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GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS
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V - STILL

Figures 3-5 represent a typical basic diagram of a WFI system..Most of the new systems now use multi-effects stills. In some of the facilities, there has been evidence of endotoxins contamination. In one system this occurred, due to malfunction of the feedwater valve and level control in the still which resulted in droplets of feedwater being carried over in the distillate.

 

 

 

In another system with endotoxins problems, it was noted that there was approximately 50 liters of WFI in the condenser at the start-up. Since this water could lie in the condenser for up to several days (i.e., over the weekend), it was believed that this was the reason for unacceptable levels of endotoxins.

More common, however, is the failure to adequately treat feedwater to reduce levels of endotoxins. Many of the still fabricators will only guarantee a 2.5 log to 3.0 log reduction in the endotoxin content. Therefore, it is not surprising that in systems where the feedwater occasionally appears in the distillate (WFI). For example, recently three new stills, including two multi-effect, where found to be periodically yielding WFI with levels greater than .25 EU/ml. Pre-treatment systems for the stills included only deionization systems with no UF, RO or distillation. Unless a firm has a satisfactory pre-treatment system, it would be extremely difficult for them to demonstrate that the system is validated.

The above examples of problems with distillation units used to produce WFI, point to problems with maintenance of the equipment or improper operation of the system indicating that the system has not been properly validated or that the initial validation is no longer valid. If you see these types of problems you should look very closely at the system design, any changes that have been made to the system, the validation report and the routine test data to determine if the system is operated in a state of control.

Typically, conductivity meters are used on water systems to monitor chemical quality and have no meaning regarding microbiological quality.

Petcocks and small sampling ports between each piece of equipment are mounted to isolate major pieces of equipment. This is necessary for the qualification of the equipment and for the investigation of any problems which might occur.

VI - HEAT EXCHANGERS

One principal component of the still is the heat exchanger.

Because of the similar ionic quality of distilled and deionised water, conductivity meters cannot be used to monitor microbiological quality. Positive pressure such as in vapor compression or double tubesheet design should be employed to prevent possible feedwater to distillate contamination in a leaky heat exchanger.

An FDA Inspectors Technical Guide with the subject of "Heat Exchangers to Avoid Contamination" discusses the design and potential problems associated with heat exchangers. The guide points out that there are two methods for preventing contamination by leakage. One is to provide gauges to constantly monitor pressure differentials to ensure that the higher pressure is always on the clean fluid side. The other is to utilize the double-tubesheet type of exchangers.

In some systems, heat exchangers are utilized to cool water at use points. For the most part, cooling water is not circulated through them when not in use. In a few situations, pinholes formed in the tubing after they were drained (on the cooling water side) and not in use. It was determined that a small amount of moisture remaining in the tubes when combined with air caused a corrosion of the stainless steel tubes on the cooling water side. Thus, it is recommended that when not in use, heat exchangers not be drained of the cooling water.

VII - HOLDING TANK

In hot systems, temperature is usually maintained by applying heat to a jacketed holding tank or by placing a heat exchanger in the line prior to an insulated holding tank.

The one component of the holding tank that generates the most discussion is the vent filter. It is expected that there be some program for the integrity testing this filter to assure that it is intact. Typically, filters are now jacketed to prevent condensate or water from blocking the hydrophobic vent filter. If this occurs (the vent filter becomes blocked), possibly either the filter will rupture or the tank will collapse. There are methods for integrity testing of vent filters in place.

It is expected, therefore, that the vent filter be located in a position on the holding tank where it is readily accessible.

Just because a WFI system is relatively new and distillation is employed, it is not problem-free. In an inspection of a manufacturer of parenterals, a system fabricated in 1984 was observed. Refer to Figure 6. While the system may appear somewhat complex on the initial review, it was found to be relatively simple. Figure 7 is a schematic of the system. The observations at the conclusion of the inspection of this manufacturer included, "Operational Procedures for the Water for Injection System failed to provide for periodic complete flushing or draining. The system was also open to atmosphere and room environment. Compounding equipment consisted of non-sealed, open tanks with lids. The Water for Injection holding tank was also not sealed and was never sampled for endotoxins." Because of these and other comments, the firm recalled several products and discontinued operations.

 

VIII - PUMPS

Pumps burn out and parts wear. Also, if pumps are static and not continuously in operation, their reservoir can be a static area where water will lie. For example, in an inspection, it was noted that a firm had to install a drain from the low point in a pump housing. Pseudomonas sp. contamination was periodically found in their water system which was attributed in part to a pump which only periodically is operational.

IX - PIPING

Piping in WFI systems usually consist of a high polished stainless steel. In a few cases, manufacturers have begun to utilize PVDF (polyvinylidene fluoride) piping. It is purported that this piping can tolerate heat with no extractables being leached. A major problem with PVDF tubing is that it requires considerable support. When this tubing is heated, it tends to sag and may stress the weld (fusion) connection and result in leakage. Additionally, initially at least, fluoride levels are high. This piping is of benefit in product delivery systems where low level metal contamination may accelerate the degradation of the drug product, such as in the Biotech industry.

One common problem with piping is that of "dead-legs". The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 - 80C circulating systems.

With colder systems (65 - 75C), any drops or unused portions of any length of piping has the potential for the formation of a biofilm and should be eliminated if possible or have special sanitizing procedures. There should be no threaded fittings in a pharmaceutical water system. All pipe joints must utilize sanitary fittings or be butt welded. Sanitary fittings will usually be used where the piping meets valves, tanks and other equipment that must be removed for maintenance or replacement. Therefore, the firm's procedures for sanitization, as well as the actual piping, should be reviewed and evaluated during the inspection.

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