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20190902

Three Tiers of Medical Device Process

Validation Plans
By

Yeong-Lin Chen

Dec 20, 2018 10:57 am EST

Abstract

Based on the characteristics of medical device process validation plans, this article presents three tiers of medical
device process validation plans structure (including Site Validation Master Plan (SVMP) - Tier I, Validation Master Plan
(VMP) - Tier II, and Individual Validation Plan (VP) - Tier III), explains the rationale of the plan structure, and provides
the key content for each validation plan.

Introduction

In the medical device industry, though not directly called out as requirement by the Food and Drug Administration’s
(FDA) Quality System Regulation (21 CFR 820) and ISO 13485 (Medical Devices - Quality Management Systems
QMS), GHTF Study Group 3 - Quality Management Systems - Process Validation Guidance mentions that a good
Validation Master Plan (VMP) identifies the processes to be validated, the schedule for validations, interrelationships
between processes requiring validation and timing for revalidations, which are critical to executing a successful process
validation program. A Validation Master Plan (or equivalent document) provides medical device manufacturers with a
roadmap by outlining the process validation requirements and providing justification for these requirements. Therefore,
medical device manufacturers should understand what makes a good Validation Master Plan. The VMP allows
companies to agree upon and document an overall validation strategy, which can be provided to regulators and
auditors to serve as clear justification for the validation effort. The VMP allows medical device manufacturers to show
that they are in control of their quality system and produce devices with a focus on product quality.

However, the VMP content and structure can vary widely in the medical device industry, and organizations may utilize
VMP very differently at their respective sites. Further, alternate VMP terminology may be used in each organization.
For example, an individual validation plan is another tool that is widely used to support the planning for more complex
projects or site. In addition, while compared to pharmaceutical industry, medical device companies could face different
product customers (e.g. pharmaceutical companies as customers for combination products), and therefore more levels
of validation plans could be needed. This article proposes a three-tier process for a validation plan structure (including
Site Validation Master Plans (SVMP) as tier I, Validation Master Plans (VMP) as Tier II, and Individual Validation Plans
(VP) as Tier III) that will provide a well-organized and structured validation program or approach to cope with the needs
of the medical device industry. These needs include product diversity, process complexity, multi-customer situation,
and validation plan documentation flexibility. Once the process validation plans are completed (or approved), their
corresponding protocol preparation can be started in accordance with the process validation plans’ requirements.

Validation Master Plan Regulation and Guidance

Validation Master Plan Regulation

 There is no formal requirement for a Validation Master Plan (VMP) as per the FDA Quality System Regulation (21 CFR
820) and ISO 13485 (Medical Devices - Quality Management Systems QMS) aimed at the medical device industry.

Validation Master Plan Guidance

The process validation guidance & guidelines, shown below, mention that having a good VMP is critical to executing a
solid process validation program.

 GHTF Study Group 3 - Quality Management Systems - Process Validation Guidance, edition 2 (January 2004) (1) –
aimed at medical device industry
 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15:
Qualification and Validation (30 March 2015) (2) – aimed at pharmaceutical industry
 PIC/S - Recommendation on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process
Validation, Cleaning Validation (25 September 2007) (3) – aimed at pharmaceutical industry

In order to facilitate the understanding of the VMP requirements described in the guidance & guidelines, all of the VMP
key points are extracted and shown in the tables below:

Table 1 - Validation Master Plan Guidance: GHTF Study Group 3 - Quality Management Systems - Process
Validation Guidance, edition 2 (January 2004)

Section No. Key Points (Validation Master Plan)

 Once the validation team has been formed, the next step is to plan the approach and define the requirements.
5.1 (Getting Many manufacturers develop what is referred to as a master validation plan which identifies those processes to be
Started) validated, the schedule for validations, interrelationships between processes requiring validation and timing for
revalidations. Once these have been established, and the purpose and scope for validations are clearly stated and
known, protocol development can commence.
 Following is a list of activities which may be used as a checklist to review validation activity:
1. Form multi-functional team for validation
2. Plan the approach and define the requirements
3. Identify and describe the processes
4. Specify process parameters and desired output
5. Decide on verification and/or validation
6. Create a master validation plan
7. Select methods and tools for validation
8. Create validation protocols
9. Perform IQ, OQ, PQ and document results
10. Determine continuous process controls
11. Control the process continuously

Table 2 - Validation Master Plan Guidance: EU Guidelines for Good Manufacturing Practice for Medicinal
Products for Human and Veterinary Use, Annex 15: Qualification and Validation (30 March 2015)
 Section No. Key Points (Validation Master Plan)

1.4 The key elements of the site qualification and validation programme should be clearly defined and documented in
a validation master plan (VMP) or equivalent document.

1.5 The VMP or equivalent document should define the qualification/validation system and include or reference
information on at least the following:

i. Qualification and Validation policy;

ii. The organizational structure including roles and responsibilities for qualification and validation activities;

iii. Summary of the facilities, equipment, systems, processes on site and the qualification and validation status;

iv. Change control and deviation management for qualification and validation;

v. Guidance on developing acceptance criteria;

vi. References to existing documents;

vii. The qualification and validation strategy, including requalification, where applicable.

1.6 For large and complex projects, planning takes on added importance and separate validation plans may enhance
clarity.

Table 3 - Validation Master Plan Guidance: PIC/S - Recommendation on Validation Master Plan, Installation and
Operational Qualification, Non-Sterile Process Validation, Cleaning Validation (25 September 2007)

Section No. Key Points (Validation Master Plan)

 The Validation Master Plan (VMP) should present an overview of the entire validation operation, its organizational
4.2 (Purpose) structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and
the planning schedule.
 VMP can help management, validation team members, and GMP inspectors understand validation programme,
timeline, responsibilities, and the firm's validation approach.

4.3 (Definition) A Validation Master Plan is a document that summarizes the firm’s overall philosophy, intentions and approach to
be used for establishing performance adequacy.
4.5 (Format and VMP Should contain the following subjects:
Content)
 Introduction
 Organizational Structure of All Validation Activities
 Plant / Process / Product Description
 Specific Process Considerations
 List of Products / Processes / Systems to be Validated
 Key Acceptance Criteria
 Documentation Format
 Required SOPs
 Planning & Scheduling
 Change Control

8 (Glossary) Validation Master plan:

A document providing information on the company’s validation work programme. It should define details of and
timescales for the validation work to be performed. Responsibilities relating to the plan should be stated.

Rationale of Three-Tier Process Validation Plans for Medical Device Industry

Three-Tier Process Validation Plans structure for Medical Device Industry is proposed in Figure 1 below:

Figure 1 - Three-Tier Process Validation Plans

And the rationale for the plans structure is illustrated in 5 different perspectives as below:

Process Validation Perspective

 Multidisciplinary approach: validation requires the collaboration of experts of various disciplines (e.g. Validation, QA,
Device Design, Product Development, Engineering, and Manufacturing).
 Time Constraint: validation studies are always the last stage prior to routine production.
 Cost: validation studies are costly as they require time of highly specialized personnel, expensive technology, and big
amounts of raw materials/components/subassemblies for testing.

All of the above factors require a well-organized and structured validation program/approach that should be adequately
described in validation plans.

Product Perspective

 The medical device industry encompasses a wide range of production technologies and applications.
 The medical device company can have an abundant product portfolio facing different customers (e.g. pharmaceutical
companies for combination products).
 Medical devices are manufactured by companies of varied size, structure, volume of production, manufacturing
processes and management methods.

Given this diversity, it is suggested that three-tier validation plans be more appropriate than just one-use or two-tier
validation plans.

Equipment/Process Perspective

 The medical device industry encompasses a wide range of production technologies and applications, and therefore the
device manufacturing equipment/process are more various and customized (with less commonality between device
products) than the pharmaceutical industry (for dosage form production).
 A medical device company could be with an abundant product portfolio, and each device product could need dedicated
and unique equipment/processes.

Given this complexity and variety, it is suggested that three-tier validation plans should be utilized rather than one or
two-tier validation plans.

Customer Perspective

 The medical device company should have an abundant product portfolio, and each product should have a specific
customer (e.g. pharmaceutical company), since the device company may need to deal with different customers’
requirements for validation plans.
 Validation plans are high level and sensitive documents. As such, customer A’s validation plans should not be exposed
to customer B's and vice versa. Validation plans should be separate for different device products (or device
customers).

Given this multi-customer situation, it is suggested that three-tier validation plans should be more appropriate than a
single or two-tier validation plans.

Documentation Perspective

 Validation plans for Tier I - SVMP should be summary documents and be brief, concise and clear. For large and
complex projects or sites, separate validation plans (Tier II – VMP, Tier III - VP) may enhance clarity, completeness,
details and validation execution efficiency.
 Validation plans should cover from top level (e.g. facilities validation plan) to middle level (e.g. specific device project
equipment/process validation plan), and to bottom level (e.g. single device component process validation plan,
individual & automated equipment validation plan) where appropriate.
 Three-tier validation plans should be more appropriate and effective for the plans preparation and execution:
o Tier 1: Site Validation Master Plan (SVMP)
o Tier 2: Validation Master Plan (VMP) (either Project-Based or Non-Project-Based), which is derived from SVMP.
o Tier 3: Individual Validation Plan (VP), which is derived from VMP.
 SVMP and VMP should not be exposed to equipment/process vendors, however, VP (e.g. VP for individual, bespoke
automated equipment) is a good document to communicate with the supplier (or vendor) for mutual understanding and
agreement on the machine design, verification, validation tasks and responsibilities.
 Three-tier plans documentation have the advantages of confidentiality and flexibility for device companies while facing
regulatory inspections and customer audits.

Given the complex documentation requirements, it is suggested that three-tier validation plans be more appropriate
than single or two-tier validation plans.

Site Validation Master Plan (SVMP) – Tier I

Site Validation Master Plan (SVMP) generally should include the following sections:

1. Introduction
2. Scope
3. Terms, Acronyms and Definitions
4. Responsibilities
5. SOPs References
6. Facility / Equipment / Process / Sterilization / Computer System Description
7. Validation Strategy
8. Validation Approach & Deliverables
9. Validation Schedule & Status
10. Validation Plans Structure, Documentation Type and Maintenance
11. Validation Supporting Systems (Deviation Management, Change Control, Revalidation, Training)

Note:

1) Section 7, 8, 9, 10, 11 will be outlined below, and the others (section 1, 2, 3, 4, 5, 6) will not be illustrated due to
depending on the characterisitcs of the medical device manufacturer.

2) Section 7, 8, 9, 10, 11 will be explained below based on an example: A medical device manufacturing site’s process
activities include plastic component injection molding process, metal component manufacturing process, printing
process, and assembly process.

Section 7 – Validation Strategy

Facility / Equipment / Process / Sterilization / Computer System Validation Strategy

 Facility Validation
o Clean Room (with HEPA Filter) Validation (e.g. for accommodating sterile device-related component and assembly
operations)
o Controlled Room (without HEPA Filter) Validation (e.g. cool room for testing used cold chain syringes storage, air-
conditioned room for real-time aging test samples, device components and assembly storage)
 Non-Project-Based (or Non-Device Project-Based) Equipment & Process Validation
o Injection Molding Machine Validation
o Plastic Material Drying & Conveying System Validation (for plastic beads drying and sending to the designated injection
molding machine)
o Stability Chamber Validation (for device pre-conditioning test, accelerated aging test)
o Non-Project-Based Test & Metrology Equipment Validation (e.g. QC, Metrology lab used gauges, instruments,
machines which are generally used for physical properties (e.g. dimension, force, torque, weight) measuring and
testing.)
 Project-Based (or Device Project-Based) Equipment & Process Validation
o Injection Molding Tool Validation (for plastic component molding)
o Equipment & Process Validation (for metal component production, plastic component printing operation, assembly
equipment, test equipment)
o Assembly Process Validation (for device subassembly and final assembly operation)
 Sterilization System Validation
o Sterilization system validation (e.g. If gamma irradiation sterilization operation is outsourced, it should mention how to
select the vendor, review/approve the validation protocols/reports)
 Computer System Validation
o Quality management system related computer system validation
o Production related computer system validation (e.g. ERP system, computerized assembly machine)

Note: In medical device industry, terms of qualification and validation should be interchangeable, and “validation” is
used throughout this article.

Section 8 – Validation Approach & Deliverables

The validation approach should be commensurate with the risk level, which is determined by risk assessment based on
factors of equipment/process/system criticality (impact level to product quality and data integrity) and risk priority
(determined by complexity and novelty).

 Facility Validation
o Clean Room Validation (IQ, OQ, PQ protocols/reports with risk assessment)
o Controlled Room Validation (IQ, OQ protocols/reports with risk assessment)
 Non-Project-Based Equipment & Process Validation
o Injection Molding Machine Validation (IQ, OQ protocols/reports with risk assessment)
o Plastic Material Drying & Conveying System Validation (IQ, OQ, PQ protocols/reports with risk assessment)
o Stability Chamber Validation (IQ, OQ protocols/reports with risk assessment)
o Non-Project-Based Test & Metrology Equipment Validation (IQ, OQ protocols/reports may be required with risk
assessment) (Since most of the gauges/instruments such as caliper, thermometer, micrometer, force gauge, load cell,
height gage, and standalone balances are simple and off-the shelf, calibration could indicate their test performance
quality, with no need to conduct IQ, OQ. However, for Instron strength test machine, IQ, OQ are generally needed
since a hkigh impact level to device quality, machine more complex, and calibration alone not being able to prove the
test performance quality.)
 Project-Based Equipment & Process Validation
o Injection Molding Tool Validation (IQ, OQ, PQ protocols/reports with risk assessment)
o Equipment & Process Validation (Test equipment: IQ, OQ protocols/reports with risk assessment; assembly equipment,
metal component production and printing operation: IQ, OQ, PQ protocols/reports with risk assessment)
o Assembly Process Validation (PQ protocols/reports with risk assessment)
 Sterilization System Validation
o Sterilization validation (IQ, OQ, PQ protocols/reports with risk assessment)
 Computer System Validation
o Quality management system related computer system validation (IQ, OQ, PQ protocols/reports with risk assessment)
o Production-related computer system validation (ERP system: IQ, OQ, PQ protocols/reports with risk assessment;
computerized manufacturing equipment: the computer system validation protocols/reports may be embedded in
manufacturing equipment IQ, OQ, PQ protocols/reports. In other words, there are no separate computer system
validation protocols/reports needed.)

Section 9 – Validation Schedule & Status

Each validation event, schedule and status are described in the following respective Validation Master Plans (VMPs)
and the corresponding Validation Master Reports (VMRs). VMRs should cover the validation event, protocol or report
numbers, report completion date, etc, and as an evidence document to demonstrate all the validation requirements
shown in the VMP are fulfilled.

 Facility Validation
o Clean Room Validation (see Clean Room Validation VMP & VMR)
o Controlled Room Validation (see Controlled Room Validation VMP & VMR)
 Non-Project-Based Equipment & Process Validation
o Injection Molding Machine Validation (see Injection Molding Machines Validation VMP & VMR)
o Plastic Material Drying & Conveying System Validation (see Plastic Material Drying & Conveying System Validation
VMP & VMR)
o Stability Chamber Validation (see Stability Chamber Validation VMP & VMR)
o Non-Project-Based Test & Metrology Equipment Validation (see Non-Project-Based Test & Metrology Equipment
Validation VMP & VMR. It is not necessary to list those simple gauges/instruments (without IQ, OQ Validation needed)
in the VMP &VMR because their related calibration information is recorded in the site calibration program.)
 Project-Based Equipment & Process Validation
o For each devices' project-specific equipment & process validation, there is a corresponding VMP & VMR.
o Since there are numerous device projects for different customers, it is not appropriate to list all the project VMPs &
VMRs in the SVMP, but they are auditable by the regulatory inspections and respective customers.
 Sterilization System Validation
o Sterilization validation (If validation is outsourced, see the device project specific equipment & process validation VMP
& VMR.)
 Computer System Validation
o Quality management system related computer system validation (see quality management system related computer
system validation VMP & VMR)
o Production related computer system validation (ERP system: see ERP system software validation VMP & VMR;
computerized manufacturing equipment: see the device project specific equipment & process validation VMP & VMR,
and/or the individual, automated equipment Validation Plan (VP) & Validation Report (VR).)

Section 10 – Validation Plans Structure, Documentation Type and Maintenance

 Validation Plans Structure

o Site Validation Maser Plan (SVMP): Generally, one SVMP at each site
o Project-Based/Non-Project-Based Validation Master Plan (VMP): Derived from SVMP, and generally multiple VMPs for
one site. Project-Based VMP aims at each device project, Non-Project-Based VMP targets each functional area.
o Individual Equipment/System Validation Plan (VP): Derived from VMP, generally multiple VPs for one site, and aims at
each individual equipment/system, for which validation plan had better be separated from the VMP due to its
complexity and VMP not suitable to share with the equipment vendor.
 Documentation Type
o Each plan or report should be uniquely numbered with version control.
o SVMP: Only with plan, and there is no corresponding report.
o VMP/VMR: Includes both validation master plan (VMP) and validation master report (VMR), VMR summarizes that all
the plan’s validation requirements have been fulfilled with protocols/reports numbers as evidence.
o VP/VR: Includes both validation plan (VP) and validation report (VR), VR summarizes that all the plan’s validation
requirements have been fulfilled with protocols/reports numbers (e.g. DQ, FAT, SAT, IQ, OQ, PQ where applicable) as
evidence.
 Maintenance
o SVMP: Should be updated at least annually.
o VMP/VMR: Project-Based VMP/VMR should avoid updating once the project validation is completed (instead utilizing
Change Control to track the change related validation/revalidation activities); Non-Project-Based VMP/VMR should be
updated at least bi-annually or updated once significant changes happen.
o VP/VR: should avoid updating once individual equipment/system validation is completed.
o Life Cycle Management: After equipment/process release, Change Control system should be used for the
equipment/process revalidation activities management.
o Validation documentation should be archived in order, in both paper-based and electronic-based forms. For the paper-
based documents archiving, temperature/humidity controlled, fireproof, waterproof and access-control rooms should be
used.

Section 11 – Validation Supporting Systems (Deviation Management, Change Control, Revalidation, Training)

 Deviation Management
o Deviation means that test results fail to meet the acceptance criteria, the validation exercise is not compliant with
SOPs, and/or approved plans or protocols are not properly executed.
o Once deviation occurs, a deviation handling system should follow to conduct investigations & root cause analysis,
corrective action, and follow-up verification while the deviation is considered significant.
 Change Control
o Pre-Equipment/System Release (before SAT completion): Equipment/system vendor should establish and maintain
their change control system.
o Pre-Equipment/System Release (after SAT completion): The equipment/system user (or customer) should establish
and maintain their validation phase change control system (a simpler one while compared with formal Change Control
system used in routine production, and also controlled/handled by the validation team).
o Post-Equipment/System Release (in production phase): Formal Change Control system (a QA controlled system with
detailed and comprehensive investigation & root cause analysis/corrective actions/verifications) should be adopted.
 Revalidation
Once equipment/system are released for routine production, the revalidation related activities should be considered
and proceed.
o Change Control Based Revalidation: Triggered by any significant changes including software/hardware/process
modification, equipment relocation, product design or specification change, and raw material change.
o QA System Based Revalidation: Warranted by any significant production quality issues identified by QA quality system
(e.g. Annual Product Review).
o Periodic Based Revalidation: For critical equipment/systems, Process Validation Periodic Review should proceed every
X years (e.g. 3 ~ 5 years depending on risk assessment) to identify any equipment/system that needs to conduct
periodic revalidation activities to make sure all the equipment/systems are under control and validated status still valid.
 Training
o All personnel directly involved in the validation activities should be trained for the equipment operation, sampling, and
testing.
o All training records should be archived with the respective validation reports.
 Validation Master Plan (VMP) – Tier II

Validation Master Plan (VMP) generally should include the following sections:

1. Purpose
2. Scope
3. Responsibilities
4. Equipment / Process Description
5. Process Validation Approach
6. Test Plan and Acceptance Criteria
7. Process Validation Requirements and Status
8. Documentation Maintenance

Note:

1) Section 4, 5, 6, 7, 8 will be outlined below, and the others (section 1, 2, 3) will not be illustrated depending on the
medical device manufacturing site and VMP subject characteristics.

2) Section 4, 5, 6, 7, 8 will be explained below based on an example: A medical device manufacturing site’s process
activities include plastic component injection molding process, metal component manufacturing process, printing
process, and assembly process.

3) The following VMP sections will be focused on Project-Based and Non-Project-Based Equipment & Process
Validation.

Section 4 - Equipment / Process Description

For Project-Based VMP

 Describe the device project assembly process with flow charts.

 Flow chart should cover all the plastic and metal components, printing, assembly stations, sterilization and assembly
equipment information.

For Non-Project-Based VMP

 For Injection Molding Machines

o Describe injection molding machine brand name, model number, serial number, and vendor contact information.
o Illustrate the molding operation principle and stages (e.g. mold closing, injection unit forward, injection molding, …….,
mold open).
 For Plastic Material Drying & Conveying System
o Describe day bin, drying bin, dry air generator, conveying equipment brand name, model number, serial number, and
vendor contact information.
o Illustrate plastic material drying & conveying process with flow diagrams.
 For Stability Chambers
o Describe stability chamber brand name, model number, serial number, and vendor contact information.
o Illustrate validation test sequence (e.g. set climate program, load test samples, proceed empty & loaded chamber tests,
download the temperature/humidity recorder data) with block diagrams.
 For Non-Project-Based Test & Metrology Equipment
o Describe non-project-based test & metrology equipment types (e.g. caliper, micrometer, height gauge, 3D vision
machine, Instron, drop test machine) and their functional purposes.
o For the high-risk test equipment (e.g. Instron, bespoke test equipment) which generally are with the characteristics of
high impact level to device quality, machine more complex, and calibration alone not being able to prove the test
performance quality, the equipment brand name, model number, serial number, and vendor contact information should
be described. In addition, validation test sequence with block diagrams should be provided.

Section 5 - Process Validation Approach

For Project-Based VMP

 All the project related plastic molding tool validation, metal component process validation, printing validation, assembly
equipment validation, test equipment validation, assembly process validation, and sterile validation (where applicable)
should be included.
 Describe the validation approach backbone IQ/OQ/PQ purpose and deliverables (protocols/reports) for each validation
type above. If any qualification stage (either IQ, OQ, or PQ) proposed to be exempted (e.g. conducted previously in
other projects), rationale and document evidence should be given to justify the exemption.
 If the equipment/system is controlled/assisted by software, computer system validation approach and deliverables
should be illustrated.

For Non-Project-Based VMP

 For Injection Molding Machines, Stability Chambers, and Non-Project-Based Test & Metrology Equipment validation,
the validation approach backbone IQ/OQ purpose and deliverables should be described.
 For Plastic Material Drying & Conveying System validation, the validation approach backbone IQ/OQ/PQ purpose and
deliverables should be described.
 Computer system validation approach and deliverables should be illustrated where applicable.

Section 6 - Test Plan and Acceptance Criteria

For both Project-Based VMP & Non-Project-Based VMP

 Test Plan
o For each equipment/process OQ, PQ validation, the test plan should be described in their validation (OQ, PQ)
protocols.
o Test plan should include the following items: Equipment/Instrument/Raw Material Description, Operating Parameter
Setting, Test Batch Setting, Test Item, Inspection Method, Sampling Plan, Sample Number Designation, Acceptance
Criteria, and Test Results Expression Form.
o Test batch size and sampling plan should be with rationale.
Note: Test Batch Setting: describes how to run the test batch (e.g. OQ plus parameter batch, OQ minus parameter
batch, PQ batch), including test batch size setting & rationale, how many consecutive batches needed, how to
differentiate the different batches, how many batches for each raw material should be used, etc.
 Acceptance Criteria
o The acceptance criteria in IQ/OQ/PQ must be predetermined, scientifically justified, and clearly described in their
validation (IQ, OQ, PQ) protocols.

Section 7 - Process Validation Requirements and Status

For both Project-Based VMP & Non-Project-Based VMP

 Validation Requirements
o All the equipment/process description, ID number, IQ, OQ, PQ requirements should be listed in tables.
 Validation Status
o All the equipment/process validation schedule and status should be described.
o Prior to completing Validation Master Report (VMR), a process validation status sheet can be prepared to describe the
validation progress status and list completed validation documents (protocols/reports) once needed.

Section 8 - Documentation Maintenance

For both Project-Based VMP & Non-Project-Based VMP

 Validation documents (e.g. validation plans, protocols/reports) should be numbered according to SOP #XXX.
 Validation documents (e.g. validation plans, protocols/reports) should be archived in both paper-based and electronic-
based according to SOP #XXX.
 All the machine supplier documents, software, and validation test raw data sheets should be archived with the
validation protocol/report documents.

Individual Validation Plan (VP) – Tier III

Individual Master Plan (VP) generally should include the following sections:

1. Purpose
2. Scope
3. Glossary
4. Responsibilities
5. System Description
6. Risk Assessment
7. Validation Strategy
8. Sampling Plan and Acceptance Criteria
9. Deliverable, Produce, Review and Approve
10. Supporting System (Change Management, Deviation Handling, Training, Documentation Maintenance)

Note:

1) Section 6, 7, 8, 9, 10 will be outlined below, and the others (section 1, 2, 3, 4, 5) will not be illustrated due to
depending on the individual equipment/system characteristics.

2) Section 6, 7, 8, 9, 10 will be explained based on an example: A medical device fully-automated assembly machine.

Section 6 – Risk Assessment

 A risk-based approach should be used to determine the scope and extent of the validation activities.
 Risk assessment should be a required input to the Design Qualification (DQ), Factory Acceptance Test (FAT), Site
Acceptance Test (SAT), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification
(PQ).
 D-FMEA (Machine Design-FMEA) and P-FMEA (Process-FMEA) should be conducted, and they could be merged into
one FMEA describing how to mitigate the identified critical risks through the risk management process.
 The results of the FMEA are reflected in the verification and validation activities through corresponding tests in the
machine verification process (FAT, SAT) and validation activity (IQ, OQ, PQ).
 The critical risk items with Severity (SEV) ≥ xx and/or RPN (Risk Priority Number) ≥ yy should be addressed by the
corresponding tests.
 Section 7 - Validation Strategy

 Machine Specification Development

o Machine User Requirement Specification (URS) -> Machine Functional Specification (FS) -> Machine Design
Specification (DS)
 Verification and Validation Phase
o Verification Phase: Machine Design Qualification (DQ) -> Software Development and Verification -> Factory
Acceptance Test (FAT) -> Site Acceptance Test (SAT)
o Validation Phase: IQ -> OQ -> PQ
 Design Qualification (DQ)
o To verify and provide documented evidence that the machine design is suitable for the intended use. DQ includes
checks of the satisfactory completion of the following items: vendor qualification, machine risk assessment (FMEA),
machine specifications (User Requirement Specification (URS), Functional Specification (FS), Hardware Design
Specification (HDS), Software Design Specification (SDS)), and URS traceability document (to make sure that the
machine specifications comply with the URS requirements).
 Software Development and Verification
o Software Development: Vendor should establish software development process SOPs and follow them to ensure
compliance.
o Software Verification: Vendor should perform code-based test, specification-based test (functional test), CFR Part 11
test, and software disaster recovery test.
 Factory Acceptance Test (FAT)
o FAT is conducted at the vendor site prior to shipping of the machine. The vendor tests the machine to demonstrate that
the machine meets the specified technical, functional and performance requirements derived from URS, FMEA, FS,
DS.
 Site Acceptance Test (SAT)
o SAT is performed at the user (or customer) facility to demonstrate the system is installed properly, interfaces with other
systems and peripherals in its working environment. SAT test should repeat the FAT test where the machine functions
could be affected during the shipment and reinstallation at the user site.
 Installation Qualification (IQ)
o Includes equipment design features, installation conditions, environmental conditions, safety features, supplier
documents, calibration, preventive maintenance, spare parts, and computer system verification.
 Operational Qualification (OQ)
o Includes Critical Process Parameters (CPP) identification, CPP DOE study, CPP window test, equipment software
verification, measurement system capability check (e.g. Gage R&R), and other challenge tests (e.g., sensor function
capability Cpk check). (Note: CPP identification and DOE Study could be conducted during verification phase.)
 Performance Qualification (PQ)
o Includes normal (or nominal) operating conditions, 3 consecutive batches, long term stability, and simulating actual
manufacturing conditions.
 Leverage and Traceability
o The test results of FAT and SAT can be leveraged for the equipment validation IQ, OQ & PQ where appropriate.
o Validation Traceability Matrix should be generated to provide traceability evidence demonstrating that all verification &
validation test items can fulfill the URS & FMEA requirements.

Section 8 - Sampling Plan and Acceptance Criteria

 DQ
o DQ is conducted via design review to verify vendor qualification report, FMEA documents, machine functional
specification and design specifications (software & hardware), traceability matrix linking machine specifications with
URS requirements are appropriate and complete.
 FAT/SAT
o Sampling plan & acceptance criteria should be based on quality risk assessment (FMEA) and vendor’s SOPs.
o Detailed sampling plan & acceptance criteria for FAT/SAT activities should be specified in their respective protocols,
which need customer review/approval.
 IQ/OQ/PQ
o Sampling plan & acceptance criteria should be based on the product quality requirements described in the URS,
product inspection instruction, product drawing, and FMEA.
o Sampling plan & acceptance criteria are associated with test item, inspection method, and test type (attribute test or
variable test).
o Sampling plan & acceptance criteria should be determined based on statistical technique (e.g. Statistical Technique
SOP #XXX).
o Detailed sampling plan & acceptance criteria for validation IQ/OQ/PQ activities should be specified in validation
protocols with rationale.

Section 9 - Deliverable, Produce, Review and Approve

The responsibilities of deliverable documents are defined in the Table 4 below:

Table 4 - Deliverable, Produce, Review and Approve

Deliverable Produce Review Approve

URS Customer Customer Customer

FS/DS Vendor Customer Vendor/Customer

D-FMEA Vendor Customer Vendor/Customer

P-FMEA Customer Vendor Customer/Vendor

URS Traceability Document Vendor Customer Vendor/Customer

DQ Protocol & report Vendor Customer Vendor/Customer

 Software Development/Verification Vendor Vendor Vendor
Summary

FAT/SAT Protocols & reports Vendor Customer Vendor/Customer

IQ/OQ/PQ Protocols & reports Customer Customer Customer

Validation Traceability Matrix Customer Customer Customer

Equipment Validation Plan & Report Customer Customer/Vendor (for Customer/Vendor (for
Plan) Plan)

Section 10 - Supporting System (Change Management, Deviation Handling, Training, Documentation

Maintenance)

 Change Management
o Pre-SAT Completion (verification phase) Changes: Vendor should establish and maintain a Change control system to
ensure appropriate handling, documentation, and approval for all the changes during the machine development, up to
SAT with customer’s review and approval (where appropriate).
o Post-SAT Completion (validation phase) Changes: After SAT completed, any change to the equipment shall be
tracked, handled and documented by customer’s validation phase change control system.
 Deviation Handling
o Deviation handling before and after SAT completion should follow vendor’s SOPs and customer’s SOPs, respectively.
o Any report (DQ, FAT, SAT, IQ, OQ, PQ) can only be closed while all the relevant deviation items are closed first or with
proper justification if the item needs to be kept open. However, prior to the last stage validation PQ report closure, all
the deviation items have to be closed first.
 Training
o All personnel directly involved in the equipment verification (FAT & SAT) or validation (IQ/OQ/PQ) activities should be
trained according to the equipment verification/validation protocols and related assembling, sampling, and testing
manner.
 Documentation Maintenance
o All the equipment specifications (FS & DS), verification (DQ, FAT, SAT) and relevant documents numbering and
archiving should follow vendor’s SOPs. And all of the vendor produced documents should be with a copy archived at
the customer site.
o All the equipment validation (VP, IQ, OQ, PQ) and relevant documents numbering and archiving should follow
customer’s SOPs.

Conclusion
Compared with the pharmaceutical industry, the medical device industry generally has more product diversity, process
complexity, customers involvement in validation, as well as documentation flexibility with validation plans, Therefore,
separate and multi-level process validation plan structures (instead of just one level – Validation Master Plan) should
be more appropriate for the medical device industry. It may be the case that process validation plans’ use, structure,
and content is not consistent across the industry. As such, a medical device process validation plan structure is
proposed in Figure 2 below, which should provide a flexible, well-organized and structured validation program for a
medical device company.

Figure 2 - Medical Device Process Validation Plans

Structure

REFERENCES

1.GHTF Study Group 3 - Quality Management Systems - Process Validation Guidance, edition 2 (January 2004).

2.EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15:
Qualification and Validation (30 March 2015).

3.PIC/S - Recommendation on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process
Validation, Cleaning Validation (25 September 2007)