Validation - Concept and Procedure

Department	Validation/Technical Services		Document no	VAL005
Prepared by:		Date:		Supersedes:
Checked by:		Date:		Date Issued:
Approved by:		Date:		Review Date:

Document Owner

Validation Manager

Affected Parties

All Validation, Technical Service, Operations, Quality Assurance, Engineering and Project staffs involved in validation projects.

Purpose

To describe general Validation concepts and practices, to describe the way processes and systems must be qualified/validated and the confirmatory documentation required.

Scope

This SOP describes general concept and procedure used to validate industrial processes and systems and the responsibility of different project teams during validation projects.

Definitions

Validation	Validation is the process of establishing a high degree of assurance that a specific process, activity or system, will consistently and reliably produce a product meeting predetermined specifications and quality characteristics. The supporting evidence is required to be appropriately documented. Processes are considered to be “validated” and the systems that perform the actions within the process are considered to be “qualified”.
Design Qualification (DQ)	Documented verification that the proposed design of the facility, equipment, or systems is suitable for intended purpose
Installation Qualification (IQ)	Documentation of the installation of a piece of equipment to confirm it conforms to the specifications of the equipment manufacturer and inhouse requirements
Operational Qualification (OQ)	Documented verification that all functional aspects of the facility or system which affects product quality, performs as intended throughout all anticipated operating range. Usually performed using Inactive ingredients
Performance Qualification (PQ)	Documentation that the process or product conforms to expectations as determined through independent parameter measurement and/or intensive sampling or challenge. Materials used in the performance qualification should be those actually used in the normal processing. Usually performed on the first three batches of product made by the new equipment/process.
Process Validation	Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality.
Validation Plan	An outline of the Validation Project listing a written plan, the test methodology, the acceptance criteria, responsibilities, timeframes etc.
Validation Master	A Management tool designed to overview the Validation Process for a new facility or

1. A Successful Validation Programme ................................................................................................ 17
2. Revalidation Master Plan................................................................................................................. 22
3. EHS Aspect..................................................................................................................................... 22
4. Document Retention........................................................................................................................ 22
5. Summery of Changes...................................................................................................................... 22

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 predetermined 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:

• Skills needed
• Facilities needed
• Equipment and technology required
• Suppliers/contractors and materials
• Capital funds needed
• 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, crossfunctional 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:

• Quality Assurance Manager
• Validation Manager
• Operations Manager.

Title: Validation – Concept and Procedure

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 prequalification 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 predetermined quality. The performance specification will reference process parameters, inprocess and product specifications. PQ requires three product batches to meet all

acceptance criteria for inprocess 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 predefined 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 rationa le 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 w ill consistently function according to their predetermined specifications and quality attributes, throughout their lifecycle. Important aspects of this validation approach are the formal management of design (through a specification process); systemquality (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.

Title: Validation – Concept and Procedure

1. A Validation Project Log Form (Form375)
2. A Validation Plan
3. Installation Qualification Report/s
4. A series of Operational Qualification Test Protocols and Raw Data Results (as defined in the Validation Plan.
5. An Operational Qualification Report
6. EHS Report
7. Quality Audit Report (for new process lines)
8. A series of Performance Qualification Test Protocols and Raw Data Results (as defined in the Validation Plan and during the OQ phase).
9. A Validation Report
10. Discrepancy Forms
11. System SOPs (a list of SOP’s relating to the process)
12. System Changes (Change Request Forms, see SOP QMS030).

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.

1. 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.
2. 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.
3. 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 QMS030.

1. Numbering System of Validation Documents
1. The Project Coordinator is responsible for registering the Validation Project with the Validation Dept by filling out a Validation Project Log Form (Form375).
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:
1. Document Change Control & Revision History
1. A revision of draft will be assigned to all first draft documents during the comments stage. The Revision Number w ill 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.
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.
2. 5.3.2. 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.
1. Document Approval

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

Document	Prepared by	Checked by	Authorised by	Approved by	Approved by
Validation Plan	Project				Validation
	Coordinator				Committee
Design	Project	Team Member	Validation or	Validation or
Qualification	Coordinator/		QA Mgr.	QA Mgr.
	Manager
IQ Report	Engineering	Engineering			Validation
	Services &/or	Services &/or			Committee
	Projects	Projects
OQ Test	Team Member	Team Member	Validation or
Protocols			QA Mgr.
Completed OQ	Team Member	Team Member		Validation or
Tests				QA Mgr.
OQ Report	Team Member	Team Member		Validation or QA Mgr.	Validation Committee
PQ Test	Team Member	Team Member	Validation or
Protocols			QA Mgr.
Completed PQ	Team Member	Team Member		Validation or

Standard Operating Procedure Title: Validation – Concept and Procedure

5.9. Figure 1 – Flowchart for Validation Stages

contractor will be identified in the protocol and review ed 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

• User Requirement Specification
• Design specifications & drawings
• Process and Utility Flow Diagrams, Piping & Instrumentation Diagrams.
• Electrical schematics/drawings
• Factory Acceptance Test (FAT) procedure and results.
• Pipework Installation
• Pipe insulation report
• Material Certification
• Welder qualifications/procedures
• Pressure test inspection report & certification
• Automatic weld record/ inspection reports
• Isometric drawings with welds indicated
• Slope verification
• Cleaning/passivation records & procedures.
• Equipment Installation & Commissioning
• Equipment insulation and label report
• Loop check documentation
• Commissioning Report
• Site Acceptance Test (SAT) procedure and results
• Electrical
• Terminations (panel checkout)
• High potential and megger test
• Grounding test
• MCC and motor check lists.
• Motor rotation.
• AC Installation
• Installation of process duct work
• Duct work leak test report
• Installation of filters and prefilters
• Fan and belt installation.
• Instrumentation
• Instrument calibration records
• Instrumentation checklists
• Supplier installation inspections

Title: Validation – Concept and Procedure

6.2.2. Local Control Panel Checkout

• Local control panels must function in accordance with the manufacturer’s specifications and inhouse 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 inhouse 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 inhouse 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 inhouse 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 inhouse 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 predetermined 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.

Products of similar formulation are grouped for each process line. From each of these groups a worstcase 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:

• Linearity of the substance assay can be demonstrated.
• Reproducibility can be demonstrated.
• Accuracy can be demonstrated.
• Repeatability can be demonstrated.
• Robustness can be demonstrated.
• 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:

• Title, statement of commitment and approval page.
• Summary description of the project and its scope.
• A statement of validation policy and the objectives of the validation activity.
• References to other existing validation documents.
• A description of the organization and responsibilities for validation.
• The validation strategy to be adopted opposite Facilities and Systems (process equipment and services including automated systems), Materials, Quality Control, Personnel including training.
• The intent in respect of Process Validation and Cleaning.
• Validation for each product range.
• The documentation management and control system to be used.
• A description of the validation change management process.
• An indicative relative timescale plan.
• 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:

Title: Validation – Concept and Procedure

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 preplanning 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 startup of the equipment.

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:

• SOPs for operation and cleaning.
• 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:

• Facilities, systems, services and equipment to be used should be qualified and calibrated.
• Analytical testing methods should be validated.
• Specifications, materials and suppliers should be established.
• Trained personnel taking part in the validation work.
• 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 inprocess and quality control results indicate the need.

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

Form370 Issue date:

Validation Discrepancy Form

(Ref. SOP VAL005, VAL010)

Project Name:		Project No:
Protocol No:

Discrepancy Description:

Sign: Date:

Change Request raised: Yes / No (if yes) Change Request No.:

Sign: Date:

File Location: Date Printed: