing is also considered an alternative method, but again requires high-level expertise and a specialised lab.” So far, the only two methods that can reach regulators’ sensitivity expectations are culture-based, which are too slow for cell therapies, or PCR methods, notes Brewer. “Other methods are limited on sensitivity and specificity,” he adds.
Risks in the manufacturing process can be addressed by automation, which delivers an improvement in consistency and a reduction in the risk of potential error, as multi-step manual processes tend to introduce the risk of deviation and inefficiency. The quality control process, however, remains challenging in terms of speed because of the nature of testing for mycoplasma and adventitious virus – which includes bacteria, fungi, viruses and other contaminants that can be inadvertently introduced into biological systems. “There is no rapid test for adventitious virus available yet,” says Brewer. “There are technologies with potential, but they are currently in the exploratory stage. Nevertheless, methods are being introduced to validate the sterility tests, and regulators understand the urgency to get patients infused. People have been trying to develop a sterility test that can be done in hours, but it is challenging with microorganisms, as the length of time they require to grow means validation by regulators is difficult.” As it stands, the emphasis in quality control is on rigour and risk reduction. It may be a long time before the process can be made significantly quicker, but patient safety and outcomes must always take precedence. ●
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
Zaharia Bogdan Rares/
www.shutterstock.com
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