VALIDATION

1. Purpose

This document covers the process for Validation of processes, products, software and sterilisation and sterile barrier systems in compliance of ISO 13485.

 2. Approval

(Version at end of page)

Signed V8 RB 15.07.2024

3. Scope

The process covers all documents and process and products as defined in the Standard of Procedure. 

4. Responsibilities

Approval: Author of the document, Marelize Robertson

Changes: Author of the document, Rachel Belcher 

5. Definitions

Protocol - the defined plan for the scope, responsibilities, activities and records of the validation 

Software - consists of information and is generally intangible and can be in the form of approaches, transactions or procedures.

Hardware - is generally tangible and its amount is a countable characteristic. Processed materials are generally tangible and and their amount is a continuous characteristic. Hardware and processed materials often are referred to as goods.

Installation Qualification (IQ) - The installation qualification demonstrates that the sterilisation equipment and any ancillary items have been supplied and installed in accordance with their specification.

Operational Qualification (OQ) - The operational qualification demonstrates that the installed equipment is capable of delivering the specified process within defined tolerances.

Performance Qualification (PQ) - The performance qualification demonstrates that the equipment consistently operates in accordance with predetermined criteria and that the process produces product or output to the required specification

Qualification - Action of proving that any equipment works correctly and actually leads to the expected results. The word validation is sometimes widened to incorporate the concept of qualification.

Calibration - Activity of verifying the accuracy of a test equipment to SI standards and /or bring the test equipment back to accuracy

Verification - checking compliance to a requirement or specification

Validation - Action of proving, in accordance with the principles of Good Manufacturing Practice, that any procedure, process, equipment, material, activity or system actually leads to the expected results (see also qualification).

6. Abbreviations

SOP – Standard Operating Procedure

QMS – Quality Management System

PARA - Preventive Action Risk Assessment

NCCA - Non-Conformance Corrective Action

SHEQ - Safety, Health, Environment and Quality

7. References

ISO 13485 clauses 4.1.6 & 7.5.6 & 7.6

Procedure for Preventative, Corrective Action and Handling of Non-Conforming Product

8. Procedure

Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded.

When any new manufacturing formulation or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.

Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.

Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.

Responsibilities are defined in the protocol

8.1. Responsibilities

The Initiator is responsible for ensuring the protocol is followed.

All department representatives for departments involved are responsible for ensuring that relevant details and/or data required in the Protocol Procedure are documented, signed and completed

8.2. Types of Validations

Protocols, not limited to or as applicable, are to be drawn up for the following :

Process Validations - Change Control

 - New Products

 - Reformulation

Cleaning Validations - All Machines  (Manufacturing and Packaging)

Machine Validations - New Equipment (Sterilisers)

Equipment Qualification - Machine Adjustments / Modifications

Material Validation - Raw and Packaging (sterile barrier systems)

Quality Control Validation - Test methods

Click for Validation Protocol FORMAT

8.3. Process

CLICK refer flow diagram

Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated.  Staff taking part in the validation work should have been appropriately trained.

Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner.

8.3.1. Documentation

A written protocol is prepared and specifies how qualification and validation will be conducted.  (the format will follow the contents of the first document approved)

The Initiator is responsible for ensuring the protocol is followed.  However, all department representatives for departments involved are responsible for ensuring that relevant details and/or data required in the Protocol Procedure are documented, signed and completed.

The protocol is reviewed and approved and specifies critical steps and acceptance criteria.

A report that cross-references the qualification and/or validation protocol is  prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies.

Any changes to the plan as defined in the protocol are documented with appropriate justification.

After completion of a satisfactory qualification, a formal release for the next step in qualification and validation is made as a written authorisation.

8.3.2. Change Control 

Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process.  Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.

All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted.  The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis.  The need for, and the extent of, re-qualification and re-validation should be determined.

8.3.3. Re-validation

Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfills the need for re-validation

8.3.4. Qualification

8.3.5. Design Qualification

(Only for new equipment/ process where there is a design feature) 

The first element of the validation of new facilities, systems or equipment is design qualification (DQ) and compliance of the design with GMP is verified against the User Requirement Specification (USR) and documented in a report

8.3.6. Installation Qualification

• installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications;

• collection and collation of supplier operating and working instructions and maintenance requirements;

• calibration requirements;

• verification of materials of construction.

Installation qualification (IQ) is performed on new or modified facilities, systems and equipment and includes;

8.3.7. Operational Qualification

• tests that have been developed from knowledge of processes, systems and equipment;

• tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions.

• The completion of a successful Operational qualification allows the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. 

• OQ permits a formal "release" of the facilities, systems and equipment.

Operational qualification (OQ) follows Installation qualification and includes;

8.3.8. Performance Qualification

• tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment;

• tests to include a condition or set of conditions encompassing upper and lower operating limits.

Performance qualification (PQ) follows  successful completion of Installation qualification and Operational qualification and includes 

Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ.

8.3.9. Qualification of established (in-use) facilities, systems and equipment

Evidence is documented in the report to support and verify the operating parameters and limits for the critical variables of the operating equipment.  Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.

8.3.10. Process Validation

The requirements and principles outlined in this procedure cover the initial validation of new processes, subsequent validation of modified processes and re-validation.

Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation).  In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation).  Processes in use for some time should also be validated (retrospective validation).

Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated.  Staff taking part in the validation work should have been appropriately trained.

Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner.

8.3.11. Prospective Validation

• short description of the process;

• summary of the critical processing steps to be investigated;

• list of the equipment/facilities to be used (including measuring / monitoring / recording equipment) together with its calibration status

• finished product specifications for release;

• list of analytical methods, as appropriate;

• proposed in-process controls with acceptance criteria;

• additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate;

• sampling plan;

• methods for recording and evaluating results

• functions and responsibilities;

• proposed timetable.

Prospective validation should include, but not be limited to the following:

Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions.  In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process.

Batches made for process validation should be the same size as the intended industrial scale batches.

If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and (where applicable) the marketing authorisation.

8.3.12. Concurrent Validation

In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts.

The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel.

Documentation requirements for concurrent validation are the same as specified for prospective validation.

8.3.13. Retrospective Validation

Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment.

Validation of such processes should be based on historical data.  The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.

The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results.

Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency.  Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process.

For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified.

8.3.14. Cleaning Validation

Cleaning validation is performed in order to confirm the effectiveness of a cleaning procedure.  The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination is based on the materials involved after review of the material specification and Material Safety Data Sheet (MSDS) and the limits must be achievable and verifiable.

Validated analytical methods having sensitivity to detect residues or contaminants are to be used.  The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.

Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts.  

The intervals between use and cleaning as well as cleaning and reuse should be validated.  Cleaning intervals and methods should be determined.

For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes.  A single validation study utilizing a “worst case” approach can be carried out which takes account of the critical issues.

Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

"Test until clean" is not considered an appropriate alternative to cleaning validation.

Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.

8.3.15. Computerised Systems

Where a computerised system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance.

Consideration should be given to the risk of losing aspects of the previous system by reducing the involvement of operators.

It is essential that there is the closest co-operation between key personnel and those involved with computer systems.  Persons in responsible positions should have the appropriate training for the management and use of systems within their field of responsibility which utilizes computers.  This should include ensuring that appropriate expertise is available and used to provide advice on aspects of design, validation, installation and operation of computerised system. 

The extent of validation necessary will depend on a number of factors including the use to which the system is to be put, whether it is prospective or retrospective and whether or not novel elements are incorporated.

Validation should be considered as part of the complete life cycle of a computer system.  This cycle includes the stages of planning, specification, programming, testing, commissioning, documentation, operation, monitoring and changing

8.3.16.  Responsibilities of the Validation Team

The activities and responsibilities for the validation team members, as applicable,  are described below:

Validation Leader

1. Compiles the protocols for approval. 

2. Collects the data, compiles the relevant reports.

3. Circulates the completed report for review and final approval.

4. Reports on adherence to planned activities to all team members on ongoing / adhoc basis.

5. Preparation and follow-up on the time plan and communication to the client

6. To manage any change control of documents, drawings, specifications etc

Engineer

1. Assures adequate resources are available to ensure qualifications and validation activities are executed in accordance with the approved protocols.

2. Approves the qualification and validation protocols for implementation.

3. May collect the data and participates in the compilation of the validation reports.

4. Reviews completed qualification and validation protocols for final approval.

5. Management / Department heads

6. Assures adequate resources are available to ensure qualifications and validation activities are executed in accordance with the approved protocols.

7. Accepts the protocols for implementation.

8. Implements and concludes the tests and reports the results

9. Collects the data, participates in the compilation of the validation reports.

10. Reviews completed qualification and validation protocols for final approval

Responsible Person

1. Review and approves the protocols for implementation.

2. Reviews the data and makes recommendations on deviations and compliance with the protocols.

3. Approves the final qualification and validation reports.

8.3.17.  Protocol Format

refer Google Folder - Validation for the set format for protocols and report that may change in format depending on product, process or activity 

9. Risk Based Approach

In the event of non-compliance follow SOP Non-Conformance Corrective Action.

The Risk Assessment to is found in SOP Preventative Action Risk Assessment refer Document.

9.1. Trend Analysis and Continual Improvement

The analytical reviews of internal audits, and any other quality related matters, are reported to management and as part of the input from Data Analysis to management review

The Trend Analysis may identify any potential and recurring incidents, where corrective action must be reported at the management review to facilitate continual improvement.

10. Revision History

Revision 8; 15.07.2024 - RB - Change over to SharePoint Site

Revision 7; 14.10.2021 - MR - Updated responsibilities

Revision 6; 05.08.2021 - MR - Reviewed

Revision 5, 24.06.2021 - TNA - New format with Approval, Scope, Responsibilities and revision history added and new google site format.  Amending Links and forms  

Revision 4; Digitally signed on 10.12.2018 by TNA

Revision 1-3, unknown due to google site change to new google site

11. Records

Name Retained in Retention period Hard copies Destroyed by

Validation Protocol Management Representative 5 years Management Representative

Google Site