Effective: 22 Jun 2018 Issued: 17 May 2018 Issue: 5 SI No

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P3026 Validation Lifecycle, Issue 5 17-May-2018

Effective: 22 Jun 2018 Issued: 17 May 2018 Issue: 5 SI No: P3026

Prepared by: A. Green

Date: 17 May 2018 (DD/MMM/YYYY)

Reviewed by: G. Ostacchini Date: 17 May 2018 (DD/MMM/YYYY)

Approved by: M. Sanders Date: 23 May 2018 (DD/MMM/YYYY)

Title: Validation Lifecycle

1 Introduction

1.1 To provide an overview of the validation lifecycle and an approach to be used for the qualification of equipment and facilities, the validation of methods and processes used for the commercial manufacture of products by or on behalf of Clement Clarke International Ltd (CCI), Haag Streit UK Ltd (HSUK) and John Weiss & Son Ltd (JW).

2 Scope

2.1 This procedure applies to all equipment processes, test methods, systems and facilities which could affect the safety, effectiveness, functionality or specified requirements of the medical devices produced or the environmental, health and safety of the plant, process, work equipment or employees of CCI, HSUK and JW.

2.2 New equipment is included within the scope of this procedure.

2.3 Suppliers to CCI, HSUK and JW of critical devices or processes are required to apply the principles of this procedure but may apply appropriate procedures from their Quality Systems in place of this procedure and its sub-procedures.

2.4 Excluded from this procedure are;

2.4.1 Non GxP equipment and systems, i.e. facilities and equipment of a general nature that do not influence product conformance to specification, or operation of the QMS (e.g. general area HVAC, fire protection systems, general facility cleaning equipment, backup generators, office facilities, financial systems).

2.4.2 New Product Development (SI P0758)

2.4.3 Computer Software Validation (SI P0005)

2.4.4 EO Sterilization and Revalidation Procedure (P3195)

3 Definitions

3.1 Area Supervisor (Process Owner)

The person with responsibility for the manufacture or other processing (e.g. testing) of product utilizing the process or equipment. It is the process owner’s responsibility to ensure that the equipment is qualified and validated appropriately.

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3.2 Site Validation Listing

Listing of Qualifications/Validations. The listing identifies the equipment/facility/system, the process(es)/test(s) for which it is used and the Process Owner (by role or position). All Validation documentation (including Verified processes) should be listed together with their date of approval. Changes and updates to the validated status should be added as they occur, and equipment/facilities that have been decommissioned shall have the date of decommissioning added.

3.3 Validation

Confirmation, by examination and provision of objective evidence, that the particular requirements for a specific intended use can be continuously fulfilled.

3.4 Process Validation

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 characteristics.

3.5 Verification

Confirmation by examination and provision of objective evidence (i.e. documentation) that the specified requirements have been fulfilled.

3.6 Verified Process

A process, the outputs of which are verified, by a means independent of the process, for every unit produced or potentially affected by the process.

In this context, process outputs are all of those product characteristics or features that are produced or potentially affected by the process.

3.7 Equipment Qualification

Establishing confidence that the process equipment and the ancillary systems are suitable for their intended use and are capable of consistently operating within established limits and tolerances.

3.8 User Requirement Specification (URS)

A document that defines the process or equipment’s intended purpose, by describing the intended use; the intended users; the intended environment of use; product requirement constraints; and the user’s needs, wants and preferences for process/equipment operation, safety and effectiveness.

User requirements are stated in the users’ language, and describe the minimum quality, regulatory, safety and performance requirements for the process or equipment. Each requirement must be written as a single uniquely identifiable sentence that is measurable as Validation or Qualification testing will normally use this document as a source of input requirements.

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3.9 Design Qualification (DQ)

Establishing by documented evidence that all of the specified requirements have been, or can be, achieved by the proposed design of the equipment or process. Typically the DQ will utilize the suppliers Functional Design Specifications (FDS), Process & Instrument Drawings (P&ID’s) and equipment layout drawings to review the suppliers’ response against the URS.

3.10 Factory Acceptance Test (FAT)

Tests carried out in accordance with documented requirements on the process or equipment prior to shipment to verify that it conforms to the User Requirements.

At this stage of the Validation process, safety and quality critical items should be examined and evaluated. FAT does not need to address all requirements specified in the URS.

3.11 Installation Qualification (IQ)

Establishing by documented evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturers approved specification and or Clement Clarke/Haag Streit’s URS, and that the recommendations of the supplier of the equipment are suitably considered.

When validating existing equipment for which original equipment specifications may not exist or are no longer relevant, the Installation Qualification shall be limited to recording the as installed status ensuring that current requirements for product quality and EHS are met and that procedures for maintenance and calibration are in place.

3.12 Operational Qualification (OQ)

Equipment (OQ-E). Establishing by documented evidence that the equipment operates in the specified manner and over the required ranges. It also ensures that the equipment interfaces (indicators, controls, alarms and limits) operate accurately as specified.

Process (OQ-P). Establishing by documented evidence that the process, when operating at the process control limits, and under the greatest allowable challenge conditions, the process results in product that meets all predetermined requirements.

3.13 Performance Qualification (PQ)

Establishing by documented evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements.

3.14 Embedded Software

Software that is an integral part of production equipment. Usually it is factory installed and can only be accessed and/or changed by the manufacturer. Systems may be configurable by the input of parameters but the software code is not accessible to the user for modification.

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3.15 Part Specific Program (PSP)

A set of logic instructions for the control of a piece of equipment to produce, process or verify a specific part number, or a set of part numbers. The instructions typically invoke generic sub-programs within the controller of the equipment in a sequence and to an extent that produces the specific effect required for the part. Typically the equipment used is able to produce or process multiple part numbers by the application of the application of the appropriate Part Specific Program. The Part Specific Programs may be written and stored on the process equipment or on other associated systems to be uploaded to the equipment when required.

3.16 Mobile Equipment

Equipment that is intended to be operated in more than one location and is not connected to any utility or other equipment in a permanent manner.

3.17 Line Addition

A new product (new catalogue number) which is in addition to an existing range of products, it is produced in the same manner as the existing range and which shares the general features of the range, it differs only in a limited respect, typically size. The new product is considered to lie WITHIN the limits of the existing range (e.g. a new size #5 is introduced to a range comprising sizes #2, #4, #6 & #8).

3.18 Line Extension

As Line Addition, except that the new part is considered to lie OUTSIDE the existing range (e.g. a new size #10 is introduced to a range comprising sizes #2, #4, #6 & #8).

3.19 Protocol

A document that states how a validation or qualification will be conducted, including manufacturing equipment and materials, test conditions, process parameters, test/verification means, test repetitions, acceptance criteria, and test documentation requirements.

3.20 Deviation

During protocol execution, the failure to meet predefined acceptance criteria or follow a predefined verification activity as specified.

3.21 Worst Case

A set of conditions, or process parameters, encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which, in combination with product specification or attributes at their limits, pose the greatest chance of process or product failure / defect when compared to ideal conditions.

Such conditions represent the greatest challenge to the process in normal operation.

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3.22 Process Window

The set(s) of input process parameters (controlling settings) which in combination represent the boundaries of conditions normally allowed in routine production.

3.23 Measurement System Analysis

Evaluation of the quality of measurement system to understand the degree of error involved in measuring a given parameter. The measurement system involves the combination of operations, procedures, gauges, instruments, environmental conditions, people and software.

3.24 Gauge Repeatability & Reproducibility (R&R)

A study to determine the error associated with measuring variables. This error is comprised of Repeatability & Reproducibility.

Repeatability: Evaluation of the variation of measurement when the same person measures the same product a number of times with the same means. The repeatability is sometimes called Equipment Variation (EV).

Reproducibility: Evaluation of the variation of measurement between several different people measuring the same product with the same means and under the same conditions. Reproducibility is sometimes called Appraiser Variation (AV).

3.25 Design of Experiments (DoE)

DoE is a systematic approach to the investigation of a system or process. A series of structured tests are designed in which planned changes are made to the input variables of a process or system. The effects of these changes on a predefined output characteristic are then assessed.

3.26 Capability / Process Capability

Process capability is a measure of how capable the process is of producing product meeting specified requirements. It is a measure of the actual variation in that product characteristic compared to the product specifications. Indices are used to report Process Capability – these are termed Pp, Cp, and Ppk, Cpk, depending on how the data is collected. These indices are measures of the actual process variation (long term and short term) in relation to the process output specification tolerance.

3.27 Essential Attribute

Any attribute that can affect the safety, quality, performance or efficacy of the product. Essential attributes can include, but are not limited to Critical Quality Attributes (CQA), Critical Process Parameters (CPP), and Risk Analysis Outputs.

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3.28 Critical Quality Attribute (CQA)

A physical, chemical, biological or microbiological property or characteristic that shall be within an appropriate limit, range or distribution in order to ensure the desired product quality.

3.29 Critical Process Parameter (CPP)

A process parameter whose variability has an impact on critical quality attributes.

3.30 Designated Reviewer

A person nominated by the Division and trained in the GMP requirements for validation documentation. Reviews validation documentation in accordance with Company policy.

4 Internal and External Documents

4.1 Internal Document References

• P0005 Computer Software Validation (CCI)

• P0758 New Product Development

• P0007 Calibration System

• P0042 Design or Process Change Control

• P3266 Logistics Procedure

• P0766 Control of Internal Documents

• P3026F(1) Validation Master Plan Template

• P3026F(2) User Requirement Specification Template

• P3026F(3) Design Qualification Template

• P3026F(4) Moulding Engineering Study Protocol / Template

• P3026F(5) Assembly Engineering Study Protocol / Template

• P3026F(6) Installation Qualification Template

• P3026F(7) Operational Qualification Template

• P3026F(8) Factory Acceptance Testing Template

4.2 External Document References

• ISO 13485:2012

• ISO 13485:2016**

** 3 year transition period

5 Responsibilities

5.1 Process Owner

• Overall responsibility for the equipment, the process and the validation.

• Nominates the Project team Leader.

• Reviews the scope of the VMP and planned approach.

• Reviews and approves the completed validation package.

• Accountable for review and update of associated procedures.

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5.2 Change Owner/Project Team Leader (may also be Process Owner)

• Defines the scope of the validation, in terms of the equipment, processes and product.

• Nominates validation team.

• Determines what other support areas will be involved.

• Accountable for execution and approval of protocols and report(s).

• Accountable for execution and completion of deviations.

5.3 Production Engineering

• Defines qualification/validation steps, writes the VMP and circulates for approval, pre and post execution.

• Ensures the qualification/validation meets the required standards.

• Writes the test protocols, deviation plans and final report.

• Executes test protocols.

• Ensures all documentation is complete and acceptable for approval.

• Ensures appropriate resolution of deviations.

• Ensures consistency of validation approach across site.

5.4 Quality Manager

• Accountable for updates to the Site Validation Listing.

• Accountable for the Issuing of document numbers and maintains the individual validation records in line with record retention requirements.

• Approves deviation plans and verifies completion.

• Acts as Designated Reviewer; to ensure the qualification/validation meets the required standards.

5.5 Environment, Health & Safety Representative

• Reviews and approves EHS related protocols.

• Ensures deviations relating to EHS issues are appropriately closed.

6 Method

**Note: please use templates mentioned in section 4.1.

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6.1 If the outputs of a manufacturing process can be directly measured, there is no need to validate because the measurements will provide verification of the process.

6.2 It is necessary to define what the process is and what results it should provide. The process may require operation of certain machinery with variable inputs and desired outputs. These details are to be described in a Validation Master Plan (VMP) which sets out the stages for the validation.

6.3 The VMP must provide a definition of the process, including inputs and outputs, and describe a procedure designed to validate the ideal process window using the four major stages; Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).

6.4 Design Qualification (DQ)

6.4.1 The DQ should be used as a tool to confirm that all requirements have, or can be, achieved by the proposed design and as a plan to document where (IQ, OQ or PQ) the requirements/functions will be qualified.

6.4.2 The DQ will be in tabular form, with the requirements and paragraph ref No’s from the URS in the left hand columns. Other columns should be used to cross reference the designer/suppliers functional design specification(s) and schematic diagrams to confirm compliance with the URS.

6.4.3 The table will also include columns detailing which stage of the qualification will be used to test each function.

6.5 Installation Qualification (IQ)

6.5.1 The IQ should describe the details of the equipment being used in the process to be validated i.e. the input materials, ambient conditions, and the machinery/tools used to perform the processing (including information about type, serial number, manufacturer, services, documentation, minimum and maximum operating conditions).

6.5.2 The IQ should confirm that the equipment meets all necessary standards (e.g. machinery safety, build standards, etc).

6.5.3 The IQ should confirm that there is sufficient documentation/information available to allow proper and safe operation (e.g. maintenance and operation manuals, accurate drawings and schematics etc).

6.6 Operational Qualification-Equipment (OQ-E)

6.6.1 The OQ-E should be designed to provide documented evidence that the equipment used in the process operates as expected, as defined by the URS and/or process requirements.

6.6.2 All alarms, interlocks, ranges and functions (e.g. temperature, speed, pressure should be tested).

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6.6.3 The OQ-E should confirm that the equipment is safe to operate and that it meets the requirements of legislative guidance (e.g. Provision and Use of Work Equipment Regulations).

6.6.4 The OQ-E should confirm that all necessary support documentation is in place and approved (e.g. maintenance and calibration schedules, SOP’s, Health & Safety assessments etc). It should also confirm that appropriate training is in place for Operatives and Maintenance personnel.

6.7 Operational Qualification-Process (OQ-P)

6.7.1 The OQ-P should be designed so as to provide documented evidence to define the “process window.” This could start with the machinery manufacturers suggested operating parameters or parameters defined in product development trials. Controlled adjustment of these parameters to define upper and lower limits for the process that will ensure any unit manufactured within these parameters will be fit for purpose.

6.7.2 Consideration should also be given to variations in input material.

6.7.3 For every chosen combination of operating parameters, an input must be provided. It may be necessary to provide identical samples of input in order to give sufficient quantities of output for analysis.

6.7.4 Analysis of outputs should include any checks normally used in production, but consideration should also be given to additional testing to verify fitness for purpose.

6.7.5 The analysis of all aspects of performance should be used to determine the operating conditions which will consistently produce outputs of the correct quality.

6.8 Performance Qualification (PQ)

6.8.1 The PQ should be arranged as a normal production run, so that the entire process can be seen to be working properly and consistently

6.8.2 A statistically significant sample of the output should be taken to verify the process consistently produces product meeting its full release specification (P3266 Logistics).

6.9 Deviations

6.9.1 During execution any deviation from the pre-approved protocol must be documented as a deviation (e.g. unexpected or unacceptable results, errors in the protocol, adjustments, breakdown or other unscheduled event).

6.9.2 Each deviation form shall be numbered and reference the relevant section of the

protocol.

6.9.3 The deviation description and the corrective action response shall be determined by the individuals executing the protocol in conjunction with the relevant technical experts.

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6.9.4 The corrective action results (e.g. implementation and demonstration of effectiveness, including re-test where appropriate) shall be reviewed and approved upon completion.

6.10 Periodic Review

6.10.1 All validation exercises should be subject to periodic review, this should be either time based (e.g. every three years) or after changes to equipment, process or input materials, (P0042 Design or Process Change) if changes occur sooner than the selected time interval.

6.10.2 Each change should be assessed for impact on the existing validated process. The assessment should be documented in the change request form.

6.10.3 Minor changes can be bundled together and assessed for impact at the end of the time interval.

6.11 Document Retention Validation documents should be retained in accordance with P0766; Control of Internal Documents

“Quality Records”

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7 Revision History

Prepared by: Reviewed by: Approved by: Revision version:

Date: Reason for change:

A.Green N/A G. Ostacchini 1 12 Jan 2012 Creation of document

K. Osborne

G.Ostacchini/ A.Green

M.Sanders 2 09 Aug 2016

Revision of procedure, update to new format. Update to related documents. Addition of 2.2 new equipment/plant as per CAPA C15-0126

A. Green G. Ostacchini M. Sanders 3 20-Feb-2017

Periodic review for CAPA C17-003. Replaced title at §5.3

O.Edoo G. Ostacchini / A.Green

M. Sanders 4 31-Oct-2017

Section 4.1 update with new validation templates and protocols. Section 6 updated to refer to section 4.1

A. Green G. Ostacchini M. Sanders 5 17-May-2018

Added internal document ref to P0766, & added §6.11 Document

Retention. Addition of 2.4.4

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8. Appendices

8.1 Example IQ/OQ Protocol

Device No. Function; Protocol Ref No.

Pre-requisites; i.e. machine switched on, temperature sensor cold.

Objective; Clearly describe the objective of the test i.e. Confirm temperature sensor xyz is correctly installed

Method; Clearly describe the test method i.e. remove the sensor and hold the probe end of the sensor, watch the display and confirm a temperature display increase

Acceptance Criteria; Clearly describe the acceptable result i.e. the temperature display increases

Results

Results acceptable Yes/No

Acceptance Criteria met, pass/fail

Tested by; Print …………………………………………………………….

Date;

Signed; ………………………………………………………………..

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8.2 Example IQ/OQ Report

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