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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Water shortages, testing expenses, and effluent treatment are important issues for pharma manufacturers.
Pure water is essential for pharmaceutical manufacturing. The United States Pharmacopeia (USP) and other global pharmacopeias require pharma manufacturers to begin with drinking water and purify it further to standards depending on the use, such as purified water or water for injection (WFI).
Modern purified water systems are well designed and generally do not have any problems meeting pharmacopeial requirements, says Nissan Cohen, principal scientist for High Purity Water Systems at Commissioning Agents, Inc., a US consultancy. Systems typically include pretreatment followed by purification, which can include reverse osmosis, deionization, distillation, ozone, and ultraviolet sterilization. Cohen sees two major issues, however, that pharma manufacturers must deal with soon or be faced with increased operational costs: drinking water shortages and inefficient legacy laboratory-based testing.
Drinking water-the source for purified water for pharma-is a limited resource. The World Health Organization (WHO) predicts that by 2025, half of the world’s population will “be living in water-stressed areas.” (1). Although numbers vary regarding the severity of this complex problem, the Water Resources Group predicts that, if nothing is done to improve efficiency, global water demand would be 40% more than accessible, reliable supply by 2030 (2).
Industrial use represents a significant part of this demand, says Nik Krpan, president of Cheme Engineering, a Canadian consultancy focused on water systems for the bio/pharma industry. “The pharma industry needs to think about how to use water more efficiently, because the cost is going up,” says Krpan.
Zero liquid discharge, a concept that is new to the pharma industry, is a potential solution to the water-shortage problem that involves recycling or reusing process water.
“There are many uses for water; the key is how to reuse what is being sent to the drain-maybe in the process itself, or in cooling towers or building sanitation systems,” says Cohen. “For example, you could take water draining from the clean-in-place system and retreat it or use it for tertiary systems in the building. As another example, water from flushing studies (in which water is run for 30 seconds before microbial sampling) could be reused.”
“Water reuse must be carefully implemented so that you don’t affect quality, but it can be done,” notes Krpan.
At the International Society for Pharmaceutical Engineering (ISPE) annual meeting, on Oct. 30, 2017, Krpan, Cohen, and others will discuss these concepts and the technologies used in zero liquid discharge in more detail.
Compendial tests required for water for pharma manufacturing are total organic carbon (TOC), conductivity, bioburden (i.e., microbial content), and, for WFI, endotoxin. It is common practice for manufacturers to use online process analytical technology (PAT) for testing TOC and conductivity for process control.
“More companies are relying on the integrity of data from online PAT instruments to increase their process understanding,” says Luke Swanson, Life Science applications engineer for GE’s Analytical Instruments, now part of Suez, which acquired GE Water & Process Technologies on Oct. 2, 2017. “A best practice is to have at least one online instrument at the end of the high purity water loop. Some companies also have one at the front end of the loop and do occasional grab samples, tested in the laboratory, in the middle of the loop as checks.”
There is a trend toward real-time release (RTR) of process water using PAT. “RTR requires the manufacturer to do instrument qualification, method validation, and process validation,” Swanson explains. “The principle behind RTR is driving cost efficiency while not compromising product integrity or traceability of release testing.”
Laboratory TOC testing, however, is still widely used for release of process water, and one of the challenges is that laboratory and online tests can have different TOC results because “carbon is everywhere, and intermediate handling steps can contaminate the sample,” explains Swanson.
Online rapid microbial testing is available, but at this point typically needs discrete sampling to verify results, says Cohen, who notes that endotoxin testing is also not yet automated.
Treating manufacturing effluents, particularly from API manufacturing, is also a concern that is increasingly being recognized by manufacturers.
“In Europe, this [need for improved effluent treatment] very much depends on the Integrated Pollution Prevention and Control (IPPC) Directive, which is now part of the Industrial Emission Directive,” notes Bjarne Sandberg, Managing Director, Cambrex Karlskoga. The company is currently constructing a new wastewater treatment plant at its facility in Karlskoga, Sweden to support the expansion of cGMP capacity for small-molecule APIs, the company announced on Sept. 26, 2017. When completed, the wastewater facility will reduce the emission of nitrogen, total organic compounds, and suspended material, improving the site’s environmental footprint (3).
“The original wastewater treatment plant at our facility in Karlskoga, Sweden was built in 2000, and this recent investment is to increase the capacity of the plant for both existing and future needs. The investment will also help improve our environmental footprint at the Karlskoga site,” explains Sandberg. Cambrex also recently completed an upgrade of wastewater handling capabilities at its Milan, Italy manufacturing facility, he reports.
1. WHO, “Drinking-Water: Fact Sheet updated July 2017,” www.who.int/mediacentre/factsheets/fs391/en/, accessed Oct. 12, 2017.
2. 2030 Water Resources Group, “Charting Our Water Future” (2009).
3. Cambrex, “Cambrex Opens API manufacturing Facility and Invests in Supporting Waste Water Treatment Plant at its Karlskoga, Sweden Site,” Press Release, Sept. 26, 2017.