Validation of Water Systems

Water is one of the most widely used substances, and raw material, or an ingredient in the production, processing, and formulation of pharmaceuticals. Control of the organic and inorganic impurities and microbiological quality of water is important because proliferation of micro-organisms ubiquitous in water may occur during the purification, storage, and distribution of this substance.

Although there are various quality grades of water used for pharmaceutical purposes, all kinds of water are usually manufactured from drinking water or comparable grade water as a source water.

Grades of water are closely related to the manufacturing methods and distribution systems of water. Major differences among these grades of water consist of the following quality attributes:

  • Microbial counts
  • Endotoxin, which is due to the presence of microbes
  • Organic and Inorganic impurities

Grades of water specified in the compendia (USP) are classified according to the quality attributes as:

  • Portable water
  • Purified water
  • Water for injection
  • Sterile water for injection
  • Sterile water for inhalation
  • Sterile water for irrigation
  • Sterile bacteriostatic water for injection

Selection of Water for Pharmaceutical Purposes

The quality attributes of water for a particular application are dictated by the requirement of its usage. Sequential steps that are used for treating water for different pharmaceutical purposes include:

  • Softening
  • Dechlorination
  • Deionization
  • Reverse Osmosis
  • Ultrafiltration
  • Distillation

The manufacturing method and distribution system also have a close relationship with the construction design of facilities and equipment. The most important items to consider are:

  • Selection of the most suitable quality grade of water for its intended use.
  • Determination of the water manufacturing system elements, including facility and equipment.
  • Design of water manufacturing system, including the design of system equipment.
  • After construction of the water system is completed based on its design, the system has to be scrutinized as to whether it has been built to design specification or not.
  • After confirming the installation of facility and equipment, the quality of water produced is examined from various viewpoints according to the predetermined specifications.
  • In the routine production of water, representative quality items of water have to be monitored to confirm the performance of normal operation, and if any undesirable trends or out of specification values are found, corrective action should be taken.
  • The steps of checking design and construction, confirming proper installation and operation, and documenting these processes are collectively called qualification or validation.

Major items of quality attributes that should be controlled and specified for pharmaceutical use are:

  • Organic Impurities
  • Inorganic Impurities
  • Particulates
  • Microbes
  • Endotoxins

Design Qualification of Water Systems

The quality attributes of water for a particular application are dictated by the requirements of its usage. Production of pharmaceutical water employs a combination of sequential unit operations that address specific water quality attributes.

The validation plan should be designed to establish the suitability of the system and provide a thorough understanding of the purification mechanism, range of operating conditions, required pre-treatment, and the most likely mode of failure. It is also necessary to demonstrate the effectiveness of the monitoring scheme and to establish the requirements for validation maintenance.

The selection of specific unit operations and design characteristics for a water system should take into consideration the quality of the feed water, the technology chosen for subsequent processing steps, the extent and complexity of the water distribution system, and the appropriate requirements.

In a system for WFI, the final process must have effective bacterial endotoxin reduction capability and must be validated for each specific bacterial endotoxin reduction capability and must be validated for each specific equipment unit. The final unit operations used to produce WFI have been limited to distillation, reverse osmosis and/or ultafiltration. Distillation has a long history of reliable performance for the production of WFI.

Other technologies, such as reverse osmosis and ultrafiltration, may be suitable in the production of WFI if they are appropriately validated for each specific set of equipment.

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  • Kuldeep Yagik

    Dear,
    Allthough its good Article but I want to discuss that “Is it required to validate or monitor Water Treatment system also with generation system & distribution system.” So please let me know.

  • Kuldeep Yagik

    Dear,
    Allthough its good Article but I want to discuss that “Is it required to validate or monitor Water Treatment system also with generation system & distribution system.” So please let me know.

  • Dr.RDPATRO

    please send the validation of WFI,Fermentors and dry heat sterilizers

  • Dr.RDPATRO

    please send the validation of WFI,Fermentors and dry heat sterilizers

  • vpandya2006@yahoo.co.in

    i want to valiadtion guild line for Havc system

  • vpandya2006@yahoo.co.in

    i want to valiadtion guild line for Havc system

  • Dr.RDPATRO

    u have cleared many doubts on validation of WFI

  • Dr.RDPATRO

    u have cleared many doubts on validation of WFI

  • Dr.RDPATRO

    excellent information was provided

  • Dr.RDPATRO

    excellent information was provided

  • lalit garg

    i want validation of wfi

  • lalit garg

    i want validation of wfi

  • i want validation of wfi but it is very critical vew

  • i want validation of wfi but it is very critical vew

  • kawther

    please can i have a draft copy for performance qualification protocol and also report what shuld i test

  • kawther

    please can i have a draft copy for performance qualification protocol and also report what shuld i test

  • punam

    plz send me guideline for validation of water system and guide me about that which parameter should be checked during water system validation….

  • punam

    plz send me guideline for validation of water system and guide me about that which parameter should be checked during water system validation….

  • lale jahani

    please send me WFI & RO validation with details that indicated which parameters are necessary to point.

  • lale jahani

    please send me WFI & RO validation with details that indicated which parameters are necessary to point.

  • Dear sir,
    i am sanjeev doing job in indswift labs like as microbiologist.
    dear sir i want some notes about water validation and dry heat sterilizers
    plz sir send me.

  • Dear sir,
    i am sanjeev doing job in indswift labs like as microbiologist.
    dear sir i want some notes about water validation and dry heat sterilizers
    plz sir send me.

  • Satish Bhatt

    plz suggest me about the step where PH adjustment in water treatment plant done & why

  • Satish Bhatt

    plz suggest me about the step where PH adjustment in water treatment plant done & why

  • VIPPAN RANA

    I WANT COMPLETE IMFORMATION OF WATER VALIDATION SYSTEM

  • VIPPAN RANA

    I WANT COMPLETE IMFORMATION OF WATER VALIDATION SYSTEM

  • Nan

    plz send me guideline for validation of water system and guide me about that which parameter should be checked during water system validation and draft copy for performance qualification protocol and also report what shuld i test

  • Nan

    plz send me guideline for validation of water system and guide me about that which parameter should be checked during water system validation and draft copy for performance qualification protocol and also report what shuld i test

  • Your Comment how many phase perform in water validation &why

  • Your Comment how many phase perform in water validation &why

  • shivnarayan

    Your Comment plz send the latest cleaninig validation guideline .

  • shivnarayan

    Your Comment plz send the latest cleaninig validation guideline .

  • Santosh Oza

    Sir,

    Can u provide guide line (Protocol) for water system validation.

  • what is the reference of time period for performance qualification (phase 1, phase 2, phase 3) is that any guide line for this time as WHO , USB , EP ………ast

  • manikandan

    i need water for injection validation procedures kindly explain to all process parameters in usp method

  • UPPANAPALLI NAGESWARA RAO

    Sir

    Please send the complete water validation process for pharmaceutical preparation for formulations and method of testing.

  • Sir

    Please send the complete validation process of Water for pharmaceutical formulations and testing method.

    Thanking you Sir

    U.Nageswara Rao

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The Difference Between Prospective, Concurrent and Retrospective Validation

Unless you’re starting a new company you will need to plan on a variety of approaches.

Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.

In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.

1. Prospective Validation

Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.

This is the preferred approach.

Production is not started until all validation activities are completed.

The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.

The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.

After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.

Periodic Basis

On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.

If any gaps are identified a remediation plan will be developed and the process will start again.

The MVP

The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.

The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.

Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.

2. Concurrent Validation

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.

Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.

The Right Decision?

The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.

As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.

The Process

The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.

Again, routine preventative maintenance, requalification and periodic review are performed.

3. Retrospective Validation

Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.

Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.

Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.

It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.

Historical Data

Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.

During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.

As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.

General Process

The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.

Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.

The MVP should also provide guidance on managing inventory during retrospective validation.

One Major Issue

One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?

As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.

Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.

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International Conference on Harmonization (ICH) in a Nutshell [Video]

The ICH is a common project of regulatory authorities and representatives of pharmaceutical industries in EU, Japan and the US.

Its mission is to discuss issues related to approval and marketing authorization of new medicinal products in these three regions.

Namely, the six parties involved are the:

  • European Commission
  • The European Federation of Pharmaceutical Industry Associations
  • The Japanese Ministry of Health and Welfare
  • The Japanese Pharmaceutical Manufacturers Association
  • The US FDA
  • The US Pharmaceutical Manufacturers Association

In addition to these principals, there are three observers representing non-ICH countries:

  • World Health Organisation (WHO)
  • The European Free Trade Association (EFTA)
  • Health Canada

Primary Objective

The primary objective of ICH is to harmonize regulatory requirements related to quality, safety and efficacy of medicinal products and to support mutual recognitions between the three regulatory authorities.

Exchange of Data

Mutual recognitions are based on the exchange of data and assessment reports which are intended to eliminate duplicative testing and inspection procedures, and thus decrease costs of, and speed up, the introduction of new medicinal products to the markets.

cGMP – Cases from History and the Regulations

If you would like to learn more about the regulations governing the GMP’s click here.

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