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

  • http://wwwyahoo.co.in dharmender singh UP Balrampur

    i want validation of wfi but it is very critical vew

  • http://wwwyahoo.co.in dharmender singh UP Balrampur

    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.

  • http://www.gmail.com sanjeev kumar

    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.

  • http://www.gmail.com sanjeev kumar

    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

  • http://www.gmail.com shivnarayan

    Your Comment how many phase perform in water validation &why

  • http://www.gmail.com shivnarayan

    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.

  • http://www.samacm.com fadi khattab

    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.

  • http://www.yahoo.com UPPANAPALLI NAGESWARA RAO

    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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Changes to equipment and documentation is an integral part of the whole GMP process in any regulated facility. In this article we will discuss how equipment is designed in a GMP facility and how good documentation practices are an essential part of quality assurance and GMP.

The content of this article has been taken from module 7 of our eLearning module on Good Manufacturing Practices (cGMP) within the life sciences.

You can view this module in full by viewing the video below.

cGMP eLearning Module – Compelling, Engaging and Interactive

 

Equipment

All equipment is designed, constructed and located to suit their intended use and to facilitate easy maintenance and cleaning.

Equipment is installed in such a way as to prevent any risk of error or of contamination, and cleaned according to detailed and written procedures and stored only in a clean and dry condition.

Production equipment should be designed in such a way as not to present any hazard to the products.

The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

Any defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective. When not in use, equipment should be covered to ensure it remains clean.

Balances

Balances and measuring equipment of an appropriate range and precision should be available for production and quality control operations.

All measuring devices are required to be calibrated and checked at defined intervals by appropriate methods, and adequate records of such tests should be maintained.

Utilities

Fixed piping should be clearly labelled to indicate the contents and where applicable, the direction of flow.

Water pipes used in production (e.g. Purified Water, Water for Injection) are sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

Electrical circuits should be identified, and a record maintained of the load on each circuit to prevent inadvertent overload.

Documentation

Good Documentation Practices are an essential part of quality assurance and GMP.

It is important for a manufacturer to get the documentation right in order to get the product right.

GMP Documentation e.g. Site Master File, Specifications, Batch Manufacturing Formulae, Batch Manufacturing Records, Processing, Labelling, Packaging, Testing Instructions, Standard Operating Procedures, Protocols, Technical Agreements, Records, Certificates of Analysis, Reports etc. should contain the following attributes of a good document:

They should be:

  • Attributable
  • Legible
  • Contemporaneous
  • Original
  • Accurate
  • Complete
  • Durable
  • Corroborated
  • Version Based
  • Accessible
  • And Authorized

Change Control

Change to GMP documentation, equipment, processes, systems, instrumentation, test methods, etc. are required to be controlled under a formal change control program.

This program must consist of Quality oversight to review the proposed changes, evaluate the potential impact of the change, determine any potential risk to product quality, and to establish the required level of supplemental validation/documentation required for the change.

In many instances, changes will also require submission to the Health Authority for approval of the change.

For example, changes impacting the submission documentation are subject to post approval change guidances according to the Health Authority regulations.

Change Control is a critical aspect of the GMP systems.

If you want to learn more about cGMP or if you want to evaluate our eLearning module for your company you can find more information here.

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The enduring assets of a laboratory’s work are the records that document those activities. When laboratory records are used to support a regulatory function, they are considered to be legal documents.

Laboratory Data Integrity – eLearning Course

 

For records to be considered reliable and trustworthy they must comply with the following criteria:

  • Legible and Understandable – they must be able to be read and understood for the lifetime of the record, without having to refer to the originator for clarification. The information may be needed in five, ten or twenty years’ time, perhaps after the originator is no longer available
  • Attributable – who made the record or created the data and when?
  • Contemporaneous – the record must be made at the time the activity was performed
  • Original – the information must not be written on a post-it, piece of scrap paper, sleeve of a lab coat etc. and then transcribed.
  • Accurate – no errors or editing without documented amendments
  • Complete – All the information and data associated with the analysis is included
  • Consistent – All elements in the sequence of analysis must be date & time stamped and must be in the expected order
  • Indelible – Records are made on to controlled documents, such as laboratory notebooks or controlled worksheets, or saved to electronic media
  • Available – over the entire lifetime of the record for review, audit and inspection

1. Legible and Understandable

A record that cannot be read or understood has no value and might as well not exist. All records should be composed so they conform to grammatical convention which should be consistent throughout.

It is best to avoid buzzwords, cliques and slang as these are prone to change with time and are often not understood outside a particular locality. It is always good practice to have any record reviewed by a second person as this can often highlight any ambiguities.

2. Attributable

The identity of the person creating a record should be documented. For paper records this is normally done by the individual signing and dating the record with their signature.

As the record you may be signing may be a legal document, you should clearly understand the implication of your signature. A signature should be individual to a specific individual and the practice of signing someone else’s name or initials is fraud, and is taken very seriously.

3. Contemporaneous

All records must be made at the time an activity takes place. Delaying writing up, for example until the end of the day, will inevitably affect the accuracy of that record as details can be forgotten or miss-remembered.

4. Original

All records must be original; information must be recorded directly onto the document. This avoids the potential of introducing errors in transcribing information between documents.

If information from an instrument is printed out, by the instrument, that printout is the original record and should be signed, dated and attached to the record.

5. Accurate

The record must reflect what actually happened. Any changes should be made without obscuring or obliterating the original information, the use of whiteout or correction fluid is prohibited.

Any changes made to a record should be signed by the person making the change and dated to show when it was made and a written explanation should also be provided. Remember, the record may be needed after you have left the company and cannot be contacted for clarification.

6. Complete

The record must contain all information associated with the analysis of the sample, including system suitability tests, injection sequences, processing methods, sample preparation procedures and results.
This must also include any reinjections or repeat analysis performed on the sample.

Remember the position of the regulatory authorities for something that needs to be done is – ‘if it isn’t documented it’s a rumour’. However, failing to disclose reanalysis or reinjection of samples will undermine confidence in the reliability of the records.

7. Consistent

Consistency in this context refers to the sequence of the component events, which the analytical method comprises, being performed in a logical order.

For example it is not possible to commence the HPLC run before the samples have been prepared, therefore the balance printout for the sample weights should be date/time stamped at least one or two hours prior to the sample injection time, to allow time to prepare the samples. Therefore all date/time stamps should be in the expected sequence.

In order to avoid confusion in this respect, it is worth ensuring all instruments that produce date/time stamped printouts are time synchronised. This is best done by reference to a standard reference time, such as a national online time server.

8. Indelible

Indelible means the record must be legible for the lifetime of the record and once it has been made it cannot be removed.

Hand written entries of information should be made in ink and not pencil which can be erased

If printouts are made on thermal paper, which darkens with time, a photocopy should be made; this should be certified as an accurate copy of the original print and attached

If print outs are attached to a page they should be

  • Secured to the page with acid free glue and industrial strength Sellotape
  • Signed and dated across the attachment and the page
  • Annotated with a reference to the document

9. Available

All records should be available for inspection, audit and review for the lifetime of the document. If a document is requested during a regulatory audit, it should be produced within thirty minutes.

Therefore, the laboratory should establish an easy to reference archive system. Records should be archived so as to preserve their integrity, such as

  • Secure facility with restricted access
  • Effective fire suppression
  • Protection from dampness or humidity
  • Controlled access to Document

Check Out Our Laboratory Data Integrity eLearning Module

If you are looking for a way to train your staff on the importance of data integrity in a regulated environment check out oureLearning Course.

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