GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS
X - REVERSE OSMOSIS
Another acceptable method for manufacturing Water for Injection is Reverse Osmosis (RO). However, because these systems are cold, and because RO filters are not absolute, microbiological contamination is not unusual. Figure 8 shows a system that was in use several years ago. There are five RO units in this system, which are in parallel. Since RO filters are not absolute, the filter manufacturers recommend that at least two be in series. Ultraviolet (UV) lights can be needed to control microbiological contamination.
The ball valves are not considered sanitary valves since the center of the valve can have water in it when the valve is closed. This is a stagnant pool of water that can harbor micro-organisms and provide a starting point for a biofilm.
As an additional comment on RO systems, with the recognition of microbiological problems, some manufacturers have installed heat exchangers immediately after the RO filters to heat the water to 75 - 80°C to minimize the microbiological contamination.
With the development of biotechnology products, many small companies are utilizing RO and UF systems to produce high purity water.
Most of these systems employ PVC or some type of plastic tubing. Because the systems are typically cold, the many joints in the system are subject to contamination. Another potential problem with PVC tubing is extractables. Looking at the WFI from a system to assure that it meets USP requirements without some assurance that there are no extractables would not be acceptable.
The use of 0.2 micron point can mask the level of microbiological contamination in the system.
While it is recognize that endotoxins are primary concern in such a system, a filter will reduce microbiological contamination, but not necessarily endotoxin contamination. If filters are used in a water system there should be a stated purpose for filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed which is based on data generated during the validation of the system.
As previously discussed, because of the volume of water actually tested (.1ml for endotoxins vs. 100ml for WFI), the microbiological test offers a good index of the level of contamination in a system. Therefore, unless the water is sampled prior to the final 0.2 micron filter, microbiological testing will have little meaning.
At a re-inspection of this facility, it was noted that they corrected the deficient water system with a circulating stainless steel piping system that was fed by four RO units in series. Because this manufacturer did not have a need for a large amount of water (the total system capacity was about 30 gallons), they attempted to let the system sit for approximately one day. Figure 9 (above) shows that at zero time (at 9 AM on 3/10) there were no detectable levels of microorganisms and of endotoxins. After one day, this static non-circulating system was found to be contaminated. The four consecutive hour samples also illustrate the variability among samples taken from a system. After the last sample at 12 PM was collected, the system was re-sanitized with 0.5% peroxide solution, flushed, re-circulated and re-sampled. No levels of microbiological contamination were found on daily samples after the system was put back in operation. This is the reason the agency has recommended that non-re-circulating water systems be drained daily and water not allowed to sit in the system.
XI - PURIFIED WATER SYSTEMS
Many of the comments regarding equipment for WFI systems are applicable to Purified Water Systems. One type system that has been used to control microbiological contamination utilizes Ozone. Figure 10 illustrates a typical system. Although the system has purported to be relatively inexpensive, there are some problems associated with it. For optimum effectiveness, it is required that dissolved ozone residual remain in the system. This presents both employee safety problems and use problems when drugs are formulated.
Published data for Vicks Greensboro, NC facility showed that their system was re-contaminated in two to three days after the ozone generator was turned off. In an inspection of another manufacturer, it was noted that a firm was experiencing a contamination problem with Pseudomas sp. Because of potential problems with employee safety, ozone was removed from the water prior to placing it in their regulating system. It has been reported that dissolved ozone at a level of 0.45 mg/litre will remain in a system for a maximum of five to six hours.
Another manufacturer, as part of their daily sanitization, removes all drops off of their ozonated water system and disinfects them in filter sterilised 70% isopropyl alcohol. This manufacturer has reported excellent microbiological results. However, sampling is only performed immediately after sanitization and not at the end of operations. Thus, the results are not that meaningful.
Figure 11 and Figure12 illustrate another purified water system which had some problems. Unlike most of the other systems discussed, this is a one-way and not a recirculating system. A heat exchanger is used to heat the water on a weekly basis and sanitize the system. Actually, the entire system is a "dead-leg."
Figure 11 also shows a 0.2 micron in line filter used to sanitize the purified water on a daily basis. In addition to the filter housing providing a good environment for microbiological contamination, a typical problem is water hammer that can cause "ballooning" of the filter. If a valve downstream from the filter is shut too fast, the water pressure will reverse and can cause "ballooning". Pipe vibration is a typical visible sign of high back pressure while passage of upstream contaminants on the filter face is a real problem. During sanitization, it is important to "crack" the terminal valve so that all the elbows and bends in the piping are full of water and thus, get complete exposure to the sanitizing agent.
It should be pointed out that simply because this is a one-way system, it is not inadequate. With good Standard Operational procedures, based on validation data, and routine hot flushing of this system, it could be acceptable. A very long system (over 200 yards) with over 50 outlets was found acceptable. This system employed a daily flushing of all outlets with 80°C water.
The last system to be discussed is a system that was found to be objectionable. Pseudomonas sp. found as a contaminant in the system (after FDA testing) was also found in a topical steroid product (after FDA testing). Product recall and issuance of a Warning Letter resulted. This system (Figure 13) is also one-way that employs a UV light to control microbiological contamination. The light is turned on only when the water is needed. Thus, there are times when water is allowed to remain in the system. This system also contains a flexible hose which is very difficult to sanitise. UV lights must be properly maintained to work. The glass sleeves around the bulb(s) must be kept clean on their effectiveness will decrease. In multi-bulb units there must be a system to determine that each bulb is functioning. It must be remembered that at best UV lights will only kill 90% of the organisms entering the unit.
XII - PROCESS WATER
Currently, the USP, pg. 4, in the General Notices Section, allows drug substances to be manufactured from Potable Water. It comments that any dosage form must be manufactured from Purified Water, Water for Injection, or one of the forms of Sterile Water. There is some inconsistency in these two statements, since Purified Water has to be used for the granulation of tablets, yet Potable Water can be used for the final purification of the drug substance.
The FDA Guide to Inspection of Bulk Pharmaceutical Chemicals comments on the concern for the quality of the water used for the manufacture of drug substances, particularly those drug substances used in parenteral manufacture. Excessive levels of microbiological and/or endotoxins contamination have been found in drug substances, with the source of contamination being the water used in purification. At this time, Water for Injection does not have to be used in the finishing steps of synthesis/purification of drug substances for parenteral use. However, such water systems used in the final stages of processing of drug substances for parenteral use should be validated to assure minimal endotoxin/microbiological contamination.
In the bulk drug substance industry, particularly for parenteral grade substances, it is common to see Ultra-Filtration (UF) and Reverse osmosis (RO) systems in use in water systems. While Ultra-Filtration may not be as efficient at reducing pyrogens, they will reduce the high molecular weight endotoxins that are a contaminant in water systems. As with RO, UF is not absolute, but it will reduce numbers. Additionally, as previously discussed with other cold systems, there is considerable maintenance required to maintain the system.
For the manufacture of drug substances that are not for parenteral use, there is still a microbiological concern, although not the degree as for parenteral grade drug substances. In some areas of the world, Potable (chlorinated) water may not present a microbiological problem. However, there may be other issues. For example, chlorinated water will generally increase chloride levels. In some areas, process water may be obtained directly from neutral sources.
In one inspection, a manufacturer was obtaining process water from a river located in a farming region. At one point, they had a problem with high levels of pesticides which was a run-off from farms in the areas. The manufacturing process and analytical methodology was not designed to remove and identify trace pesticide contaminants. Therefore, it would seem that this process water when used in the purification of drug substances would be unacceptable.
XIII - INSPECTION STRATEGY
Manufacturers typically will have periodic printouts or tabulations of results for their purified water systems. These printouts or data summaries should be reviewed. Additionally, investigation reports, when values exceed limits, should be reviewed.
Since microbiological test result from a water system are not usually obtained until after the drug product is manufactured, results exceeding limits should be reviewed with regard to the drug product formulated from such water. Consideration with regard to the further processing or release of such a product will be dependant upon the specific contaminant, the process and the end use of the product. Such situations are usually evaluated on a case-by-case basis. It is a good practice for such situations to include an investigation report with the logic for release/rejection discussed in the firm's report. End product microbiological tested, while providing some information should not be relied upon as the sole justification for the release of the drug product. The limitations of microbiological sampling and testing should be recognized.
Manufacturers should also have maintenance records or logs for equipment, such as the still. These logs should also be reviewed so that problems with the system and equipment can be evaluated.
In addition to reviewing test results, summary data, investigation reports and other data, the print of the system should be reviewed when conducting the actual physical inspection. As pointed out, an accurate description and print of the system is needed in order to demonstrate that the system is validated.