Validating High-Purity Water Systems
In the production of pharmaceuticals, the most widely used raw material is water. As a raw material, high purity water is unique in that it is the only component, which must be produced by the manufacturer, because it is not available from a vendor in a ready-to-use form. Water is utilized in the production of every type of pharmaceutical; in some products, such as parenterals, it is a critical component. In such applications Water-For-Injection (WFI) systems are used to generate water for use in manufacturing applications.
Regadess of the system used to generate high purity water, under Federal regulations 21CFR 210 and 211, it must be validated. One of the primary references used in the validation of high purity water systems is the Parenteral Drug Association’s Tech nical Report No. 4, “Design Concepts for the Validation of a Water for Injection Sys tem.” According to the report,
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 function.
So while there are several strategies that may be employed in the validation of high purity water systems, the following strategy contains all the necessary elements.
A Design/installation review. While not always considered an actual part of the validation process, the installation review is a critical step in ensuring that the validation is not put at risk and is successfully completed. Once the installation is finalized, a complete and up-to-date description and design drawing of the system should be added to the file and included in the final report. It is important that the design drawing include all components of the system and clearly identify all sample points and their designations. If the design drawing does not include these elements, the water system is considered to be in an “objectionable condition” and the validation is at risk.
It is advisable to review the design drawing annually to ensure that it is accurate and up to date. These reviews often identify unreported changes and are effective in confirming reported changes to the system.
B SOP development and confirmation. Once the system design and installation has been finalized, the next step is to develop the operational parameters and cleaning and sanitizing protocols. Once developed, these procedures become the SOPs for the system’s normal operation. During this step, data are collected over a period of two to four weeks, and samples should be collected daily after each purification step and from all points of use. At the end of the period, if the system has successfully generated water of the appropriate quality, these procedures are established as the water system’s SOPs.
C Demonstration of effectiveness. During this phase of the validation the objective is to demonstrate that the water system consistently produces water of the desired quality when operated within the parameters outlined in the SOPs over a long period of time. It is important that the data is collected in accordance with the SOPs. WFI system samples are taken daily at a minimum from one point of use and weekly from all points of use. This type of operation should identify any inconsistencies in the feedwater quality due to seasonal variations or other changes in the quality of the source water. A water system cannot be considered validated until the manufacturer has a year’s worth of operational data.
D Data compilation and sign-off. The final step in validating a high purity water system is assembling the data into a validation report. The final report should include all the data collected in Steps B and C, along with any conclusions derived from the data. Once the final report is complete, it is important to ensure that the appropriate personnel review and sign off on it.
Any validation strategy should include the elements outlined above: development of the SOPs through data collection, a demonstration that the SOPs are effective, and assurance that the system is capable of consistently producing, over a long period, water that meets the quality specifications. While including these elements in the validation strategy increases the odds of successfully validating the water system, even a well thought out strategy is susceptible to failure because of often overlooked details. The validation process is long and complex and small details can often be overlooked.
The following are some of the more commonly overlooked considerations:
1 Feedwater. During a water system validation, consideration has to be given to the quality and seasonal variation of the feedwater. In some instances, it is also beneficial to consider the quality of water in surrounding municipalities in the event that water must be diverted from an alternate, neighboring source. (Feedwater may be diverted as a result of such events as construction or an emergency such as a major fire. In such cases, the feedwater entering the facility may be contaminated with elevated levels or different types of flora.)
2 Air contamination. A common omission from SOPs is a list of the correct procedures to preclude contamination from non-sterile air after a water system is drained. Point-of-use piping extensions, particularly those that utilize tubing or hoses for application, can allow non-sterile air to come in contact with the system when the valves are not opened in the proper sequence. The SOPs should be reviewed to ensure that proper valve sequencing prevents contamination from non-sterile air.
3 Component design is an important consideration. While component design has become more sophisticated in recent years, each of the following system elements can benefit from further thought:
Carbon beds remove organic compounds from the feedwater. One of the most common organic compound removed is chlorine, which municipalities use to control bacterial growth in drinking water. Since carbon beds filter the organic material needed for bacterial growth, this material becomes concentrated in the carbon beds; if the beds are not properly maintained, they can harbor bacteria and endotoxins. Hot water or steam should be used periodically to purge the system of such contaminants. It is important that the SOPs include these maintenance procedures.
Holding tanks. The design element that causes the most concern vis-a-vis the holding tank is the vent filter. Most new tanks utilize jacketed vent filters to prevent condensate or water from blocking the hydrophobic filter. It is important that maintenance SOPs include procedures for regular checking of the vent filter integrity. For this reason, the filter should be located in a position that provides easy access for testing. The SOPs should also include complete flushing or draining of the holding tanks on a regular basis.
Heat exchangers should be designed to prevent distillate contamination from feedwater. Double tubesheet design and positive pressure are the two most common methods used; if positive pressure is utilized in the design, monitoring systems should ensure that higher pressure is constantly maintained on the distillate side.
Distillation stills are used in the production of WFI because they kill microbial organisms, deactivate endotoxins, and eliminate dissolved solids not removed by previous filtration steps. It is important that the condenser be designed with double tubesheet to ensure that the distillate will not come in contact with the coolant, thus preventing recontamination. Another consideration for distillation stills is the quality of the steam supplied to the process; the quality of the steam must be controlled to prevent recontamination.
Pumps. All pumps experience wear and some burn out; it is therefore important that the maintenance SOPs include a program for the upkeep of all pumps in the system. If a pump is not in continuous operation, the reservoir is a potential source of contamination; when the pump is not in use, water may collect in the low point of the pump housing, potentially harboring microorganisms. It may be advisable to install a drain in the low point of the pump housing.
Piping. Most WFI and other high purity water systems utilize stainless steel (SS) piping in their construction. Where low level metal contamination is a concern, polyvinylidene fluoride (PVDF) piping has been used in place of the SS piping. Systems utilizing PVDF piping, however, require additional support in the piping layout. While the system is in use, the circulation of hot water may reduce the rigidity of the piping, causing it to sag. In cases where the piping sags or bends, stress can create fissures in joints, which may result in leakage and/or contamination. Other considerations for the piping include the elimination of “dead-legs” and the use of welding or sanitary fittings for all joints and connections in the system design.
4 Microbial Limits. When establishing the microbial specifications for a high purity water system, the most commonly used reference is the USP 24 (Table 1). It is important to understand that the limits set forth by USP 24 are not absolute, and as such the FDA does not view them as pass/fail limits. Instead, they are viewed as action limits and in some cases may not be stringent enough. It is important that users take into account not only the USP guidelines but also their understanding of the dosage form in which the high purity water will be used when setting alert or action limits. In, for example, situations in which the final dosage form does not have a preservative system, more stringent action limits may be required to produce safe and effective products. Conversely, some dosage forms that have low moisture content may tolerate higher microbial levels and as such the action limits may be established at higher values.
In WFI systems it is possible that a system may pass either the microbial or endotoxin action limit but fail the other. It is therefore import that both endotoxin and microbial levels are closely monitored.
When alert and action limits have been established, it is imperative that the user have an SOP for investigating deviations. Once a deviation is detected, the user must investigate the cause, determine a corrective action, and assess the impact of the contamination on adulterated product. Throughout this process, the findings and conclusion should be documented and assembled in a corrective action report. Finally, there should be a process in place to confirm any changes to the system or SOPs as a result of the corrective action.
5 Cost of operation. While not a factor in validation, cost considerations are important. High purity water systems, which operate between 65Þ and 80Þ C, are generally recognized as self-sanitizing. While these systems cost more initially than “cold” systems, the savings realized through reduced operations, maintenance, and testing—and the prevention of potential problems—may make the investment worthwhile.
The quality of the high purity water generated by WFI and other systems is critical to the processing of pharmaceuticals. Validation of the high purity water system and close adherence to the SOPs are essential to maintaining the quality and integrity of the generated water. When conducting a high purity water system validation, considering the points outlined in this article will increase the odds of a successful validation and preserve the integrity of process water.