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32 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2020 P h a r mTe c h . c o m Quality ily due to the fact that the source cells cannot be sterilized. This can raise concerns over the risks of contamination as well as cross-contamination. Contamination control over the manufacturing of a cell-based product requires mapping out the entire process (4). This approach helps developers and manufacturers understand the risks involved at each step of the manufacturing process. Having a proactive contamination-control mindset is key to mitigating risks in general. "There are unique challenges in both allogeneic and autologous cell therapy production, given the human origin of the cells," says Andrew Bulpin, head of process solutions, MilliporeSigma. In al- logeneic therapies, these cells typically come from healthy donors, Bulpin points out, but there is a limit to how many doses can be grown from a sin- gle donation, given the limited number of times a cell can double. This introduces the need to ad- dress donor-to-donor variability in incoming ma- terial for therapeutic uses. "Autologous therapies have the other extreme— each dose starts with the cells of the sick patient. This introduces supply chain challenges (i.e., har- vesting, shipping from the patient, manipulating, shipping to the patient, and administering cells)," Bulpin adds. Care must be taken to ensure the chain of custody so that each patient receives his or her own cells. Adding to the complications is the variability in cell health from the patient, which demands that processing be extra robust. Cell health assays To assess cell health and the presence of any contami- nation in autologous or allogeneic therapies, a range of assays is required to test the source materials. Ac- cording to Bulpin, this includes assays that are highly sensitive and specific to a particular target contami- nant (e.g., polymerase chain reaction [PCR] assays), as well as assays that offer broad detection capabilities, such as next generation sequencing (NGS), in-vitro cell-based assays, and in-vivo assays. "The choice of assay is influenced by a number of factors, including the ability of the contaminant to be cultivated in vitro or tested in vivo, but also the expectations of the regulatory agencies that will be reviewing the assay data," Bulpin states. PCR assays are used to detect mycoplasma and disease-causing viruses in both autologous and alloge- neic source cells, Bulpin says, and they typically gener- ate results in one to three days. A broader cultivation assay—based on a rapid, semi-automated method— is often employed for the detection of bacteria and fungi, and usually generates results in five to 10 days, he says. "Turnaround of these assays is time critical in delivering successful treatment to the patient from whom the cells have been isolated. For allogeneic cells, broad detection assays are also used to address the risk of 'unknown' and known contaminants being passed from donor to recipient. Tests include the use of trans- mission electron microscopy, NGS, and in-vitro cell- based assays," he says. Commercial scale For commercial-scale manufacturing in the case of allogeneic cell therapies, it is important to perform "There are unique challenges in both allogeneic and autologous cell therapy production..." —Andrew Bulpin, MilliporeSigma