| Title: Water Purification, Storage and Distribution for Pharmaceutical Production | |||||
| Guidance Number: 078 | |||||
| Prepared by: | Date: | Supersedes: | |||
| Checked by: | Date: | Date Issued: | |||
| Approved by: | Date: | Review Date: | |||
Water Purification, Storage and Distribution for Pharmaceutical Production
Introduction
This document provides guidance for the purification, storage and distribution of water used for Production including water used for cleaning of product contact equipment, containers, and closures.
1. Selection of Water Quality Requirements for APIs, Drug Products, and Medical
Device Manufacturing should be based on the stage of production, intended use of the water, and the end product requirements. Water should meet the minimum quality requirements defined in Table 1.
For Veterinary Pre-mixes and Soluble Powders that are used in the field and mixed with potable water or animal feed, potable water may be used for equipment cleaning and manufacturing.
2. Potable Water may be used in the final steps in the manufacture of APIs for use in nonsterile drug products, if the Site Quality Team has approved a documented rationale justifying the continued use of potable water. Such documented rationale should include, but not be limited to, information which demonstrates that:
- Potable water is compatible, throughout seasonal variations, with the API process steps in which it is used;
- Use of potable water is consistent with registration commitments for the API;
- There is an effective change control system for the potable water distribution piping that is defined as a direct impact system; and
A monitoring system is in place to ensure the ongoing review of potable water quality. Sources of information to support the rationale include, but are not limited to:
- Review of API quality data;
- Review of API validation data;
- Review of potable water chemical and microbiological quality;
- Review of the customer complaint history for problems traceable to potable water; and
- Review of API registration requirements.
The rationale should conclude that no quality or regulatory risk is identified for the API and for the drug product in which it is used.
3. For Highly Purified Water (HPW) and Water for Injection (WFI) Systems recirculating distribution loops should be maintained at > 70o C. Such heated distribution loops are considered self-sanitizing. For HPW and WFI systems with distribution loops and/or storage tanks that are maintained at <70oC, written system sanitization procedures should be followed that are based upon accepted sanitization methods (e.g., thermal treatment), and should be validated.
4. Distribution Systems for Purified Water (PW), HPW, and WFI should include:
- Water circulation with continuous flow velocity sufficient to achieve turbulent flow during normal operating conditions and sufficient return flow to ensure positive pressure in the distribution system during periods of peak draw (i.e., maximum water use);
- Provisions for maintaining sanitary conditions through periodic sanitization and/or flushing should be established in cases where the preferred length of a dead-leg is not designed to meet the maximum 3 hydraulic diameter guideline;
- Sloped pipes to drain pitched 1/16 inch per foot (5 mm/m) minimum;
- Diaphragm or compression valves that allow complete drainage;
- Sample ports at defined locations;
- Air breaks in drain piping; and
- Piping from water distributions systems to manifolds and process vessels should provide draining following use or should be blown down 5.
Passivation Procedures should be performed upon system installation and upon observation of widely distributed rouge on inspection of piping and gaskets. After system modification, the need and degree of passivation should be determined based upon impact assessment. After passivation, the water system should be flushed, sampled, and tested to ensure that passivating chemicals have been removed.
6. Quality Monitoring of (Potable) Water used as Feed Water for Water Purification Systems should be performed by obtaining and reviewing test data from the supplier or tested on Site or by a contract lab at least semi-annually, and through monthly sampling for coliforms and total viable organism (TVO) counts. Potable water used in manufacturing should be sampled and tested as indicated in Table 2.
7. Reverse Osmosis (RO) Systems, used for water treatment, should be monitored on-line by measuring the conductivity of the output water. RO systems should be cleaned and sanitized based on validated intervals.
8. Anion/Cation Exchange Resins and Continuous Electrodeionization (CEDI) Systems should be monitored by measuring the conductivity of the output water. Resins should be regenerated or replaced based on performance monitoring.
9. Hydrophobic Microbial-Retentive Vent Filters on still condensers and storage tanks should be integrity tested before and after use (see PQS P4104). Vent filters for HPW and WFI systems should be sterilized before use. Vent filters should be maintained condensate free (e.g., heated filter housing) and replaced annually or at intervals indicated by validation or qualification studies, whichever is shorter.
10. In-Line UV Lights can be used to minimize microbial levels in ambient temperature recycle streams (e.g., recirculating water purification and PW distribution systems). UV lights should be monitored for emission wattage and replaced when emissivity reaches 80 percent, or as recommended by vendor technical specifications, and at least once a year.
11. A Water Testing Plan should be established to quantify system performance, including seasonal effects, and should be part of the water system validation.
Operational Qualification (OQ) testing is typically performed daily during the first month of validation. During Performance Qualification (PQ), an additional month of daily sampling should be performed followed by less intensive sampling during the remaining months. OQ and PQ should be conducted over a period of one full year to assess the potential effects of seasonal changes on the water system. Data acquired during the year should be summarized and analyzed at least every two months, and should be used to establish alert and action levels based on process capabilities.
Water data should continue to be recorded, analyzed, and trended as the data are collected by the Site Quality Team.
12. Water Used in API and Drug Product Production should be sampled as required in Table 2. Where the type of water used at a sampling location changes with the manufacturing step for water used in the final steps of an API process, the frequency of sampling may be varied to match the water use.
13. Water Sampling Procedures should be established and sampling personnel should be qualified in these SOPs (see Table 2).
14. All Water Types should be sampled and tested for microorganism counts (TVO). Low Endotoxin Deionized Water, HPW, and WFI samples should also be tested for bacterial endotoxins. Where on-line conductivity and TOC probes are used with established alert and action levels, chemical testing frequency may be less frequent than defined in Table 2 and is based on validated intervals.
15. In the Event the PW, HPW, or WFI Distribution System is monitored continuously by validated in-line controls, sampling and testing for bacterial endotoxins and microorganisms (as applicable) may be suspended for intervals (such as weekends) of up to 3 days, provided that the water is not used for production, is continuously recirculating through the distribution system, and all normal operating ranges (NORs) are maintained.
16. Following a Water System Shutdown that Exceeds a Validated Time Interval, action should be taken to ensure acceptable water quality. Selected samples representative of the water quality, including the worst case system location at a minimum, should be collected and tested. All test results should be reviewed and approved before any products manufactured using the water are released.
17. Where Sample Ports Cannot be Located in Close Proximity to the Water Use Point (e.g., within a meter), documented rationale should be provided to justify the sample locations.
18. Water Samples at Points of Use should be collected in a manner consistent with manufacturing practices including, but not limited to, the following:
- Where sanitization of outside surfaces of sample ports is performed prior to collecting a sample (e.g., wipe-down with a sterile alcohol wipe), a study should be performed to demonstrate that the sanitization process does not inhibit microbial recovery, unless the sampling procedure includes specific measures to neutralize or remove the sanitizer; and
- If a hose is used to transfer the water for use in manufacturing, sampling should be performed through the same or an equivalent hose. If sampling through the hose is not possible on a routine basis, a study should be performed to demonstrate the equivalence of sampling with and without the hose.
19. Water Leaks should be reported and repaired.
20. Hoses should be disconnected, drained, and allowed to dry following use, and stored in a manner that provides for continuous drainage. If manufacturing requires prolonged use of hoses (e.g., > 24 hours), studies should be performed to demonstrate lack of microbial proliferation.
21. Bacterial Endotoxin Testings (BET) of Low Endotoxin Water, HPW, and WFI Storage and Distribution Systems should be performed according to the sampling frequency defined in Table 2 and selected samples representative of the water quality, including the worst case system location at a minimum, should be collected and tested after any repair or disturbance to the system. Samples for BET should be collected in pyrogen-free containers.
Bacterial endotoxin alert and action levels should initiate an immediate investigation, resample, and retest. When action levels are exceeded, further use of the water should be evaluated and approved by Site Quality Team. The investigation should extend to any batches or lots produced using the water that exceeded the action level.
22. Microbial Alert and Action Levels for water should be based on process capabilities and process requirements or the values in Table 1, whichever are lowest.
23. Chemical Alert and Action Levels for water should be based on process capabilities and process requirements, and the requirements in Table 1.