VAL-005 Validation – Concept and Procedure

1. Philosophy of Validation

According to GMP definition Validation is “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.”

Appropriate and complete documentation is recognised as being crucial to the validation effort.  Standard Operating Procedures (SOPs), manufacturing formulae, detailed batch documentation, change control systems, investigational reporting systems, analytical documentation, development reports, validation protocols and reports are integral components of the validation philosophy.  All validation documentation is prepared and maintained to be readily accessible to Operations personnel.  The validation documentation provides a source of information for the ongoing operation of the facility and is a resource that is used in subsequent process development or modification activities.

All validation activities will incorporate a level of Impact Assessment to ensure that systems, services and products directly influenced by the testing have been identified.  Additionally, an EHS Audit, incorporating risk assessment activities, are performed by the EHS management on all product lines to address the safety issues involved in the manufacturing process.

A revalidation programme will be implemented based on routine equipment revalidation requirements and on the Change Control Policy.

2. Responsibilities

It is the responsibility of the Project Manager to source appropriate resources, assign responsibility and obtain agreement to participate in the project. Considerations should include:

a. Skills needed

b. Facilities needed

c. Equipment and technology required

d. Suppliers/contractors and materials

e. Capital funds needed

f. Special resources identified.

Project teams are assembled for a limited or fix duration to deal with new equipment, processes or systems.  Team members can be drawn from single departments, cross-functional divisional areas and contractors.  Skills, which do not exist inside the organisation, or for which there is insufficient capacity, will need to be sourced externally.

All Validation Plan and Reports are reviewed, approved and accepted, as applicable by members of the review team identified below as a minimum. It is the responsibility of the individual project teams to identify appropriate and/or additional reviewers as identified in the individual Validation Plan for that project:

a. Quality Assurance Manager

b. Validation Manager

c. Operations Manager.

Specific test protocols are prepared and reviewed by identified technically competent persons, and authorised by members of the above Validation Review Team as identified in the individual Validation Plan for that project

3. Validation Approach and Concepts

3.1.         Types of Validation

3.1.1.     General Categories

Prospective validation –
Establishing documented evidence that a piece of equipment/process or system will do what it purports to do, based upon a pre-planned series of scientific tests as defined in the Validation Plan.

Concurrent validation –
Is employed when an existing process can be shown to be in a state of control by applying tests on samples at strategic points throughout a process; and at the end of the process.  All data is collected concurrently with the implementation of the process until sufficient information is available to demonstrate process reproducibility.  (The sampling can then be reduced at that stage to normal in‑process levels.)

Retrospective validation –
Establishing documented evidence that a process does what it purports to do, based on review and analysis of historical data.

3.1.2. Specific Categories

Design Qualification (DQ)

The intent of the DQ is met during the design and commissioning process by a number of mechanisms, which include:

a. Generation of User Requirement Specifications

b. Verification that design meets relevant user requirement specifications.

c. Supplier Assessment /Audits

d. Challenge of the design by GMP review audits

e. Product Quality Impact Assessment

f. Specifying Validation documentation requirements from equipment suppliers

g. Agreement with suppliers on the performance objectives

h. Factory Acceptance Testing (FAT), Site Acceptance Testing (SAT) & commissioning procedures

i. Defining construction and installation documentation to assist with Installation Qualification (IQ).

Installation Qualification (IQ)

IQ provides documented evidence that the equipment or system has been developed, supplied and installed in accordance with design drawings, the supplier’s recommendations and In-house requirements.  Furthermore, IQ ensures that a record of the principal features of the equipment or system, as installed, is available and that it is supported by sufficient adequate documentation to enable satisfactory operation, maintenance and change control to be implemented.

Operational Qualification (OQ)

OQ provides documented evidence that the equipment operates as intended throughout the specified design, operational or approved acceptance range of the equipment, as applicable.  In cases where process steps are tested, a suitable placebo batch will be used to demonstrate equipment functionality.

All new equipment should be fully commissioned prior to commencing OQ to ensure that as a minimum the equipment is safe to operate, all mechanical assembly and pre-qualification checks have been completed, that the equipment is fully functional and that documentation is complete.

Performance Qualification (PQ)

The purpose of PQ is to provide documented evidence that the equipment can consistently achieve and maintain its performance specifications over a prolonged operating period at a defined operating point to produce a product of pre-determined quality. The performance specification will reference process parameters, in-process and product specifications. PQ requires three product batches to meet all acceptance criteria for in-process and product testing. For utility systems, PQ requires the utility medium to meet all specifications over a prolonged sampling period.

The PQ documentation should reference standard manufacturing procedures and batch records and describe the methodology of sampling and testing to be used.

Cleaning Validation (CV)

CV provides documented evidence that a cleaning procedure is effective in reducing to pre-defined maximum allowable limits, all chemical and microbiological contamination from an item of equipment or a manufacturing area following processing. The means of evaluating the effectiveness of cleaning involves sampling cleaned and sanitised surfaces and verifying the level of product residues, cleaning residues and bacterial contamination.

The term CV is to be used to describe the analytical investigation of a cleaning procedure or cycle. The validation protocols should reference background documentation relating to the rationale for “worst case” testing, where this is proposed. It should also explain the development of the acceptance criteria, including chemical and microbial specifications, limits of detection and the selection of sampling methods.

Method Validation (MV)

MV provides documented evidence that internally developed test methods are accurate, robust, effective, reproducible and repeatable.  The validation protocols should reference background documentation relating to the rationale for the determination of limits of detection and method sensitivity.

Computer Validation

Computer Validation provides documented evidence to assure systems will consistently function according to their pre-determined specifications and quality attributes, throughout their lifecycle.  Important aspects of this validation approach are the formal management of design (through a specification process); system-quality (through systematic review and testing); risk (through identification and assessment of novelty and critical functionality) and lifecycle (through sustained change control).

Where equipment is controlled by embedded computer systems, elements of computer validation may be performed as part of the equipment IQ and OQ protocols.

4. What Gets Validated

4.1. General Criteria

4.1.1. All process steps, production equipment, systems and environment, directly used for the manufacture of sterile and non sterile products must be formally validated.

4.1.2. All major packaging equipment and processes should be validated. This validation is less comprehensive.

4.1.3. All ancillary systems that do not directly impact on product quality should be qualified by means of a technical documentation of the extent of the system and how it operates, (i.e. Good Engineering Practice).

4.2. Specific Criteria

4.2.1. Facility

a. Manufacturing Area Design.

b. Personnel and material flow etc.

4.2.2. Process and Equipment Design

a. Process steps and equipment description. i.e. Dispensing, Formulating, Packaging

b. Equipment washing and cleaning. etc

4.2.3. Utility Systems Design

a. Raw/purified steam

b. Purified water

c. Compressed Air

d. Air conditioning system

e. Vacuum

f. Power supply

g. Lighting

h. Cooling water

i. Waste etc

4.2.4. Computerised Systems Design

a. Information system

b. Laboratory automated equipments

c. Manufacturing automated equipments

d. Electronic records etc

5. Validation Documentation

5.1. Validation Documents

A typical documentation package relating to a Validation Project will consist of the following, as a minimum:

A File Index

A Validation Project Log Form (Form-375)

A Validation Plan

Installation Qualification Report/s

A series of Operational Qualification Test Protocols and Raw Data Results (as defined in the Validation Plan.

An Operational Qualification Report

EHS Report

Quality Audit Report (for new process lines)

A series of Performance Qualification Test Protocols and Raw Data Results (as defined in the Validation Plan and during the OQ phase).

A Validation Report

Discrepancy Forms

System SOPs (a list of SOP’s relating to the process)

System Changes (Change Request Forms, see SOP QMS-030).

5.1.1. All Validation Documents are to be clearly identified with numbered pages, with clear units of measure stated, results/signatures recorded in black or blue pen, and signatures of persons performing tests and dates conducted are all to be captured.

5.1.2. The original copies of approved Validation documents are the responsibility of the Project Coordinator typically Validation Manager.  During the Validation Project they are to be kept in a secure place and copies issued to members of the Validation Team as required, in a controlled manner, by the Project Coordinator.  The original approved copies are to be included in the Validation File.

5.1.3. Raw Data relating to the execution of Operational and Performance Qualification tests can consist of result sheets, temperature recordings, etc. Raw Data is the real time recording of the results obtained and must always be signed and dated by the person performing the test and then included in the Validation file.  Operational and Performance Qualification protocols and the Raw Data relating to them are to be filed in a separate section or volume of the Validation file.  It is the responsibility of the person/s assigned responsibility for checking and approving the completed protocols to ensure that the data presented in the Reports is factual and truly represents the Validation effort.  The Reports are then presented to the Validation Committee for their approval.

5.1.4. The composite Validation Files are to be appropriately numbered and indexed to allow for easy review of the Validation effort and are to include a section to record any changes that are hence made to the validated equipment/process/system, in accordance with SOP QMS-030.

5.2. Numbering System of Validation Documents

5.2.1. The Project Coordinator is responsible for registering the Validation Project with the Validation Dept by filling out a Validation Project Log Form (Form-375).

5.2.2. The Validation Dept is responsible for allocating a unique Project No. to each Project.  The same code number will be utilised for the numbering of associated documentation relating to that Validation file e.g. Validation plan, IQ, Qualification test protocols, Validation reports, and other associated documentation and will be used on all validation forms.  Validation documentation will be numbered according to the following designated sequence:

Validation Projects and Files

Allocating Validation Project No and File Number

Each Validation Project and File Number will be numbered in the following manner:

Where:

Allocating Validation Protocol No.

Plans/Qualification Test Protocols/Reports/Forms

Each qualification test protocol or report will be assigned a unique protocol number.

Protocols will be numbered according to the following designated sequence:

Where:

5.3. Document Change Control & Revision History

5.3.1. A revision of draft will be assigned to all first draft documents during the comments stage. The Revision Number will be incremented with each review.  Any revisions made to the draft documents during the comment stage are to be resubmitted for approval in their entirety.

5.3.2. At the conclusion of the comments stage when the document is ready for formal checking and authorisation the Revision Number is to be converted to 1.  Any changes made to approved documents are recorded by assigning a new revision number and authorisation by the same people who approved the original document.  A document revision history is to be included at the end of each document showing the revision number, reason for the revision, and a signature for the retrieval of the outdated documents and destroyed when the new version is issued. Revalidation documents are called Addendum (A) and follow a similar format to the original protocols.

5.4. Document Approval

All Validation Documents are to be prepared, reviewed and approved by the following system or as specified in the Validation Plan:

Key:

Prepared by:

Document written by.

Checked by:

Reviewed for technical accuracy.  To ensure that all the engineering and operational aspects have been considered and, where appropriate, that the work has been performed in accordance with the approved programme / protocol.

Authorised by:

Reviewed for conformance to in-house requirements and approval for use given. That all cGMP and regulatory requirements have been considered, met and documented as appropriate.

Approved by:

Completed programme reviewed for conformance to in-house requirements.

5.5. Recording Raw Data

5.5.1. Raw data generated in conducting the Qualification Tests must be recorded on the test results sheets as they are generated.  The person conducting the tests and recording the data must sign and date the documentation where required.  Alterations to raw data must follow SOP QMS-020 where the original data is not obliterated, but crossed out, the new data clearly recorded, and the changes initialled and dated.  All data relating to the executing of the test Protocol must be recorded even that which did not meet the acceptance criteria.

5.5.2. Where data is created electronically and stored or archived, there may be practical issues with maintenance of the original format. In such cases, the transfer process for raw data from one format to a different format must be validated.

5.6. Discrepancy Forms

Where a problem occurs, such as acceptance criteria not being met, a Discrepancy Form (Form-370) must be filled out detailing the discrepancy – the action that has been taken to address the discrepancy and a sign off to indicate that the actions have been satisfactorily completed and are effective in addressing the problem.

5.7. Attachments

Any Attachments to the Validation documents must be identified clearly and legible for traceability, as well in numerical sequence.

5.8. Protocol Revision

Should a recorded discrepancy necessitate the rewriting of the test protocol then the document must follow standard document change control procedures.  A new Protocol must be issued with a new Revision No. and again go through the approval process prior to use.  Outdated versions of the Protocols must be retrieved and destroyed when the new version is issued.  The numbering system for Protocols consists of a sequential increase in the digit, viz:

Original            1.0

1st Revision     2.0

2nd Revision    3.0 and so on.

5.9. Figure 1 – Flowchart for Validation Stages

5.10. Completed Protocol Review

After completing the required tests, a summary of the results is to be entered into the Qualification protocol.  A conclusion is then to be written by the person responsible for executing the protocol.  The completed test program is to be reviewed and signed for by the same people who checked and authorised the document in its approval stage or as specified in the validation plan.

5.11. Report Writing

Installation Qualification Report

On completion of the documentation relating to the Installation Qualification the report is to be review for technical correctness and completeness by two people.  One is to be from the Engineering Services area and checks for the Electrical Installation aspects, the other is to be from the Projects group or the Production (Process Engineers) group and is to check for material and mechanical aspects of the installation before being submitted for approval by the Validation Committee.

Operational Qualification Report

On completion of all the Operational Qualification tests a report with a conclusion is to be written by an assigned Validation Team Member.  This report and the substantiating Raw Data is to be reviewed for technical content (checked by) and for compliance with in-house requirements and appropriateness of the conclusion (approved by) before being submitted for approval by the Validation Committee.

Quality Audit Report

A Quality Audit is to be conducted for any new process line being introduced for the first time prior to Performance Qualification.  Any Deviation Report (DR) rose during the audit need to be reviewed and have an agreed problem analysis and Corrective and Preventative Action plan assigned to it.

Validation Report

On completion of all the Performance Qualification tests a report listing all the qualification tests conducted during the Validation Programme with a conclusion is to be written by an assigned Validation Team Member.  This report and the substantiating Raw Data is to be reviewed for technical content (checked by) and for compliance with in-house requirements and appropriateness of the conclusion (approved by) before being submitted for approval by the Validation Committee.

6. Acceptance Criteria Guidelines

Specific acceptance criteria for validation projects is determined during the development phase and documented in the Validation Plan.

6.1. General Criteria for Installation Qualification

The IQ must demonstrate that the system has been designed, supplied and installed in accordance with design specifications and drawings, the supplier’s recommendations and organization’s in-house requirements.

Acceptance criteria for all IQ protocols will be based on the following requirements.  The applicability of each criterion will be assessed during the protocol preparation stage (or in the validation master plan if a plan is to be prepared for each system or group of systems or validation discipline).

6.1.1. Documentation Package Review

The system must be supplied and installed in compliance with approved engineering design and installation drawings, specifications supplier recommendations and  in-house requirements.  As applicable, this documentation shall be included with the protocol or its storage location identified.  IQ documentation to be provided by the contractor will be identified in the protocol and reviewed for accuracy and completeness during the IQ.  The following is a list of documentation, which would typically be required to support IQ:

Equipment Design Documentation

a. User Requirement Specification

b. Design specifications & drawings

c. Process and Utility Flow Diagrams, Piping & Instrumentation Diagrams.

d. Electrical schematics/drawings

e. Factory Acceptance Test (FAT) procedure and results.

Pipework Installation

a. Pipe insulation report

b. Material Certification

c. Welder qualifications/procedures

d. Pressure test inspection report & certification

e. Automatic weld record/ inspection reports

f. Isometric drawings with welds indicated

g. Slope verification

h. Cleaning/passivation records & procedures.

Equipment Installation & Commissioning

a. Equipment insulation and label report

b. Loop check documentation

c. Commissioning Report

d. Site Acceptance Test (SAT) procedure and results

Electrical

a. Terminations (panel checkout)

b. High potential and megger test

c. Grounding test

d. MCC and motor check lists.

e. Motor rotation.

AC Installation

a. Installation of process duct work

b. Duct work leak test report

c. Installation of filters and pre-filters

d. Fan and belt installation.

Instrumentation

a. Instrument calibration records

b. Instrumentation checklists

c. Supplier installation inspections

d. Instrument data sheets.

Operating Documentation

Supplier operating & maintenance manuals.

6.1.2. Equipment & Instrument Lists

All process and ancillary equipment and instrumentation must be identified and clearly described as to vendor, model, serial number; instruments must be calibrated according to approved procedures and have calibration certificates issued.  Motors, agitators and pumps must be identified as to vendor and model, electrical requirements, power and/or capacity output.

Spare parts lists and preventative maintenance schedules must be obtained.

6.1.3. Materials of Construction & Lubricants in Potential Product Contact

Materials of construction and lubricants in potential product contact must conform to design specifications and be suitable for the intended application.

6.1.4. Utilities Verification

Utilities must be properly installed and available as specified by the manufacturer’s design specifications and in-house requirements.

6.1.5. SOP Verification

SOPs shall be listed and verified to be in place.  SOPs should accurately describe the equipment setup and operation.

SOPs must be available to support the satisfactory operation, maintenance, cleaning and change control of the equipment.

Training records should be available for all personnel operating the machinery.

6.1.6. Acceptance

All documentation identified as required in the approved protocol must be obtained and filed in the established Validation Filing System. See section 5.2

Change control on all equipment and systems must be instituted in the facility from the start of IQ either using manufacturer’s or in-house Change Control procedures.  Any changes during OQ to system turnover must be made in accordance to the in-house Change Control Procedure.

All discrepancies must be satisfactorily resolved prior to system acceptance.

6.2. General Criteria for Operational Qualification

The OQ must demonstrate that the system operates as intended throughout the specified design, operational or approved acceptance range of the equipment, as applicable.

Acceptance criteria for all OQ protocols will be based on the following requirements.

6.2.1. Record of Test Instrumentation

Indicating and recording Instrumentation utilised to obtain test data required by the protocol must be calibrated according to approved procedures and traceable ISO, AS or British standards and have calibration certificates.

6.2.2. Local Control Panel Checkout

Local control panels must function in accordance with the manufacturer’s specifications and in-house requirements.

6.2.3. Verification of Alarms & Interlocks

Alarms and interlocks must function in accordance with design and manufacturer’s specifications and as required by in-house SOPs.

6.2.4. Verification of Specific Functionality across Operating or Selected Range

Critical parameters and required functionality must be identified based on the User Requirements Specification and GMP requirements.

The equipment or system must demonstrate functionality as specified in the supplier’s literature and as required by in-house SOPs throughout its design range, normal operating range or predetermined acceptance range as applicable for each critical parameter identified.

If time is identified as a critical parameter, the predetermined acceptance range will be determined based on the maximum batch run duration.

The equipment or system must maintain critical operating parameters within design or performance specifications, as specified by the manufacturer’s documentation or the applicable in-house SOP.  If literature is not available, then in accordance with expected states as specified in this document and the protocols.

All process equipment operational settings must be documented during the validation studies.

6.2.5. Acceptance

All documentation identified as required in the approved protocol must be obtained and filed in the established Validation Filing System. See section 5.2

Any changes during OQ to system turnover must be made in accordance to the in-house Change Control Procedure.

All discrepancies must be satisfactorily resolved prior to system acceptance.

6.3. General Criteria for Performance Qualification

The PQ must demonstrate that the system can consistently achieve and maintain its performance specification at a pre-determined operating point.

Acceptance criteria for all PQ protocols will be based on the following requirements.

6.3.1. Record of Test Instrumentation

Indicating and recording Instrumentation utilised to obtain test data required by the protocol must be calibrated according to approved procedures and traceable to ISO, AS or British standards and have calibration certificates.

6.3.2. Verification of Required Performance Attributes

All process equipment operational settings must be documented during the validation studies.

Critical parameters and required functionality identified at the OQ stage must be demonstrated at the normal operating point during 3 consecutive production runs.

The PQ must demonstrate that the integrated manufacturing process can consistently produce a product of predetermined quality.

The effectiveness of key processing steps will be monitored and the critical data collected will be reviewed and compared to specified parameter values.  Key parameter trends and variations must be analysed to assure proper process performance.

The actual operating range must be identified, monitored and documented as part of the PQ.

For process systems, all product specifications for acceptance criteria must be listed in the protocol or referenced to product specifications or manufacturing formulae.

For process systems, the volumes and yields obtained at the various process steps must be documented as part of the manufacturing procedures.  In-process tests required by the SOPs must be within established specification range.

For process systems, product produced during 3 successive batch runs must meet all quality control specifications for in-process and final product testing.

All raw materials utilised must be obtained from approved suppliers and must meet all quality control specifications.

All process equipment operational settings must be documented.

6.3.3. Acceptance

All documentation identified as required in the approved protocol must be obtained and filed in the established Validation Filing System. See section 5.2

Any changes during PQ to system turnover must be made in accordance to the in-house Change Control Procedure.

All discrepancies must be satisfactorily resolved prior to system acceptance.

6.4. General Criteria for Cleaning Validation

Cleaning Validation (CV) verifies through a test protocol that the residual limits for product carryover and microbial contamination is repeatable and consistently in compliance with the maximum allowable levels when defined cycles or procedures are completed.

Acceptance criteria for all Cleaning protocols will be based on the following requirements.

a. OQ/PQ test protocols, analysis results of samples collected.

b. Sampling procedures must be documented in relevant OQ/PQ test protocols.  Sample locations must be clearly documented.

c. Data on recovery studies must be provided, if appropriate.

d. Analytical methods must be documented and reference made to method validation.

e. All product contact parts meet applicable chemical, microbiological acceptance criteria and are visibly clean.

f. Rationale for setting acceptance criteria limits must be provided.

6.4.1. Acceptance

All documentation identified as required in the approved protocol must be obtained and filed in the established Validation Filing System. See section 5.2

Any changes to Cleaning critical parameters must be made in accordance to the in-house Change Control Procedure.

All discrepancies must be satisfactorily resolved prior to system acceptance.

Products of similar formulation are grouped for each process line.  From each of these groups a worst-case product will be calculated.  This calculation is based on the solubility of the ingredients.  The acceptance criteria are calculated based on the concentration of the most toxic product in the group.

6.5. General Criteria for Analytical Method Validation

A method is considered acceptable if:

a. Linearity of the substance assay can be demonstrated.

b. Reproducibility can be demonstrated.

c. Accuracy can be demonstrated.

d. Repeatability can be demonstrated.

e. Robustness can be demonstrated.

f. Limits of detection & limits of quantification and known impurities are identifiable.

7. A Successful Validation Programme

7.1. Documentation relating to a Validation Programme

7.1.1. Validation Master Plan

The Validation Master Plan (VMP) is a strategic document, which identifies the elements to be validated, the organisational responsibility and the documentation to be produced.  At minimum the VMP should address the following:

a. Title, statement of commitment and approval page.

b. Summary description of the project and its scope.

c. A statement of validation policy and the objectives of the validation activity.

d. References to other existing validation documents.

e. A description of the organization and responsibilities for validation.

f. The validation strategy to be adopted opposite Facilities and Systems (process equipment and services including automated systems), Materials, Quality Control, Personnel including training.

g. The intent in respect of Process Validation and Cleaning.

h. Validation for each product range.

i. The documentation management and control system to be used.

j. A description of the validation change management process.

k. An indicative relative timescale plan.

l. Clear acceptance criteria against which the outcome of the validation exercise will be judged.

7.1.2. System and Component Impact Assessment

A system /component impact assessment is a process of determining which systems and components should be subject to qualification, as part of risk – based approach to validation.

A system or component impact assessment is made by evaluating the impact that a system and components has on the quality of the product.  The system/components should be categorised as one of the following:

a. Direct Impact

b. Indirect Impact

c. No Impact

Only Direct Impact Systems and Components are subject to qualification, though all systems and components are subject to Good Engineering Practice (GEP).

Indirect Impact System /Components can affect the performance or operation of a Direct Impact System/Component and therefore:

Any interfaces need to be carefully assessed.

It should be ensured that Direct Impact System/Components could detect or prevent a product quality-threatening problem with an Indirect Impact System/Component linked to it.

In the instance when a system or component can be used as both a Direct and Indirect Impact, the requirements of the Direct Impact shall take precedence to ensure compliance to cGMPs.

The approach to the assessment will depend upon factors such complexity and novelty of each system, and the impact of each system on the product quality.

7.1.3. Validation Plan

For systems having a direct impact on product quality, a Validation Plan should be developed defining methods, acceptance criteria and relevant SOPs and responsibilities.  The programme is established before any actual validation activity is started and is approved by the Validation Committee.  Protocols are to be written and authorised to cover all aspects of the Validation Programme.

7.1.4. Design Qualification (DQ)

The purpose of the design qualification is to ensure that the design of the proposed new facility and system or equipment meets cGMP requirement and is suitable for its intended purpose.  Compliance with both the cGMP and suitability of use should be documented.  The underlying theme of assuring design compliance prior to the construction or manufacturing of the facility, system and equipment is inherently logical and avoids costly error judgement.

7.1.5. Installation Qualification (IQ) Report

The performance of inspection in order to confirm that a subject is delivered and installed properly according to the user’s specifications.

7.1.6. Operational Qualification (OQ) Test Protocols

The performance of tests to determine that the operation of a subject conforms to specifications.

Operational qualification is usually performed with ingredients, provided they reflect the actual conditions at normal processing.  The tests are to determine the limits of capability for a process within which the defined quality is achieved.

7.1.7. Operational Qualification Report

This document summarises all the tests that have been conducted as part of the Operational Qualification (OQ).  The Operational Qualification Report will stipulate the tests required to be conducted during the Performance Qualification phase.

Approval of this report by the Validation Committee signified that a provisional approval (of a maximum of 6 months duration) has been granted to enable the equipment/system to be utilised for production use.

7.1.8. Performance Qualification (PQ) Test Protocols

The Performance Qualification phase consists of the conducting of tests defined in the Validation Plan and during the Operational Qualification phase to determine if the equipment/process/system continues to operate in a reliable manner required to attain a specified quality in the process output/product.

Materials used at performance qualification should be those actually used at the normal processing.  Performance Qualification usually consists of the manufacture of three consecutive production runs that satisfy all of the acceptance criteria.

7.1.9. Validation Report

This document summarises all the tests that have been conducted as part of the Operational Qualification (OQ) and the Performance Qualification (PQ).  It addresses the requirements for the Validation programme stipulated and the Validation Plan.  Approval of this report by the Validation Committee signifies that full approval of the equipment/system for routine production use has been granted.  The Validation Report will stipulate the required Revalidation programme.

7.1.10.  Revalidation

The routine performance of tests to check that a validated subject or an element of a subject still does what it is expected to do.

7.2. Activities to be conducted during the Validation Programme

7.2.1. General Points

All Validation projects are to be logged with the Validation Department.  The Validation Department is responsible for allocating a Project Number that is to be referenced on all validation documentation.

All DQ, IQ, OQ and PQ Protocols shall define the acceptance criteria with qualification procedures, be reviewed and approved by the persons identified in the Validation Plan prior to execution.

All checks and testing must be carried out using measuring instruments that are identified and calibrated according to established methods.  All calibrations must be recorded.

Only validated test methods are to be used.

The different steps of the Validation Programme (IQ, OQ & PQ) should be followed as identified in the Validation Plan.

All qualification test results obtained during the testing must be recorded even those that did not meet the acceptance criteria.

The test results must be clearly written up and compared with the test acceptance criteria.

Results should be reviewed by the same members of the Project Team who approved the Test Protocol.

An effective change control procedure should be operational and encompass the whole project from the pre-planning stage through to the final acceptance of the process validation exercise.

7.2.2. Preparatory Work – The Validation Programme

(This is to be documented as a Validation Plan.)

Each project must have a Project Coordinator who is responsible for the completion of the validation and successful start-up of the equipment.

The Project Coordinator is assisted by a Project Team consisting of staff from Production/QA/Engineering Services/Projects/Validation (and possibly other specialists).

A Gantt chart may be prepared to list the activities, their times and their sequences.

Should pre-delivery testing be carried out (acceptance trials), the Project Team must prepare and approve the testing protocols – type of test; duration of testing; results required.

7.2.3. Installation Qualification (IQ)

Installation Qualification (IQ) is defined as a documented verification that key aspects of the installation have been checked and that the installation adheres to appropriate standards and codes (e.g. surface finish, grade of stainless steel).  Areas to be examined and documented include:

a. Performance characteristics of different sub-systems and the entire equipment according to the manufacturer or supplier.

b. Check and record the compliance of the equipment with the specified requirements (e.g. as expressed in the specification, if applicable).

c. Calibration and labelling of instruments and gauges.

d. Preparation of SOPs to draft status.
NOTE:  The SOPs may require modification during the Operational Qualification phase when more knowledge of the equipment/system is obtained.

e. Preparation of maintenance instructions.

f. Draw up a logbook for the equipment (if applicable).

g. Preparation of cleaning instructions.  Document in SOP.

h. Document location of drawings, installation schematics equipment manuals, spare parts list, etc., if they are not included as part of the Validation File.

i. Ensure all subparts of the system are identified either by labelling or on diagrams e.g. pipe weld positions, valves.

7.2.4. Operational Qualification (OQ)

The Operational Qualification (OQ) is defined as a documented verification that a system or sub-system performed as intended throughout all anticipated operating ranges or at a specified range.  OQ is intended to establish that everything works as intended, and that, e.g. pumps deliver water at appropriate rates and pressures, valves seal and open properly; alarms and other controlled devices respond appropriately, i.e. determine the process capability of the total process and if necessary sub-sections should be established and comply with agreed levels.

For each test function to be examined the following is to be documented:

a. Process description of the subsection being tested.

b. Test Objectives.

c. Results required – Acceptance criteria.

d. Test method to be used including a Sampling Plan for material to be tested.

e. Results obtained.  Raw data is filed separately and a summary of the results documented in the OQ protocol.

f. Conclusion.

g. Attachments.

Materials used in the Operational Qualification should be those to be used at the normal running of the process.

Compiling and Filing of the entire documentation.  Approval of the results of the test program.

At the conclusion of the Operational Qualification phase, the following documentation must be available:

a. SOPs for operation and cleaning.

b. Training manual or appropriate documentation.

When all the Operational Qualification tests have been conducted and results are deemed to be acceptable the information is compiled into an Operational Qualification Report.  The OQ Report is reviewed and the test results are evaluated to ensure that the proposed qualification program and requirements have been fulfilled.  This OQ Report is then reviewed for approval by the Validation Committee.

Once approval by the Validation Committee has been given a “Provisional Approval for use by Production” (with a 6 month expiry) is applied to the equipment/system/process.

7.2.5. Performance Qualification (PQ)

The Performance Qualification phase consists of additional Validation tests, or the results of extended testing may be included as part of the equipment/systems Performance Qualification.  All results obtained during the Performance Qualification must be recorded, even those not meeting the requirements.

Confirmation testing for Production Process (Process Validation)

Three consecutive successful production batches should be documented to demonstrate conformity to specification.

At the time commencing process validation, other related elements of validation should be in place:

a. Facilities, systems, services and equipment to be used should be qualified and calibrated.

b. Analytical testing methods should be validated.

c. Specifications, materials and suppliers should be established.

d. Trained personnel taking part in the validation work.

e. The rationale for commencing Process Validation prior completion of the required elements should be formally documented and approved.

7.3. Validation Report

A Validation Report must be issued by the Validation Team when specified acceptance criteria given in the protocol are met.  This report must address the Validation requirements stipulated in the Validation Plan and include references to the Qualification Tests conducted (both in the Operational and Performance Qualification stages), results and observations obtained from the testings and state the required revalidation program required.  The report is then to be reviewed by the Validation Committee (this must be within 6 months of the original Provisional Approval for use by Production).

7.4. Revalidation

Based on the validation results and the type of subject a revalidation plan must be established.  Revalidation is further required if the finding of the in-process and quality control results indicate the need.

The revalidation programme is to be included in the Revalidation Master Plan.

For critical process, Revalidation is normally carried out on an annual basis or when significant changes are made to the equipment/process, and is the subject of a separate SOP VAL-010.

If revalidation activities are not completed within the validation life of the equipment a specific temporary limited approval must be obtained from the Quality Assurance Manager to allow for the continued use of the equipment/system/process in production.

8. Revalidation Master Plan

An overall plan describing and defining the subjects for revalidation is to be prepared by the Validation Department.  The plan must include organisation and timetable for the revalidation activities.  Details are specified inSOP VAL-010.

9. EHS Aspect

Environmental, Health and Safety aspects must be considered throughout all Projects from the design phase through to handover to Production.  At the conclusion of the Operational Qualification phase, prior to approval for Production use, an EHS Audit of the Equipment/System is to be conducted (usually by the EHS Manager).  Any major deficiencies must be addressed prior to approval of the OQ phase.  All EHS Non-compliances identified are entered into the Deviation Report System, see SOP QMS-035.

10. Document Retention

All protocols, records, reports and certificates must be retained as long as the validated subject is in use plus an extra period of 6 (six) years or specified by the regulatory authority. The Validation Department is responsible for the filing. Approval to dispose validation files must be granted by the Validation Manager.

11. Summary of Changes