Qualification should be completed before process validation is performed.
The process of qualification should be a logical, systematic process and should start from the design phase of the premises, equipment, utilities and equipment.
Depending on the function and operation of the equipment, utility or system, only installation qualification (IQ) and operational qualification (OQ) may be required, as the correct operation of the equipment, utility or system could be considered to be a sufficient indicator of its performance
(refer to Section 11 for IQ, OQ and performance qualification (PQ)).
(The equipment, utility and system should then be maintained, monitored and calibrated according to a regular schedule.)
Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.
Calibration and verification
Calibration and verification of equipment, instruments and other devices, as applicable, used in production and quality control, should be performed at regular intervals.
Personnel who carry out calibration and preventive maintenance should have appropriate qualifications and training.
A calibration programme should be available and should provide information such as calibration standards and limits, responsible persons, calibration intervals, records and actions to be taken when problems are identified.
There should be traceability to standards (e.g. national, regional or international standards) used in the calibration.
Calibrated equipment, instruments and other devices should be labelled,coded or otherwise identified to indicate the status of calibration and the date on which re-calibration is due.
When the equipment, instruments and other devices have not been used for a certain period of time, their function and calibration status should be verified and shown to be satisfactory before use.
Validation master plan
The validation master plan (VMP) should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following:
— a validation policy
— organizational structure of validation activities
— summary of facilities, systems, equipment and processes validated and to be validated
— documentation format (e.g. protocol and report format)
— planning and scheduling
— change control
— references to existing documents.
Qualification and validation protocols
There should be qualification and validation protocols describing the qualification and validation study to be performed.
As a minimum the protocols should include the following significant background information:
— the objectives of the study
— the site of the study
— the responsible personnel
— description of SOPs to be followed
— equipment to be used; standards and criteria for the relevant products and processes
— the type of validation
— the processes and/or parameters
— sampling, testing and monitoring requirements
— predetermined acceptance criteria for drawing conclusions.
There should be a description of the way in which the results will be analysed.
The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.
Qualification and validation reports
There should be written reports on the qualification and validation performed.
Reports should reflect the protocols followed and include at least the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods.
The results should be evaluated, analysed and compared against the pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-limit results should be investigated. If these deviations are accepted, this should be justified. Where necessary further
studies should be performed.
The departments responsible for the qualification and validation work should approve the completed report.
The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful.
The quality assurance department should approve the report after the final review. The criteria for approval should be in accordance with the company’s quality assurance system.
Any deviations found during the validation process should be acted upon and documented as such. Corrective actions may be required.
There are four stages of qualification:
— design qualifi cation (DQ);
— installation qualifi cation (IQ);
— operational qualifi cation (OQ); and
— performance qualifi cation (PQ).
All SOPs for operation, maintenance and calibration should be prepared during qualification.
Training should be provided to operators and training records should be maintained.
Design qualification should provide documented evidence that the design specifications were met.
Installation qualification should provide documented evidence that the installation was complete and satisfactory.
The purchase specifications, drawings, manuals, spare parts lists and vendor details should be verified during installation qualification.
Control and measuring devices should be calibrated.
Operational qualification should provide documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications.
Tests should be designed to demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions).
Operation controls, alarms, switches, displays and other operational components should be tested.
Measurements made in accordance with a statistical approach should be fully described.
Performance qualification should provide documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use.
Test results should be collected over a suitable period of time to prove consistency.
Re-qualification should be done in accordance with a defined schedule.
The frequency of re-qualification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance.
There should be periodic re-qualification, as well as re-qualification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement).
Re-qualification should be considered as part of the change control procedure.
Processes and procedures should be re-validated to ensure that they remain capable of achieving the intended results.
There should be periodic re-validation, as well as re-validation after changes.
Re-validation should be done in accordance with a defined schedule.
The frequency and extent of re-validation should be determined using a risk-based approach together with a review of historical data.
Periodic re-validation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment.
The following should be considered when periodic re-validation is performed:
— master formulae and specifi cations;
— records (e.g. of calibration, maintenance and cleaning); and
— analytical methods.
Re-validation after change
Re-validation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Re-validation should be considered as part of the change control procedure.
The extent of re-validation will depend on the nature and significance of the change(s).
Changes should not adversely affect product quality or process characteristics.
Changes requiring re-validation should be defined in the validation plan and may include:
• changes in starting materials (including physical properties, such as density, viscosity or particle size distribution that may affect the process or product);
• change of starting material manufacturer;
• transfer of processes to a different site (including change of facilities and installations which influence the process);
• changes of primary packaging material (e.g. substituting plastic for glass);
• changes in the manufacturing process (e.g. mixing times or drying temperatures);
• changes in the equipment (e.g. addition of automatic detection systems,installation of new equipment, major revisions to machinery or apparatus and breakdowns);
• production area and support system changes (e.g. rearrangement of areas,or a new water treatment method);
• appearance of negative quality trends;
• appearance of new fi ndings based on current knowledge, e.g. new technology;
• support system changes.
Changes of equipment which involve the replacement of equipment on a “like-for-like” basis would not normally require a re-validation.
installation of a new centrifugal pump to replace an older model would not necessarily require re-validation.
Changes should be controlled in accordance with a SOP as changes may have an impact on a qualified utility, system or piece of equipment, and a validated process and/or procedure.
The procedure should describe the actions to be taken, including the need for and extent of qualification or validation to be done.
Changes should be formally requested, documented and approved before implementation. Records should be maintained.
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Reference: WHO Technical Report Series, No. 937, 2006