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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Process intensification in continuous biopharmaceutical processing can change the way the equipment is used and thus affect cleaning methods.
In biopharmaceutical manufacturing, process intensification can change the way the equipment is used and thus affects cleaning methods. “Process intensification continues to influence trends, such as higher-titers in bioreactors, greater binding capacity in resins, improvements in upstream clarification, and other advances in technology and equipment design,” notes Beth Kroeger, senior manager for Technical Services at STERIS. Manufacturers that take advantage of these technology advances, however, should also consider how cleaning can be affected. Kroeger and Paul Lopolito, senior manager for Technical Services at STERIS, shared some points to consider in an interview with Pharmaceutical Technology.
PharmTech: How have changes in biopharmaceutical equipment use affected cleaning requirements?
Lopolito and Kroeger (STERIS): One area we see a change to equipment design, as a result of process intensification advances, is in the use of inline conditioning skids and inline dilution where buffers are prepared from buffer concentrates. Use of buffer concentrates meets an obvious need to mitigate the amount of storage space required for several large volume tanks and bags. However, the use of buffer concentrates along with the increase in throughput lead to a change in how buffer tanks should be cleaned and maintained. In the past, based on solubility of buffers, water has been suitable for cleaning buffer tanks. This industry practice was confirmed during a benchmarking session at a CIP [clean-in-place] Technology and Industry Summit where 90% of the participants indicated water was used to clean some part of the process, with buffer tanks listed as the predominant equipment cleaned in this manner (1,2). This method, however, is no longer applicable with the shift to in-line dilution and the manufacture of concentrated buffer solutions. We have seen several issues stemming from manufacture of buffer concentrates, ranging from faster development of air-liquid interface rings to issues with micro-pitting and rouge formation. It is important to bear in mind the types of solutions prepared in these tanks if a site is considering implementing these types of bioprocess skids and to incorporate a robust cleaning and routine passivation and derouging step in the cleaning process to properly maintain the tanks.
Similarly, perfusion systems used for process intensification allow for higher-titers, cell debris, and media constituents to remain in the bioreactor a longer time than fed-batch systems, and the increased amounts of anti-foam agents added could make cleaning the bioreactor more difficult. This [challenge] is most pronounced at the air-liquid interface of the bioreactor, baffles, air sparger, and agitator shaft.
PharmTech: Can data analytics be used to identify when cleaning is needed in continuous processes?
Lopolito and Kroeger (STERIS): Predictive maintenance can be applied to any type of situation, whether the maintenance events are mechanical or, in this case, cleaning equipment used for continuous processing. Predictive modeling leverages data obtained between equipment cleaning processes to better predict cleaning frequencies, preventing failures due to residue buildup, loss of passive surface characteristics, or microbial contamination. Testing may include measurement of conductivity by trending drift in conductivity results; total organic content; bioburden; in-line ultraviolet spectroscopy measurements; and bacterial endotoxin testing. In addition to determining equipment cleaning frequencies based on data, routine stainless-steel maintenance frequencies could also be determined based on iron-monitoring testing, non-viable particulate monitoring, and surface passivation testing. The concept of predictive modeling within laboratory test methods has been useful in modifying routine cleaning procedures to mitigate risk or fine-tune preventive maintenance activities. About six years ago, we worked with one biopharmaceutical company that monitored a solution hold time in tanks, and, after a preset time, the tank was passivated with an acid detergent to prevent micro-pitting and untimely corrective action activities. Another biopharma site confirmed that final acid rinse temperature was not sufficient to maintain the corrosion resistant passive layer and that increasing the temperature and lowering the concentration would prevent the micro-pitting and unscheduled equipment downtime (3).
1. Benchmarking Sessions at the Seventh Annual CIP Technology & Industry Benchmarking Summit (Longmont, Colo., April 2013).
2. P. Lopolito, et al. “Cleaning Buffer Preparation Tank Air-Liquid Interface Rings,” ispe.org Pharm. Eng.(January/February 2016).
3. E. Rivera, P. Lopolito, and D. Hadziselimovic, Pharm. Tech. 41 (2) 54–60 (2017).
Vol. 45, No. 6
When referring to this article, please cite it as J. Markarian, “Considerations for Cleaning Biopharmaceutical Process Equipment,” Pharmaceutical Technology 45 (6) 2021.