SYSTEM VALIDATION

A basic reference used for the validation of high purity water systems is the Parenteral Drug Association Technical Report N°4 titled "Design Concepts for the Validation of Water for Injection Systems."

The introduction provides guidance and states that; "validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce micro-organisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended functions."

In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated? How can the quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.

After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of water system validation can begin. During this phase the operational parameters and the cleaning/sanitation procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOP's for operation of the water system.

The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in accordance with the SOP's. The sampling is performed as in the initial phase and for the same time period. At the end of this phase, the data should demonstrate that the system will consistently produce the desired quality of water.

The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOP's over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater will be picked up during this phase of validation. Sampling is performed according to routine procedures and frequencies. For water for injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full year worth of data.

While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOP's. Second, there must be data demonstrating that the SOP's are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feedwater does not adversely affect the operation of the system of the water quality.

The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for the operation and quality assurance of the water system.

A typical problem that occurs is the failure of operating procedures to preclude contamination of the system with non-sterile air remaining in a pipe after drainage. In a system, as illustrated in Figure 1, a typical problem occurs when a washer or hose connection is flushed and then drained at the end of the operation. After draining, this valve (the second of the system) is closed. If on the next day or start-up of the operation the primary valve off of the circulating system is opened, then the non-sterile air remaining in the pipe after drainage would contaminate the system. The solution is to provide for operational procedures that provide for opening the secondary valve before the primary valve to flush the pipe prior to use.

Another major consideration in the validation of high purity water systems is the acceptance criteria. Consistent results throughout the system over a period of time constitute the primary element.