Design Considerations for Water for Injection (WFI) Distillation Systems for Improving Quality, Project Performance, and Equipment Life Cycle Cost Reduction was featured in the September/October 2015 issue of Pharmaceutical Engineering® magazine.

This four-part series presents and discusses a number of key requirements and design, quality, and engineering considerations that have high importance in end-user usability, cost control and end-product quality that help manage risks in Water for Injection production and processes.  We wrap-up the WFI Distillation Systems series with part four which reviews:

  • Importance of Gas Separation
  • Feed Water Quality Considerations
  • Conductivity

Importance of Gas Separation for WFI Distillation Systems

Gases affect the conductivity of water significantly, and removing non-condensable gases from the feed water is necessary in order to reach an acceptable quality of WFI.

Gases are present in natural waters, and the content varies significantly from one place to another. The most common gases are carbon dioxide, nitrogen, and oxygen. Of these three, carbon dioxide is the most difficult to remove since it has the highest solubility in water. Nitrogen and oxygen are present mostly as free N2 or O2, and removing them is fairly easy. Dissolved CO2 is more difficult to remove and requires additional treatment. Softening, or reverse osmosis/de-ionization (RO/DI), do not remove gases efficiently enough.

Generally speaking, there are two ways to remove dissolved gases: vacuum, which requires the use of an additional gas separator or increasing temperature and surface area. This can take place in the pre-heaters and gas separator in the first column of an MWS. The gas separator consists simply of a spray nozzle that gives the warm feed water of the surface area needed to separate the gas. This drives the gases out of the water and into the atmosphere through a gas vent. These are totally integrated in the still and thus eliminate the need for additional equipment. Gas removal in an MWS can be further enhanced by adding a gas vent to the distillate collection line coming from the pre-heaters. These are usually enough to ensure adequate gas removal.

Feed Water Quality Considerations WFI Distillation Systems

Even though it is possible to produce good-quality WFI directly from softened water, the old principle “The cleaner in, the cleaner out” is still valid. Distillation is an excellent method for removing impurities from water, but it can’t remove everything. On the other hand, there is no single method that can remove everything at once.

When it comes to the MWS, there are a few impurities in feed water that require special attention. Chlorides are particularly harmful to stainless steel at elevated temperatures, but they are easy to remove during pretreatment. If problems occur with chlorides, it is almost always occasional. Hardness causes scaling, but it is rarely present with water softening. RO/DI remove silica and hardness, just like other ionic impurities, from feed water. Generally speaking, scaling can be reduced even if some impurities remain in the feed water by ensuring an even distribution of feed water to the evaporator to keep all heat-exchanger tubes continuously wet. Behavior of the still is also more predictable when feed-water distribution works well.

In a cold system, there is always a risk of growth in the purification unit and downstream of it. High temperature that yields high F0, though the contact time is short, is effective against any bacterial growth. Obviously this advantage is difficult to get in colder systems.

An MWS is less effective at removing total organic carbon (TOC), but it can be removed from feed water using activated carbon. Gases usually do not need special treatment; the integrated gas separator of the MWS is adequate for removing gases unless the feed water gas content is exceptionally high.

Good quality feed water is a typical general requirement (< 5 μS/cm). For example, using softened water instead of RO or DI water always leads to two things:

  1. More frequent cleaning intervals of process contact surfaces
  2. An increased amount of blowdown from the distillation process and gas removal to be able to produce sufficient quality WFI

Typical blowdown ratio of a distillation system is 5% to 15%, and with softened water the amount can easily get up to 30%, which means an increase of 100% or more in the reject water amount. Such increases of rejects clearly reduce the efficacy of WFI production. In addition, an endotoxin load to the still may increase. This means a higher risk of carryover of endotoxins to WFI, although an MWS is generally very effective at removing them.

Conductivity Is Not Enough

Conductivity is an excellent way to continuously monitor distillate quality because it is simple, reliable, and sensitive. However, it is not sufficient because it indicates only the presence of ionic impurities and is not selective. If conductivity increases, other means are required in order to determine the cause. In addition, it does not detect endotoxins, bacterial growth, or TOC, all of which are important for WFI quality and have been defined in the pharmacopeias. Continuous TOC monitoring in WFI systems is normal practice, and it can be added to a still as well. When the purification and monitoring systems are maintained properly, an acceptable TOC level in distillate can be reached and monitored easily. Naturally, care must be taken with maintenance and the calibration of the analyzer, particularly because the levels are low. Detecting endotoxins on-line is not possible with current technology. Yet endotoxins are one of the most critical and likely impurities in water, so it is a top priority to remove them from WFI. An MWS is known to have a very good ability to remove endotoxins continuously. A four-log reduction can be shown routinely, and higher reductions have been reached in tests. This topic has been discussed thoroughly over the years, so we will not put more emphasis on it here.

Detecting bacterial growth on-line is possible using current technology, but it is not yet a common occurrence. Limit of determination can also be a concern. Bacterial growth is not directly related to TOC either. This emphasizes the importance of having a reliable method for eliminating it, and this has been discussed above. In addition, growth in a still after the columns is highly unlikely because the lowest temperature inside the WFI pipes is the same as the distillate outlet temperature. As a result, the risk for growth in the WFI line downstream of the still is also highly reduced. The risk for growth in the feed-water lines of an MWS can be reduced with a sanitization sequence. Feed-water lines can be sanitized if desired.

In conclusion, there are many factors that affect the design process, and they need to be evaluated to achieve the desirable result. Risk mitigation and product quality must never be compromised, but weighing different alternatives and possibilities objectively will help to find the most suitable solution.

By:  Juha Mattile, Sr. Product Manager for Steris Finn-Aqua High Purity Water & Team, VHP Sterilization and Effluent Decontamination systems and Mike Parkka, Project Manager for Steris Finn-Aqua

Catch up now on parts one through three of the WFI Distillation Systems series:

In July, the ISPE Training Institute will be conducting a manufacturing efficient, product quality and GMP compliance training focusing on:

Sign up today!

RELATED POSTS