Validation Guidelines for High Purity Water Systems

Date 11 November 2022

Water is one of the most used raw materials in the industry. It is also important in manufacturing Active Pharmaceutical Ingredients (API).

Water system validation is essential to understanding the dynamic operation in pharma. Water system validation, whether it's WFI water system validation of monitoring the efficacy distribution pipes, is an important strategy for ensuring consistent quality.

Importance of Water System Validation

It is important to first understand what water system validation is. It is a set of pre-determined checks, verification strategies that are used by pharma manufacturing companies to verify that their products and processes comply with the strict water system validation guidelines established by international regulatory bodies like WHO and ICH.

A proper Water System Validation ensures:

  • The water purification system operates in accordance to the design parameters
  • The purification system is capable of producing water of the desired quality.
  • The water produced and the system that it was designed are free from physical, chemical and microbial contaminants. They meet different USP monographs, and retain the same quality throughout generation, storage, distribution.

Water System Validation strategies that are efficient must prove the effectiveness of

  • Engineering Designs
  • Operational Procedures
  • Creating, installing, and running a successful operation requires a lot of planning.
  • Variations in periodic usage patterns

Validation of the high purity Water System Phases

Three distinct phases are required to validate high-purity water for pharma.

Phase 1

This phase is also known as the investigation phase. It lasts for approximately 2-4 weeks. This is when water must be operating continuously and the following parameters will be analyzed:

  • Tests and sampling of feed water
  • Analyzing water at each step
  • Testing for chemical and microbial contaminants
  • Cleaning, sanitizing and maintenance procedures.
  • Limits on alert and action
  • Production volume
  • Test-failure procedure

Phase 2

As part of Phase 2, Phase 2 will follow the completion of Phase 1. Phase 1 was successful. Phase 2 will continue for 2-4 weeks. The sampling process is the same as in Phase 1. However, the goal is to ensure that the results are consistent when the system operates under standard operations.

Phase 3

Phase 3 typically lasts for one year. During this phase, the water can still be used for manufacturing. This is a long-term analysis and involves:

  • After the completion of phases 1 & 2, water sampling frequency will be reduced.
  • Accounting for seasonal variation. This phase also includes seasonal trending.

After validation, a report is created. This is used for primary documentation during periodic inspections. The SOP, or Standardized Operation Procedure, is then determined.

Documentation Required

The following documents are required for a standard validation protocol:

Design document verification with a description and details of the installation process

  • Parameters of operation
  • Maintenance details
  • Training records
  • Environmental records
  • Plant inspection details

Commonly overlooked items

The process of water system validation in the pharmaceutical sector is complex and requires many factors to be considered. There is a possibility that some factors will be overlooked. Here are some of the things you should pay attention to:

  • Ultra Violet Lights- Water purification is an integral part of the process. They are used to kill microorganisms during purification. The standard procedure is to change the UV lamps every six months. Additionally, the ballast that provides power should be replaced every 2-3 years.
  • Feedwater - Quality and seasonal variation play an important role in the success or failure of pharmaceutical water system validation. Test the feedwater for pH, hardness and flow. Also, test it for contaminants like iron, chlorine, and conductivity. It is important to record operational data and check for emerging trends. An alert system should also be developed to notify the user of any inconsistencies.
  • Biofilm - A slimy, hydrophobic film that forms on the inside of pipelines. They contain bacteria, microbes, and pathogens. The biofilms are attached to the pipe's surface, which can not only affect the quality of water flowing through it but also cause corrosion. It is costly to get rid of biofilms so it is best to avoid them as much as possible. Biofilm problems can be prevented by chemical cleaning and acidic agent sanitization.
  • Air Contamination - Non-sterile water is another possible contaminant that could hinder the purification process. This is a critical factor in the validation process. Proper valve sequencing will eliminate any possibility of air contamination.
  • Microbial Limits - Although USP 24 is the most widely accepted reference for high purity water in pharmaceutical, it is not an absolute. It is dependent on the final dosage form and specific circumstances. This variation must be taken into consideration and the corrective actions should be taken.
  • Operation Cost - This consideration is probably the most practical, but it is easy to forget. Due to the high cost of operation, a complex system might prove difficult to maintain over the long-term. Self-sanitizing systems that maintain water temperatures between 65 and 80 degrees Celsius are a great way of saving money. Preventive measures can help reduce costs as they are often more costly than corrective measures.

WFI Validation

WFI water system validation is one of the most sensitive pharma products. It deserves a closer look. WFI water system validation isn't fundamentally different from other validation protocols. It follows the same principles of ensuring that the product meets all standards, including design, installation and operation. A WFI water system validation must ensure the following:

  • For USP monographs on WFI, chemical tests are required
  • Bacteriological purity less than 10cfu/100ml
  • Endotoxins less than 0.25EU/ml
  • Hot Water for Injection should not exceed 80 deg Celsius
  • Particulate matter

Two of the most widely accepted methods for determining standard validation protocols are the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH guidelines for water system validation) and WHO guidelines for purified waters system validation.

Although there may be differences in the details, all regulatory bodies around the world agree that validation is essential to ensure safety and maximize the use of resources for people involved in manufacturing pharma products.