Validation Group

Good Practice Guide

Qualification and Validation
A guide to effective qualification based on
Customer - Supplier Partnership

A guidance document by the ECA Foundation

Version 3.0, November 2024
 Good Practice Guide Qualification and Validation

A guidance document by the ECA Foundation

Version 2.2; November 2022
Author Team:
Rolf Bauer, Syntegon Technology GmbH1
Eva‐Maria Baumgartner, Syntacoll GmbH
Alexander Bengs, Sanofi‐Aventis Deutschland GmbH
Lene Bjerregaard, Novo Nordisk A/S
Clemens Borkenstein, ZETA GmbH
Kevin Bound, GEA Group
Franco Casinelli, Johnson & Johnson
Dr Berthold Düthorn, Syntegon Technology GmbH
Josef Duft, Dockweiler Austria
Ralf Gengenbach, gempex GmbH
Markus Greindl, Chemgineering AG
Maik Guttzeit, Bayer AG
Andreas Houman, Novo Nordisk A/S
Gergana Ivancheva, Merck KGaA
Michael Jahnke, Octapharma GmbH, Deutschland
Igor Krasula, valicare s.r.o.
Peter Larsson, Novo Nordisk A/S
Gert Moelgaard, Moelgaard Consulting
Markus Multhauf, Freier Ingenieur Pharmatechnik
Alejandro Parisi, Roche Diagnostics GmbH
Sven Pommeranz, ECA, Validation Group
Sven Poulsen, Getinge AB
Philipp Roth‐Kleyer, Boehringer Ingelheim AG & Co. KG
Ulrike Opitz, Bayer AG
Thomas Rücker, Thomas Rücker – Engineering & Consulting
Thomas Schneppe, formerly BayerAG
Ayse Schulze, Hansella GmbH
Corinna Simeit, Mettler‐Toledo PCE
Rafael Leandro de Souza, Pharmaplan AG
Florian Stern, Bachem AG
Jesper.M. Wagner, Niras A/S
CARA Subgroup (Leader: Rafael Leandro de Souza)
Gert Moelgaard, Moelgaard Consulting
Berthold Düthorn, Syntegon Technology GmbH
Gergana Ivancheva, Merck KGaA
Jesper M. Wagner, Niras A/S
Eva Baumgartner, Syntacoll GmbH
Gert Moelgaard, Moelgaard Consulting

1
Members active in 2024 are shown underlined in the author column

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 Good Practice Guide Qualification and Validation

Contracting Subgroup (Leader: Markus Multhauf)

Rolf Bauer, Syntegon Technology GmbH
Ralf Gengenbach, gempex GmbH
Ulrike Opitz, Bayer AG
Peter Larsson, Novo Nordisk A/S
Thomas Schneppe, formerly Bayer AG
Thomas Rücker, Thomas Rücker – Engineering & Consulting

Remote Testing Subgroup (Leader: Clemens Borkenstein)

Ayse Schulze, Hansella GmbH
Gert Moelgaard, Moelgaard Consulting
Rafael Leandro de Souza, Pharmaplan AG
Gergana Ivancheva, Merck KGaA
Rolf Bauer, Syntegon Technology GmbH
Maik Guttzeit, Bayer AG
Sven Poulsen, Getinge
Thomas Rücker, Thomas Rücker – Engineering & Consulting

Categorisation Subteam (Leader: Maik Guttzeit)

Ralf Gengenbach, gempex GmbH
Michael Jahnke, Octapharma GmbH, Deutschland
Eva Baumgartner, Syntacoll GmbH
Florian Stern, Bachem AG
Gergana Ivancheva, Merck KGaA
Lene S. Bjerregaard, Novo Nordisk A/S
Clemens Borkenstein ZETA GmbH
Gert Moelgaard, Moelgaard Consulting

Electronic documentation Subgroup (Leader: Dr Berthold Düthorn)

Thomas Schneppe, formerly Bayer AG
Ayse Schulze, Hansella GmbH
Philipp Roth‐Kleyer, Boehringer Ingelheim AG & Co. KG
Andreas Houmann, Novo Nordisk
Alejandro Parisi, Roche Diagnostics GmbH
Igor Krasula, Valicare s.r.o.
Gert Moelgaard, Moelgaard Consulting
Alexander Bengts, Sanofi GmbH
Florian Stern, Bachem AG

Editing Subgroup (Leader: Dr Berthold Düthorn)

Gert Moelgaard, Moelgaard Consulting
Ralf Gengenbach, gempex GmbH
Eva Baumgartner, Syntacoll GmbH
Sven Pommeranz, ECA, Validation Group
Corinna Simeit, Mettler‐Toledo PCE

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 Good Practice Guide Qualification and Validation

Comparision of Guidelines Subgroup (Leader: Sven Pommeranz)

Markus Multhauf, Freier Ingenieur Pharmatechnik
Gergana Ivancheva, Merck KGaA
Dr Berthold Düthorn, Syntegon Technology GmbH

Technical Review:
Robert Schwarz, FH Campus Vienna, Austria
Guido Heuwes, Heuwes Ingenieurbüro

Regulatory Review:
Michael Hiob, Ministry of Justice and Health, Kiel, Germany

Approved by:
Wolfgang Heimes, Administration Manager, European Compliance Academy

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 Good Practice Guide Qualification and Validation

Table of Contents

DOCUMENT REVISION HISTORY 6

1 INTRODUCTION 7

2 SCOPE OF THIS GUIDE 11

3 OUTLINE OF THE APPROACH 12

4 ESSENTIAL JOINT ACTIVITIES 19

5 CUSTOMER ACTIVITIES 22

6 SUPPLIER ACTIVITIES 33

7 SUPPORT BY CATEGORISATION 39

8 SUPPORT BY USE OF ELECTRONIC DOCUMENTATION 45

9 ABBREVIATIONS 48

10 BIBLIOGRAPHY 50

Appendices

Appendix 1: Explanation of the Integrated Qualification Core Concept

Appendix 2: User Requirement Specification (URS) Template
Appendix 3: Supplier Evaluation
Appendix 4: CARA and Verification Planning Tools Templates
Appendix 5: Change Management and Deviation Management Template
Appendix 6: Project Quality Plan (PQP) Template
Appendix 7: Qualification Documentation Template
Appendix 8: Remote Testing of GMP Manufacturing Systems
Appendix 9: Categorisation of Manufacturing Systems: Template
Appendix 10: Pharmaceutical Customer and Supplier Contract Checklist
Appendix 11: Electronic Documentation (ED)
Appendix 12: Technical Glossary

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 Good Practice Guide Qualification and Validation

Document Revision History

Version Date Reason for Change Status

Version 3.0 01 November 2024 Revision in Categorization and Critical Final
Aspects Risk Assessment as well in
Remote Testing. Changed the titles of
chapters 7 and 8. Several formatting
improvements. Changed the main title
of the document.
Version 2.2 14 November 2022 Considered several comments from Final
regulators, moved the topic about
contracting qualification activities from
the “supplier” section to the “joint
activity” section and revised the related
appendix 10, revised the section for
“remote testing” including the appendix
8, revised the section about electronic
documentation, added a new appendix
11 for electronic documentation,
Version 2.1 14 December 2021 Minor updates especially listing of Final
subgroup members

Version 2 15 November 2021 Updates: new chapter contracting of Final

qualification services and Remote FAT
and SAT, revision chapter electronic
documentation, new appendices
FAT/SAT and contracting, revision of
appendix Integrated Qualification Core
Concept, revision chapter and annex
categorisation

Version 1 20 October 2020 Final version of the Good Practice Guide Final
Public Draft 2 1 Oct 2019 Second draft issued for public Public Draft
comments

Public Draft 1 11 Sep 2018 First draft issued for public comments Public Draft

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 Good Practice Guide Qualification and Validation

1 Introduction

The purpose of this guide is to enable effective and GMP‐compliant Qualification and Validation (Q&V)
projects by mutual understanding between pharmaceutical customers and suppliers on projects
related to pharmaceutical manufacturing systems, including equipment, facilities and utilities.

This guide is about close involvement of suppliers of pharmaceutical technical equipment and projects
to enable a more effective project execution by reducing multiple testing throughout the qualification
activities and to enable a more integrated approach to qualification and validation. It must be
emphasized that the ultimate legal responsibility for qualified equipment and validated processes
cannot be delegated and shall be retained by the pharmaceutical customer.

The guide is following the principles as outlined in the Process Validation Guide from US Food and Drug
Administration (FDA) (2011) and the European GMP Annex 15 on Qualification and Validation (2015).
Both are based on the Quality Risk Management guideline ICH Q9, from International Council of
Harmonisation (ICH). This guide is based on these regulations with main focus on Annex 15 and does
not create new legal obligations for suppliers or for pharmaceutical customers beyond these
regulations.

Traditionally pharmaceutical companies have used a qualification approach based on, e.g., Design
Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), Performance
Qualification (PQ) and Process Validation (PV) phases. The EU GMP Annex 15 on Qualification and
Validation from 2015 is flexible on the naming and combinations of qualification activities. Thus, the
Qualification and Validation activities can be planned based on best practices and use supplier
activities and documentation where appropriate.

The core principle of this guide is that a quality management system is already in place when suppliers
are working on the design, construction and testing of any manufacturing system, including but not
limited to a good and accurate documentation that supports qualification and related documentation.
This is part of “Good Engineering Practice” (GEP). During the cooperation between pharmaceutical
customers and suppliers both win most if they share knowledge in an integrated approach using the
supplier’s understanding of their systems and the pharmaceutical customers of their products,
requirements, and regulatory context of their application.

Suppliers are directly or indirectly affected by many of the GMP regulations and may have to follow
some of the pharmaceutical customer’s procedures. Pharmaceutical customers have their individual
quality systems, technical requirements and procedures and they may differ significantly between
companies, thereby complicating the cooperation between pharmaceutical customers and suppliers.

The core concepts of this guide facilitate the cooperation by describing elements of an efficient
cooperation approach that is based on principles of Good Engineering Practice (GEP). It is compatible
with other standards and industry guide, including ASTM E2500 Standard Guide for Specification,
Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Equipment and supports qualification as required in GMP regulations.

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 Good Practice Guide Qualification and Validation

The term Supplier is used throughout this guide as an “organisation that provides a product or a
service” (ISO 9001:15) and may include relevant subcontractors, manufacturers etc. A good
cooperation in projects gives a pharmaceutical company an opportunity to learn from the accumulated
best practices and expertise from the suppliers without any confidential information being revealed.
It enables suppliers to plan, execute and document their test and verification activities so it can be
demonstrated that the manufacturing systems are fit for the intended use.

The term manufacturing system is used as umbrella term for facilities, equipment and utilities related
to pharmaceutical manufacturing. The term is defined in the ASTM E2500 standard as “elements of
pharmaceutical and biopharmaceutical manufacturing capability, including manufacturing systems,
facility equipment, process equipment, supporting utilities, associated process monitoring and control
systems and automation systems, that have the potential to affect product quality and patient safety”.

The term Commissioning is used in the meaning “a planned, managed and documented approach to
the setting to work, start‐up, regulation and adjustment, and installation/operation/performance
verification necessary to bring equipment, automation and systems to a fully operational state meeting
safety and end‐user requirements“ (ASTM E2500). These activities may include acceptance testing,
especially Factory Acceptance Test (FAT) and Site Acceptance Test (SAT).

The term Verification is used according to ISO 9000 as “confirmation, through the provision of objective
evidence, that the specified requirements have been fulfilled” (ISO 9000:2015). In pharmaceutical
context ASTM E2500 describes verification as “a broad umbrella term that includes specific actions to
confirm, with a high degree of assurance, that a particular fabrication, configuration, installation,
operation or performance specification has been satisfied and is suitable for its intended purpose.
Verification actions can be of a variety of types, including physical inspection, structural or functional
test, document review, performance monitoring etc. Commissioning and qualification activities are
types of verification” (ASTM E2500). The approach in this guide is mainly focused on qualification of
critical aspects of the manufacturing system and application of Good Engineering Practices.

The term Qualification is used to the EU GMP Annex 15 on Qualification and Validation as ‘documented
verification’. This is also in accordance with the ASTM E2500 definition: “a systematic approach to
confirming that manufacturing systems, acting singly or in combination are suitable (fit) for intended
use with respect to patient safety and product quality. Qualification begins with defining suitability for
use in a particular manufacturing context, typically based on process and quality risk control strategy,
and ends with formal acceptance and release for manufacturing followed by life cycle continuous
improvement.”

The term Critical Aspects is used as intended in EU GMP Annex 15: “It is a GMP requirement that
manufacturers control the critical aspects of their particular operations through qualification and
validation over the life cycle of the product”. The ASTM E2500 definition is “typically functions,
features, abilities and performance, or characteristics necessary for the manufacturing process and
systems to ensure consistent product quality and patient safety. They should be identified and
documented based on scientific product and process understanding”.

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 Good Practice Guide Qualification and Validation

The intent of the guide is to meet the EU GMP Annex 15 expectations for Qualification and Validation
without adding further requirements as well as to meet expectations from US FDA’s Process Validation
Guide and other regulatory guidance on qualification and validation. This includes the expectations on
e.g. Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and
Performance Qualification (PQ) as documented verification activities which may be organised based
on Factory Acceptance Test (FAT), Site Acceptance Test (SAT) and other activities, as described in the
following sections.

The approach of Integrated qualification and validation implies a science‐ and risk‐based approach in
cooperation with suppliers, based on quality risk management, scientific product and process
understanding and use of GEP and GMP regulation in close cooperation between pharmaceutical
customers and suppliers. The guide may be used together with other industry guides on both
commissioning and qualification as well as on validation that are mentioned in the bibliography (see
section 10). Qualification and validation activities may be integrated more than is common practice
and this guide covers several activities and documents as illustrated below in figure 1.

Figure 1 Input to successful project and partnership

The aim of the guide is to enable fast and efficient activities with sufficient documentation to ensure:
 Increased understanding of the project, the process and the technical solutions involved
 Reduction of time and effort to achieve compliant systems
 Managed changes during design phase and testing phase
 Less need for expensive and time‐consuming re‐testing (no need for retesting unless for
deficiencies that have been corrected)
 Reduced risk of creeping escalations of requirements by using established tools and methods

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 Good Practice Guide Qualification and Validation

 Transparency in projects to ensure delivery on time, according to budget and the agreed
quality standards
 Common language, terminology and documentation expectations

Although this guide has separate sections for involved parties (suppliers, customers) it is strongly
recommended to have a complete reading in order to comprehend the approach for a successful
project.

This guide is published by European Compliance Academy (ECA) by a Qualification and Validation Task
Team which consists of pharmaceutical companies, pharma equipment, systems and solution
suppliers, engineering and consulting suppliers that openly share experiences and knowledge to bring
the industry forward ‐ with mutual benefits for both parties. It has been reviewed by several individuals
and organisations of which some are listed above. The Qualification and Validation Task Team thanks
ECA and all involved individuals and organisations for their support.

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 Good Practice Guide Qualification and Validation

2 Scope of this Guide

The guide is applicable to new manufacturing systems, including facilities, equipment and utilities and
its principles may also be used for projects executed in existing factories with existing manufacturing
systems such as upgrade or expansion projects. It can be applied for both, the manufacturing of drug
substances and drug products.

It covers the project expectations and requirements for both the pharmaceutical customer and the
suppliers of manufacturing systems and solutions to the pharmaceutical industry as well as engineering
and consulting suppliers for effective cooperation on commissioning, qualification and validation.

The main purpose of the qualification activities described in this guide is to demonstrate that a
manufacturing system is fit for its intended use, including that it is installed and can be operated as
intended throughout the range of the process, as described in EU GMP Annex 15 and in FDA’s Process
Validation guide.

The guide builds on existing guidelines, standards, and company case studies to improve
understanding and best practice sharing. It does not specifically cover computerised systems because
this subject is well covered in the GAMP®5 Guide (Good Automated Manufacturing Practices, 2nd
edition) from ISPE. It includes qualification and validation based on other media than paper and also
remote testing without physical presence. Many companies have experienced significant savings,
improved documentation and reduced travel needs due to these methods.

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 Good Practice Guide Qualification and Validation

3 Outline of the Approach

3.1 Introduction
Pharmaceutical companies must comply with Good Manufacturing Practice (GMP) regulations,
including requirements concerning the quality management of the manufacturing process, including
the involved manufacturing systems. This guideline is based on a project model that supports the
following:
 An efficient, cooperative project management process
 Avoidance of duplications of tests by re‐use of accepted results from previous testing,
including those from suppliers
 Identification and testing of Critical Aspects of a manufacturing system based on quality risk
management principles
 Use of Good Engineering Practice
 Use of Good Documentation Practice
 Integrated testing of equipment and process control
 Utilisation of punch list (open item list) for non‐conformities
 Use of electronic documentation
 Remote testing
The overall project flow in this guide reflects the ASTM E2500 project life cycle model, as illustrated in
figure 2, which is commonly used in several industry guides related to how commissioning and
qualification activities can be aligned.

Figure 2 ASTM E2500 project life cycle model

To clarify the cooperation between pharmaceutical customers and suppliers this guide has enhanced
the project life cycle with some typical supplier activities in order to illustrate the supplier‐related
activities during the project execution. Especially, the assembly and construction activities that follows
specification and design and test activities that precede the verification activities have been added, as
illustrated in Figure 3. Typical supplier activities (possibly in cooperation with the customer) are
indicated in grey. These are typically supplier activities of importance for the cooperation between the
pharmaceutical customer and the supplier.

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 Good Practice Guide Qualification and Validation

Figure 3 Enhanced project life cycle model

3.2 Cooperation between Customer and Supplier

The cooperation between the pharmaceutical customer and supplier(s) of manufacturing systems may
simplify qualification and validation activities significantly. Suppliers should be aware that there are
specific pharmaceutical requirements and should ensure that they deliver good quality manufacturing
systems in a broad sense, including comprehensive documentation and testing of their manufacturing
system delivery. Well documented activities can be used by the pharmaceutical customer to
demonstrate that the system is designed, built and tested in a way that ensures that it is “fit for the
intended use”.

The cooperation and responsibilities of each activity should be agreed early in a project to make sure
that the related measures and controls are established throughout the entire system life cycle and that
documents, changes and deviation management follows good documentation practice.

Suppliers to the pharmaceutical industry generally have a very deep understanding of their equipment
and its use from many customers. However, suppliers should understand that pharmaceutical
customers might have different quality systems, different applications and different approaches to
fulfil the GMP requirements.

An effective project typically benefits from the use of a variety of principles such as:

 Customer‐supplier partnership: A good cooperation intent and team‐spirit between the

pharmaceutical customer and the supplier’s organisations should be based on clear contractual
and commercial terms and may include mutual incentive elements to stimulate win‐win solutions
between pharmaceutical customer and supplier. The coordinated activities on both sides should
start early and be continued throughout the project, including e.g., how to behave in a cleanroom
environment during the installation process, how to operate in classified areas or how to ensure a
clear transfer from project into operations.

 Company standards and guidelines: Many pharmaceutical companies have their own company
specific standards and guidelines. If they are intended to be applied in a project, this should be
agreed upon before the project execution starts. Companies may use this ECA guideline as a
reference for mutual agreement on how to cooperate and document the project outcomes as part
of the overall package.

 Subject Matter Experts (SMEs): Specialists, who cover the most important areas of expertise such
as product, process, quality, qualifications and technical knowledge as well as members of the
quality organisation should be involved in key roles, including both technical, pharmaceutical, and

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 Good Practice Guide Qualification and Validation

quality‐related areas of expertise. They should preferably be acting as a team and meet frequently
at cross‐functional project meetings for e.g., risk assessment, Design Review, qualification planning
etc.

 Cross‐functional teamwork: A good cross‐functional cooperation on both the pharmaceutical

customer organisation and the supplier organisation, especially an effective cooperation between
the technical side (engineering/manufacturing/process etc.) and the quality side within the
pharmaceutical customer’s organisation. For example, the quality function may delegate activities
to an internal engineering department or other areas of expertise within the company.

 Good Engineering Practices (GEP) consists of proven and accepted engineering methods,
procedures and practices that provide appropriate and well‐documented solutions to meet user‐
requirements and compliance with applicable regulations, including GMP regulations. It includes
change management and deviation management, and it underpins activities in day‐to‐day
operations and planning for a pharmaceutical business. Well documented activities can be the
basis for verification and qualification activities. For a basic understanding see ISPE Good Practice
Guide on Good Engineering Practice.

 Good Documentation Practices: Clearly understood and agreed practices should be used for both
pharmaceutical customer and supplier activities. This enables technical solutions and technical
documentation to be used in the pharmaceutical company's final qualification documentation.
Handwritten entries should be made in clear, legible, indelible way and records should be made or
completed at the time each action is taken, and any alteration made to the entry on a document
should be signed and dated and permit the reading of the original information as well as the reason
for the alteration should be recorded. In general, ALCOA principles should be considered. Raw data
from test documentation should be kept for reference. For further description, see EU GMP
volume 4, Part 1, Chapter 4 Documentation.

 Single test approach: The use of Good Engineering Practices, including Good Documentation
Practices, is important to enable a single test approach where the quality activities and the related
documentation is sufficient to be part of the overall qualification documentation that should
demonstrate the “fitness for intended use” of the manufacturing system. Where single test
approach is part of the qualification activities, the documentation and test executions need to
comply with good manufacturing regulations.

 Life cycle approach: The pharmaceutical customer must control the critical aspects of their
manufacturing systems during the full life cycle of the product and the manufacturing process; not
just as a project with an end. Any planned changes concerning the manufacturing system and
processes, which may affect the quality of the product, should be formally documented and the
impact on the qualified and validated status etc. should be assessed. The life cycle may involve the
supplier on issues such as spare parts, maintenance, service agreements etc.

In some cases, depending on the project, other special approaches may apply to support effective
qualification and validation activities:

 Worst Case Approach: Tests should be planned with worst‐case scenarios in mind based on a risk
assessment with realistic worst‐case situations on operational conditions and process parameters

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 Good Practice Guide Qualification and Validation

(e.g., highest temperature, biggest volume etc.) as part of planning for an effective testing
approach, as expected in EU GMP Annex 15, Qualification and Validation.

 Fast Track Projects: In fast‐track projects where the project time is on high priority, the user
requirement specifications, test methods and documentation standards are always on the critical
path of the project. An early agreement on these may have significant advantages for the overall
timeline of the project. Also, close cross‐functional cooperation between production, engineering,
quality etc. in the pharmaceutical customer organisation is very important to ensure an effective
project execution under fast‐track conditions. When running a project on a fast track, GMP
requirements shall not be compromised.

3.3 Risk Management in the Project

Pharmaceutical companies are expected to use risk‐based approaches in their quality activities. This is
done on their regular business as well as within investment projects for new systems or processes. The
regulatory expectations have evolved towards science‐ and risk‐based principles based on a scientific
understanding of the pharmaceutical product and processes and quality risk management. This guide
follows a risk‐managed approach based on commissioning, qualification and validation activities that
goes ‘hand in hand’: The stepwise risk‐managed model enables concurrent remediation of errors and
deviations with follow‐up verification as an integrated part of the commissioning, qualification and
validation activities.

The approach to commissioning, qualification and validation in this guide is aligned with the Quality
Risk Management principles of the ICH Q9 Quality Risk Management guideline:

 The evaluation of the risk to quality should be based on scientific knowledge and ultimately
link to the protection of the patient; and

 The level of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk.

The EU GMP Annex 15 on Qualification and Validation states the following regulatory expectation:
“It is a GMP requirement that manufacturers control the critical aspects of their particular operations
through qualification and validation over the life cycle of the product and process”.
Annex 15 states in addition: “A quality risk management approach should be applied throughout the
life cycle of a medicinal product. As part of a quality risk management system, decisions on the scope
and extent of qualification and validation should be based on a justified and documented risk
assessment of the facilities, equipment, utilities and processes.”

This guide applies these principles and the concept of pharmaceutical quality risk management, also
in a supplier context. Annex 15 states: “Data supporting qualification and/or validation studies which
were obtained from sources outside of the manufacturers own programmes may be used provided that
this approach has been justified and that there is adequate assurance that controls were in place
throughout the acquisition of such data.”
Quality risk assessment typically starts during the development activities of the pharmaceutical
product(s) to be manufactured. The pharmaceutical customer should at least identify the Critical

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 Good Practice Guide Qualification and Validation

Quality Attributes (CQA) of the pharmaceutical product and the Critical Process Parameters (CPPs) of
the manufacturing process and other attributes that are Critical to Quality (CTQ) as described in Section
5.2. In this guide these are identified by an initial Quality Risk Assessment by the pharmaceutical
customer, preferably long before a project starts.

Quality Risk Management may be supplemented with other risk management activities for issues such
as project risk, environmental, health and safety (EHS) related risk etc.

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 Good Practice Guide Qualification and Validation

3.4 Roles and Responsibilities

The pharmaceutical customer, namely the head of production is responsible for qualification and
validation activities even if it is done with support of the supplier.

Within a pharmaceutical company the overall responsibility for a project related to a manufacturing
system involves members representing the quality function. Based on the principles of quality risk
management the responsibility for certain areas of a project can be delegated to other subject matter
experts.

Within a supplier company the contact persons and their responsibilities in the project should be
defined to facilitate the cooperation between subject matter experts on the pharmaceutical customer
and the supplier side.

Subject Matter Experts (SMEs) can take a lead role in the design, construction, assembly,
commissioning, qualification and validation activities within their area of expertise and responsibility.
Subject matter experts within similar areas of expertise can facilitate the cooperation between the
pharmaceutical customer and supplier within their area of expertise on e.g., mechanical issues,
automation issues etc. Generally, the pharmaceutical customer’s head of production and SMEs have
responsibility for the overall qualification and validation planning and execution whereas the supplier`s
SMEs have focus on detailed design, construction and verification activities to ensure that the system
meets the user requirements and is tested to ensure correct installation and function as intended.

Typical examples of SME roles are:

 Quality SME: e.g., pharmacist or other experts with product‐ and process know‐how and
experience with the pharmaceutical quality system, the production principles, quality risk
management etc.

 Qualification SME: e.g., engineer, chemist, pharmacist, etc. involved in the planning and execution
of the qualification and validation activities, working with suppliers etc.

 Process SME: e.g., chemist, pharmacist, process engineer etc. involved in process aspects,
including process know‐how, material selection, overall design, risk management etc.

 Technical SME or Equipment SME: e.g., mechanical, utility or HVAC engineer with special
knowledge in utilities, cleanrooms, risk management etc.

 Automation SME: e.g., experts in design, implementation, testing and documentation of

automation‐ and IT systems, including network, data integrity, configuration management for
computerized systems etc.

 Production SME: e.g., manufacturing personnel with knowledge concerning the operation
including sampling, writing of SOPs (Standard Operating Procedures), training of operators, etc.

The subject matter experts, their roles, responsibilities and areas of expertise should be documented
on both the pharmaceutical customer and supplier side and the cooperation should be described, for

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 Good Practice Guide Qualification and Validation

example as RACI matrix of Responsible, Accountable, Consulted, and Informed stakeholders in the
project.

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 Good Practice Guide Qualification and Validation

4 Essential Joint Activities

4.1 Overview
In order to ensure an effective project execution, it is important that some activities are executed in
close cooperation between pharmaceutical customer and supplier, including the following:

 User Requirement Specification (URS): The URS is the starting point of the qualification activities
and should be a point of reference throughout the project. It is the pharmaceutical customer’s
responsibility and should reflect the pharmaceutical customer requirements for the manufacturing
system in scope of the project. The URS issued by the pharmaceutical customer may be updated
to a final, agreed URS which is supported by and agreed with the supplier. An agreed URS for the
manufacturing system is the starting point for the supplier activities to ensure a successful project.
The URS is further described in sections 5 and 6 as well as in Appendix 2.

 Risk Management: Risk management and especially Quality Risk Management (QRM) activities
including risk assessment and risk mitigation should start with the pharmaceutical customer’s risk
assessment, especially regarding the product and the processes in scope. Risk mitigation should
be reflected in the URS where applicable and it is typically useful to involve the supplier in the
identification, assessment and management of risk in order to build on the supplier’s experience
from similar applications. Several quality risk management methods and tools are described in the
ICH Q9 document on Quality Risk Management. See section 5.4. and Appendix 4.

 Project Quality Plan (PQP): Pharmaceutical customer and suppliers should agree on a common
Project Quality Plan which is typically developed by the supplier. Often both, pharmaceutical
customers and suppliers have separate plans for their quality activities. A PQP should be agreed as
basis for the common quality activities of the project, depending on the size and complexity of the
project. See section 6.2. and Appendix 6.

 Project Management: The core element for a successful project execution is a close cooperation
between pharmaceutical customer and supplier and both should be jointly involved in project
management activities, e.g., scheduling, progress tracking, documentation, deviation and change
management.

 Design Review: Design Reviews are typically performed to investigate how the requirements
outlined in the URS or the GMP guides are reflected in design and can be implemented in the
layout, the infrastructure, the construction and assembly of the manufacturing system.

 Design Qualification should ensure and evident how the specifications from the URS are met in
the design specification of the supplier. Even the DQ is under the responsibility of the
pharmaceutical customer, the DQ can be a highly interactive work process between customer and
supplier (s. above Design Review), which is finalised by customer’s DQ report.

 Commissioning and Acceptance Testing (FAT and SAT): Factory Acceptance Test (FAT) is executed
in the supplier’s factory before shipping to the pharmaceutical customer and Site Acceptance Test
(SAT) is executed at the pharmaceutical customer’s site after transportation and installation. These

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are examples of commissioning activities and should be clearly defined and agreed, including the
documentation requirements, procedures and acceptance criteria.

The test documentation may be fully or partly used by the pharmaceutical customer to support
Installation Qualification (IQ) and Operational Qualification (OQ) or the pharmaceutical customer
may decide to do additional activities and/or call them IQ, OQ or IOQ activities, depending on
company preferences. Special attention should be given in case activities e.g., FAT are done
remotely or generally based on electronic systems. See section 6.9. and Appendix 8.

An important part of this is the availability of the supplier documentation as outlined in the original
project scope agreement e.g., in the form of a Supplier Turnover Package that is handed over from
the supplier to the pharmaceutical customer at the end of the project, containing design
documents (as built status), material certificates, calibration certificates, manuals etc. including
documentation necessary for the life cycle management of the manufacturing system. Special
attention should be given to documents that are required legally, such as instruction manuals, EU
Declaration of Conformity etc.

4.2 Contracting Manufacturing System Qualification by Suppliers

4.2.1 Roles, Responsibilities and Tasks
As mentioned in chapter 5.1, a written contract is needed between the pharmaceutical customer and
the supplier to ensure a unique understanding of roles, responsibilities, and tasks, when manufacturing
system qualification is outsourced to the supplier. This is also a fixed requirement as e.g., stated in the
EU GMP, Volume 4, Part I, Chapter 7 “Outsourced Activities”. It is stated there, that for “any activity
covered by the GMP Guide” (which includes the qualification & validation activities), such a contract is
needed.

While the Project and Quality Plan (PQP acc. Chapter 6.2) is part of the deliverables and is created once
the supplier is onboard, the contract as described here, is a written legal agreement established prior
to project execution. Other than Quality Assurance Agreements (QAA), typically set‐up for contract
manufacturers and solely dealing with assignment of QA tasks, the supplier contract in most cases is a
mixture of commercial and quality related aspects, also focusing on performance and guaranty values,
for which the supplier finally should be responsible, and payment is based on. Depending on the scope
of supplies, deliverables and responsibilities even may include the quality of the product produced at
a certain process stage with a specific and highly complex (e.g., fully automated) manufacturing
system. In this case, even additional contracts may become necessary to cover all details of task and
responsibility sharing.

Talking about GMP, qualification and validation responsibilities, the EU GMP Guide Part I for medicinal
products states that the heads of production and quality control should “ensure the qualification and
maintenance of their departments, premises and equipment and to ensure that the appropriate
validations are done” (2.7 and 2.8).

In practice the responsibility for qualification cannot be delegated but qualification tasks may be
delegated, also to outside parties, provided there is quality oversight of the tasks.

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4.2.2 Content of a Contract

Dependent on the size of a project, such contracts can be extensive and may include descriptions of
scope and details of deliverables, timelines for deliverables, milestone plans, prices, payment terms,
liabilities and many more. Regarding qualification activities, contracts moreover include the scope of
qualification support and phases of qualification to be supported. Also, in many cases it is regulated
how the qualification work of a supplier will finally be integrated into the pharmaceutical customer’s
overall qualification system. This may be the way to fully accept the supplier’s qualification documents
or only to accept the test plans and records, while the qualification cover sheets are those of the
pharmaceutical customer.

For this part of the contract – the outsourced qualification – it is important to regulate in detail, who
is doing what to which extend and how in details the documentation should look like and who is going
to sign the documents for which role of responsibility.

The checklist in Appendix 10 provides help to check a contract for completeness of quality and
qualification related aspects, which should be regulated between the pharmaceutical manufacturer
and the supplier.

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5 Customer Activities

5.1 Introduction
Within the pharmaceutical customer’s organisation, a qualification and validation project is typically
managed according to a Validation Master plan (VMP) as described in EU GMP Annex 15. It outlines
the qualification and validation activities for the project.

Suppliers typically receive a Request for Proposal (RfP) document with an initial User Requirement
Specification (URS) and other documents related to the scope of the project and its commercial terms.
The initial URS should be negotiated and adapted as an agreed User Requirement Specification which
is a common point of reference throughout the qualification project.

The pharmaceutical customer’s initial requirements, especially regarding the pharmaceutical products
and processes are an important starting point for Quality Risk Management activities of the project
and especially the identification of the Critical Aspects of the manufacturing systems in scope.

The pharmaceutical product and process requirements are proprietary knowhow of the
pharmaceutical company and as such highly confidential. Some pharmaceutical companies use a
“Product and Process User Requirement Specification” (PPURS) as an overview document. It also
reflects the marketing authorization/product registration aspects. The PPURS is an overview with the
essential product and process information for a specific product across all its manufacturing steps
typically including a quality risk assessment summary of the product and processes. This serves as the
initial quality risk assessment for the product and the process in scope. The PPURS is normally not
shared with suppliers but used as basis for the URS requirements for each manufacturing system,
based on the product‐ and process‐related requirements and associated quality risk assessments. As
soon as sensitive information is exchanged a non‐disclosure agreement should be in place. Appendix
2 includes an overview of a typical structure of a PPURS.

Before selecting and contracting the supplier there should be a thorough supplier assessment as
described in section 5.3 and appendix 3.

Once the supplier is identified the project activities should be negotiated and agreed, e.g., in one or
more joint workshops. It is important that the customer’s initial URS and information needed to
identify, assess and control critical aspects of the manufacturing systems is discussed with the
supplier(s) and adapted as a mutually agreed and understood set of project requirements und put into
an agreed URS as the point of reference throughout the rest of the whole project.

There must be a written contract between the pharmaceutical customer and the supplier which clearly
establishes the roles and responsibilities of each party (see sections 4. 2 and 6.2). The pharmaceutical
customer is responsible for assessing suitability and the competence of the supplier as well as for
ensuring that the principles and guidelines of GMP are followed and the results are reliable, including
aspects of data integrity. Also, the mutual understanding of terminology and definitions between
supplier and pharmaceutical customer is essential for project success, including impact of key
regulatory terminology. The pharmaceutical customer should clearly define which regulations will be
applied (EU, FDA regulation or others) and prepare for early input in the project, preferably as part of
a Project Quality Plan (PQP). A template example of a PQP is in Appendix 6.

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The pharmaceutical customer activities described in this guide should be conducted with a life cycle
perspective and the project life cycle should be described in PQP, e.g., design, review, construction,
testing etc. involving the supplier’s quality system and relevant guidelines, standards etc. as Good
Engineering Practices.

Depending on the scope of services agreed between the pharmaceutical customer and the supplier
the European GMP regulations regarding outsourced activities need to be considered as applicable.
The regulatory expectation is that the pharmaceutical customer is responsible for any outsourced
activities, incorporating quality risk management principles.

5.2 User Requirement Specification

The requirements concerning manufacturing systems should be defined in a User Requirement
Specification (URS) that describes what is needed in terms of function, features, abilities and
performance characteristics for the systems to fulfil the intended use. It is a regulatory expectation
that essential elements of quality requirements related to the pharmaceutical product and the
manufacturing process are defined as well as requirements related to the mitigation of GMP‐related
risks to an acceptable level. Where the marketing authorization holder and the manufacturer are not
the same, appropriate arrangements should be in place taking into account the requirements of the
marketing authorization.

The URS should be based on the intended use of the equipment and should be a point of reference
throughout the project life cycle. Especially for the Design Qualification and the final Performance
Qualification the URS is important to demonstrate that the user requirements can be met, and that
the manufacturing system is fit for intended use.

The URS should be well structured, clear, and precise on what has to be accomplished (‘must have’)
and outline the activities or documentation to be delivered.

The agreed URS should be part of the contract. It may be combined with other specifications, e.g.,
general technical and GMP‐related requirements, company standards and guidelines etc. Appendix 2
contains a template example of an URS.

5.3 Supplier Assessment

The supplier selection should include an assessment of the supplier’s ability to deliver the expected
technical scope of supply and related services. This selection should be part of the Quality Risk
Management. The Quality Unit and associated departments of the pharmaceutical customer should
run the supplier evaluation in a systematic manner and therefore, are responsible to assess, approve
and monitor providers of outsourced activities.

This assessment should include, but is not limited to, the supplier’s capabilities for provision of
expected technical documents, design documentation, test protocols, test execution, deviation
management and change management as addressed by Good Engineering Practice. These activities
and documents may be part in the supplier’s quality management system. Therefore, the supplier
selection is an important part of the pharmaceutical customer’s responsibilities and the assessments
of suppliers and their capabilities should be documented.

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Especially if suppliers are using their own format for test documentation it is important that they follow
a quality system that ensures consistency, traceability and good documentation practice. For ISO 9001
certified suppliers this is part of their quality system certification and should be easily assessable.

The pharmaceutical customer should involve relevant subject matter experts in the supplier
evaluation, depending on the scope of the project. This may involve quality, engineering, automation,
production or other areas of subject matter expertise. Supplier assessment often requires auditing the
supplier’s facilities, processes and organisation. The intensity and scope of assessment can vary and
be influenced by the quality impact of supplier's scope of delivery.

The outcome of the supplier assessment should be used to determine:

 Which parts of the supplier’s quality system to use and/or supplement in the project

 Expected extent to suppliers testing and documentation may be used as part of the qualification

 Expected level of oversight and participation that the pharmaceutical customer or 3rd parties
should perform

 Expected level of additional testing and documentation to be performed by the pharmaceutical

customer or 3rd parties

These conclusions should be reflected in the Project Quality Plan. After the selection of the supplier
there should be a quality agreement for the project, typically in an agreed Project Quality Plan (PQP)
written by the supplier.

Appendix 3 includes a list of issues to be considered in a supplier evaluation.

5.4 Quality Risk Assessment and Critical Aspects

The Quality Risk Assessments are part of the Quality Risk Management activities that in context with
commissioning, qualification and validation should identify and manage risks primarily associated with
product quality finally linked to the end user’s (patient) safety and therefore requiring the thorough
assessment of

 product quality attributes

 ability to maintain the process in the state of control during routine commercial production.

 compliance with general regulatory and GMP requirements

 other technical and operational aspects with potential impact on product quality.

For pharmaceutical product quality the quality risk management activity typically starts with the
Critical Quality Attributes (CQA) of the product and the related Critical Process Parameters (CPP) of the
production process in scope of a project. For recently approved pharmaceutical products these are
defined in the Marketing Authorisation or in regulatory approval documents. For older (legacy)
products, they should be identified by the pharmaceutical company. In either case these critical
attributes are assessed in a first Quality Risk Assessment, called QRA 0 in this guide, which is followed
by subsequent risk assessments named QRA 1, etc.

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Any deviation from predefined limits may have a potential impact on safety, efficacy and quality. CQAs
are typically linked to the product specifications considering assay, impurities, potency and any other
chemical, physical or microbial properties. For more explanation of CQA and CPP please see EU GMP
Annex 15 or ICH Q8 Pharmaceutical Development.

Product quality and related CQAs are influenced by the manufacturing process. The identification and
control of CQAs and CPPs are essential for keeping a process reproducible and thus to allow production
of the pharmaceutical products according to their specification and approval.

There can be other production issues than CPPs that can affect the product quality. Some
pharmaceutical companies use the term Critical to Quality (CTQ) for such aspects (e.g., the
environmental conditions).

The control of CQAs and CPPs as well as other CTQs may be affected by the manufacturing systems
with certain functions, features, and performance elements, which in general are called Critical Aspects
(CA) as defined in the ASTM E2500 standard. The identification of CAs is essential in quality risk
management activities for a manufacturing system and should be addressed during the course of the
manufacturing system risk assessment (QRA 1 etc.).

Table 1 illustrates a Critical Aspects project example for a formulation tank system where the
uniformity of the product is ensured by controlled agitation. From the product and process
development the product uniformity is identified as a CQA, and it depends on two CPPs: the agitation
speed and agitation time.

During the Design Review (in QRA 1) it may be decided to mitigate risk to the product uniformity by
adding measures to prevent failure on the product (risk control mechanism) and measure to detect
the failure (risk detection) such as agitator control or alarm on agitator speed. ISPE’s Baseline Guide
for Commissioning and Qualification, revision 2 uses the term “Critical Design Elements (CDE)” to
identify critical aspects risk control in the design. Other measures may be procedural controls (SOPs)
for the agitation process.

Table 1 Example for link between CQA/CPP and Critical Aspects (CQA) and Critical Design Elements (CDE)

CQA CPP Quality risks Critical Aspects

Risk control Risk detection
Product Agitation speed Agitator speed Speed Control Alarm on speed
uniformity failure system (CDE) deviation (CDE)

Agitation time Agitation time Speed agitation Recording of

failure system (CDE) agitation time
(CDE)
Work instruction
(SOP)

Identification of CAs should be part of the risk assessment of the manufacturing system, as described
in section 5.5 Critical Aspects Risk Management.

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In case that CQA and CPPs are not know in early phases of a project, e.g., development for the product
is not completed, it is necessary to make assumptions for CQAs and CPPs and document them.

5.5 Critical Aspects Risk Management

Once the critical aspects are identified, the associated risk management activities during project
execution should be executed and documented. A useful tool for this is a matrix for Critical Aspects
Risk Assessment (CARA) as described in Appendix 1. The CARA matrix is used to document the quality
risk management activities of the Critical Aspects during QRA 1, 2 and 3. It lists all the critical aspects
of the manufacturing systems, their failure modes, the identified risk control mechanisms and related
activities of the project execution. The CARA matrix is a life cycle document that is updated stepwise
as the project is executed.

The Critical Aspects Risk Assessments may use the risk management method called “Failure Mode,
Effects and Criticality Analysis” (FMECA) or similar method for each manufacturing system. It should
identify all Critical Aspects, related to CQA, CPP or other CTQ aspects as described in section 5.4. As
illustrated in the example in Appendix 1, the CARA matrix includes the risk analysis with failure modes,
possible risk mitigation changes and the associated verification activities. It is typically prepared during
design phase and can be used for Design Qualification Each update should be approved by the quality
assurance function of the pharmaceutical customer.

The Critical Aspects should be identified early and included in the URS, so they are shared with the
supplier during design, review and verification activities. That means that CARA can be used to
document the iterative process to identify risks to critical aspects, determine how to control them and
improve the design until the point, where all risks to the quality of the product have been controlled
to an acceptable level.

There may be several Design Review meetings during a project depending on its scope and approach.
There should be a clear conclusion on that the design meets its intended use and related GMP
requirements so the design has been qualified (see also 5.6 Verification and Qualification). For complex
systems, a formal design freeze or design approval may be agreed by supplier and customer.

The Design Reviews may be supported by a Requirement Traceability Matrix (RTM), which links all
the URS requirements with relevant design information for each requirement. This is useful to ensure
that all URS requirements are met and may also be used to plan verification activities.

It may be useful in larger project to list all tests for the URS requirements (both those related to Critical
Aspects and all others) in a separate Test Matrix (TM) to plan if they are to be done in FAT, SAT, or
other testing activities. Appendix 4 also includes a template example of a TM. The TM and the RTM
may be combined in one document.

These tools can be used to streamline the qualification activities and support a good cooperation with
mutual understanding between customers and suppliers and to avoid multiple testing throughout the
qualification activities.

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Figure 4 (based on the ASTM E2500 standard with addition of the supplier involvement on
Construction/Assembly and Test [Installation, Operation], marked in grey) illustrates a science‐ and
risk‐based qualification approach where the starting point is the initial quality risk assessment
associated with the pharmaceutical product and process, based on the development of the
pharmaceutical product and process (QRA 0). Follow‐up risk management activities are the Critical
Aspects Risk Identification (QRA 1), the Design Qualification (QRA 2) and the Qualification Completion
Risk Assessment (QRA 3). The risk management approach may be adapted according to the project
specific needs.

Risk management activities should be carried out by a team of SMEs within key areas such as quality,
process, engineering, automation/IT, equipment design etc.

Figure 4 Enhanced project life cycle approach with Quality Risk Management activities

Quality Risk Assessment 0 (QRA 0): Product and Process Critical Requirements
The initial Quality Risk Assessment 0 (QRA 0) should be started during the pharmaceutical company’s
process development, ideally based on the control strategy as described in Section 5.4. This includes
the CQAs of the pharmaceutical product, Critical Process Parameters CPPs of the production process
and other requirements that are CTQ aspects of the pharmaceutical product. QRA 0 should define the
“Severity” as the consequence of a hazard impacting the CQA.

CTQ aspects (incl. CQAs and CPPs) may be part of a Product and Process User Requirement
Specification (PPURS) in some pharmaceutical companies (see Section 5.1), thus linking to the market
authorisation of the pharmaceutical product.

Quality Risk Assessment 1 (QRA 1): Critical Aspects Identification

The agreed URS for a manufacturing system should be reviewed and possibly adjusted to ensure that
risk mitigation and GMP compliance have been addressed sufficiently in the URS, and that all critical
aspects as outlined in QRA 0 are reflected.

Quality Risk Assessment 2 (QRA 2): Design Qualification

The design of the manufacturing systems should be reviewed by the pharmaceutical customer and
supplier for sufficient quality risk mitigation and GMP compliance, including formal acceptance of
residual risk elements. This may raise new requirements in the URS, based on identified risk mitigations
by change to design or functionality (or by procedural measures in e.g., Standard Operational

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Procedures (SOPs) for the operation of the production). If the risk cannot be mitigated to an acceptable
level, the design should be changed or appropriate procedures (SOP) need to implemented to mitigate
risk. Based on this the detailed test execution and acceptance criteria for at least Critical Aspects and
other GMP aspects should be established and documented as part of the overall qualification plan.
Output of this QRA phase is the DQ report. This is a customer responsibility and may be supported by
the supplier.

Quality Risk Assessment 3 (QRA 3): Qualification Completion Risk Assessment

After the completion of the testing activities, the test results are reviewed and documented to accept
and release the system for subsequent Process Validation activities. When all tests are passed and the
test documentation acceptable, the verification review conclusion may be documented in a System
Acceptance and Release Report.

5.6 Verification and Qualification

Design Qualification should be completed prior to construction and building of each individual
equipment. Design Qualification shall be completed prior to testing (for details see CARA 2 and 6.5).

Qualification should verify that the manufacturing system meets the requirements regarding
installation, operation and performance requirements, including that it is fit for its intended use for
the specific process of the customer.

All testing activities should be pre‐defined, and the test results documented in such a way, that they
can be used as documented evidence as described in section 3.2 Good Engineering Practice. During
testing Change Management (section 6.3) and Deviation Management (section 6.4) should be applied
to ensure the validity of the test and documentation.

Appendix 5 includes template example for deviation management. Both supplier and pharmaceutical
customer should agree on how to manage open issues. Typically, deviations related to Critical Aspects
should involve the quality assurance function of the pharmaceutical company.

The combination of commissioning and qualification is explained in section 6.8. Appendix 7 shows a
qualification documentation template example.

5.7 Integration Testing

Integration testing is recommended and may involve all manufacturing systems and utility systems in
scope and is typically done under production‐like conditions with all auxiliary equipment and
associated environment to demonstrate that the systems can operate in accordance with the process
requirements. The testing is typically done based on GEP and should include all anticipated operating
ranges of routine production as well as interventions, and start‐up and stoppage.

Many pharmaceutical companies require integration testing to be completed before starting the
Performance Qualification. Some do integration testing and Performance Qualification (PQ) of each
manufacturing system with an “interim release” before the overall, integration test of all systems incl.
utilities.

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5.8 System Acceptance and Release Report

The completed testing and verification activities may be concluded in a System Acceptance and
Release Report (SARR) to document that the inspection and test activities for all manufacturing
systems are completed. In the event, that several manufacturing systems forms a production line,
SARR must consider each single equipment as well as the entire production line. It may refer to the
Project Quality Plan and other supporting documents such as Test Matrix, CARA, and others.

It should be approved by the pharmaceutical company’s quality assurance function and should include
a clear conclusion on whether the manufacturing system is fit for its intended use, as specified in the
URS. It may include verification that the pharmaceutical company’s quality system is feasible for the
operation of the manufacturing system(s), including relevant SOPs, training etc. It typically marks the
formal release of the manufacturing system from qualification to the subsequent Process Validation
activities.

5.9 Process Validation

5.9.1 Introduction
Process Validation activities are required by the regulatory authorities worldwide and the expectations
for a successful Process Validation are a precondition for the permission to produce a pharmaceutical
product commercially. The regulations of Process Validation generally follow the core concept of
Quality Risk Management and a robust process development so the activities for Process Validation
should be based on the same Quality Risk Assessments including the Critical Quality Attributes of the
product, the Critical Process Parameters of the process and other Critical Parameters as described in
Section 5.5 Critical Aspects Risk Management.

The fundamental purpose of the Process Validation is to demonstrate that the process, when operating
within established parameters can effectively and reproducibly produce a product meeting its
predetermined specifications and quality attributes. In pharmaceutical terminology it must be shown
that all critical quality attributes of the product and all critical process parameters are consistently met
during manufacturing and that operating ranges can be maintained during routine production by the
developed control strategy consisting of the master batch record, the in‐process controls, the sampling
and specifications.

Process Validation requires qualification of the manufacturing systems to demonstrate that they are
fit for their intended use. Besides, Process Validation should build on knowledge from the process
development, and it should be followed by an ongoing evaluation of the process performance during
commercial production. The terminology is slightly different between US FDA’s Process Validation
Guide (2011) and the EU GMP Annex 15 on Qualification and Validation (2015) but the expectations
are very similar.

Thus, Process Validation has become a continual effort to be performed throughout the entire life
cycle of the process, called Ongoing Process Verification (OPV) (US FDA’s Process Validation Guide uses
the term Continued Process Verification while the EU GMP Annex 15 is using Ongoing Process
Verification for similar regulatory requirements). The OPV program should include the use of statistical

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tools to support the conclusions regarding control of the process and product quality with the
established manufacturing process, where applicable as part of an ongoing program.
Pharmaceutical companies subjected to US FDA approval may notice that in contrast to the US FDA
Process Validation guide, the EU regulations have no sharp boundary between the stages of validation
(US: Stage 1 is development of the process design; Stage 2 is process Performance Qualification (initial
Process Validation); Stage 3 is continued process verification).

The EU GMP Annex 15 mentions three approaches to Process Validation: 1. Traditional Process
Validation, 2. Continuous Process Validation and 3. Hybrid approach, which is a mix of 1 and 2. For all
three approaches to Process Validation the ongoing process verification is required during life cycle.

In both EU and US regulations validation activities should be based on the product‐ and process
knowledge when deciding test parameters, sampling frequency, amount and a statistical evaluation
on the process performance, number of validation batches to be manufactured and related acceptance
criteria. EU GMP Annex 15 states that “A Process Validation protocol should be prepared which defines
the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance
criteria which should be based on development data or documented process knowledge”. Thus, the
quality risk assessment and related identification of CQA, CPP, etc., which is used for qualification
should serve as a basis for the Process Validation activities and documentation in an integrated
qualification and validation approach.

Before commercial distribution of a product can begin, all involved manufacturing systems must be
qualified and all processes must be validated to demonstrate that they are fit for their intended use
and can produce the product robust and reliably throughout its lifetime. The ongoing process
verification effort will continue as long as the product is produced and distributed commercially.

There are several industry guidelines about the Process Validation activities as a separate activity.
There should be a link between the qualification and validation activities. Ideally, they are based on
the same initial Quality Risk Assessments and the Critical Aspects of the qualification activities should
be consistent with the Process Validation activities. In many pharmaceutical companies’ qualification
and validation activities are managed by different departments and different SMEs (as outlined in
section 3.4 Roles and Responsibilities). So, a cross‐functional cooperation is important to achieve
synergies between qualification and validation activities.

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Figure 5 Input and output from integrated Qualification and Validation

5.9.2 Involving Suppliers in Process Validation Activities

The cooperation between the pharmaceutical customer and the supplier may extend into the Process
Validation activities, although the cooperation traditionally ends with the System Acceptance and
Release. There may be an overlap between the Performance Qualification and the Process Validation
activities, but the Process Validation must be done on real products with all necessary support systems,
utilities, personnel, SOPs etc. whereas Performance Qualification may be done on a simulated product.

Advanced manufacturing systems which include a high degree of process and product knowledge, e.g.,
for continuous manufacturing or other emerging technologies or to implement in an early stage the
precondition for a high‐level process control strategy, encourage such cooperation since the supplier
typically assist in setting up the process model and formulas that the process will be using. The Process
Validation for such systems may include online measurement of important product attributes by
Process Analytical Technology (PAT) and this can be used for a continuous process verification
approach that may require a very close involvement of the supplier during both qualification and
validation of the manufacturing system. The same purpose belongs to the continued or ongoing
process verification which requires, implementing as high‐level model, interface functions for export
of CPPs or online measurements for CQAs for the monitoring program to demonstrate that the process
remains capable. This phase can be supported by the supplier based on an agreement fixed in a service
contract.

Example: A CQA of a typical blistering process is the tightness of the blister. This CQA is influenced by
3 CPPs for the sealing process: Time, Temperature and Pressure. The CQA and the CPPs were identified
in the initial quality risk assessment (QRA 0) as part of developing a robust sealing process with stable
performance.

The initial Process Validation data can be used as basis for the continued / ongoing process verification
acceptance criteria (e.g., by statistical Control Chart SPC) or for periodic activities, e.g., re‐calculation
of the capability indices, or trend evaluation. The approach to calculate process capabilities can be
used for follow‐up qualification assessments as well, e.g., to calculate machine capabilities.

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Overall, the effort of qualification and validation, including the optional involvement of suppliers in
Process Validation activities, should bear in mind that a regulatory GMP inspection scope is broader
than the qualification and validation and involves registration documents with the following
requirements:

 descriptions of the fundamental manufacturing process

 the design of the equipment used

 details of the in‐process controls

 the risk assessments for determining the scope of validation

5.9.3 Involving Suppliers in Feasibility Testing

For standard equipment or configured standard equipment (see section 7) it may be useful to test the
feasibility of the manufacturing system before proceeding with the equipment. This typically involves
the supplier in feasibility tests with the real product or a simulated product prior to order. For
economic reasons alone, FAT feasibility studies are often carried out at the supplier's premises before
a purchase contract is concluded. If such tests are to be used for a later qualification, the client must
ensure in good time that the EU‐GMP‐requirements with regard to test design and documentation are
complied with. The early cooperation between the pharmaceutical customer and the supplier could
streamline the overall qualification and validation activities, e.g., for sterilisation or freeze‐drying
cycles, grinding processes, packaging processes etc. as illustrated in figure 6.

Figure 6 Initial feasibility testing and final performance testing

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6 Supplier Activities

6.1 Introduction
Generally, suppliers make significant effort in comprehensive testing of their products and solutions
to demonstrate that they deliver manufacturing systems of good quality. If the supplier’s Good
Engineering Practice is matching GMP requirements with regard to procedures, acceptance criteria
and documentation including data integrity, then the pharmaceutical customers may use the outcome
of these supplier activities to support demonstrating that the manufacturing system is designed,
constructed, and tested to fulfil the requirements.

If this is the aim of a pharmaceutical customer and it is made clear at a very early stage of a project, it
is possible to avoid testing the same attributes multiple times in various stages of acceptance tests.
The aim of a ‘single‐test qualification’ approach is to use testing results throughout the complete
project.

6.2 Agreed URS and Project Quality Plan (PQP)

The supplier’s quality activities start from an agreed User Requirement Specification as described in
section 5.2. Some suppliers have templates or examples for their specific equipment which may be a
good starting point or useful inspiration for the development of a URS. The pharmaceutical customer
has the knowledge about the product, the process, the GMP requirements and other important
requirements that can be understood by the supplier by means of a clear and comprehensive
cooperation. The supplier input is an important contribution to the final and agreed URS as part of the
contractual agreements including also scope of supply, services, timelines, and other supporting
documents.

A separate Project Quality Plan (PQP) may be agreed with an overview of the project and the quality
activities, possibly as attachment to the contract. It typically includes the project scope, organisation,
reference to supplier’s quality system, document list and distribution, approval matrix, Design
Reviews, sub‐contractor management, procedures related to construction, overview of testing
activities, change management, deviation management, storage, and shipping, as well as reference to
relevant principles, procedures, standards and applicable guidelines. This document is normally
created by the supplier and agreed with the pharmaceutical customer. Appendix 6 includes a PQP
template example.

6.3 Change Management

The project change management activities are an important part of the project management activities
but also of the planning and execution of the related review, inspection and test activities. The handling
should be described in the PQP to ensure that relevant requirement documents, design documents
etc. are updated to reflect agreed changes. Changes should be documented so they can be tracked,
and they should be linked to Quality Risk Management.

At this point, it should be pointed out, that the supplier should not make unauthorized changes,
outside the terms of the Contract, which may adversely affect the quality of the outsourced activities

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for the client. The distinction between an "engineering change" and a GMP‐related change should not
be left to the supplier alone.
Normally suppliers have an internal change management process, based on their quality management
system. The link between the project change management and the supplier’s internal change
management is important, especially in the follow‐up on deviations, non‐conformities etc. during
review and testing. It is typically associated with a so‐called ‘open punch list’ or ‘open items list’ as
exemplified in Appendix 5.

The supplier is also expected to have change management to ensure that all parts of the design,
hardware and software and other outcomes are kept up‐to‐date and that subsequent changes are
cascaded to all relevant elements of design etc.

It may be useful to distinguish between the engineering change management and GMP‐related change
management of the supplier. For GMP related changes it can be necessary to involve the
pharmaceutical customer’s quality function (e.g., when related to Critical Aspects). Appendix 5
includes a template example of Project Change Management with further explanation.

6.4 Deviation Management

The management of deviations and non‐conformities should be agreed including documenting
deviations and non‐conformities as well as the correction of errors. It should cover deviations from
agreed procedures and methods. This is important for the project progress and workload whether
identified defects are recorded on the punch list for GEP correction or on a list involving formalised
deviation management, typically to be approved by the pharmaceutical customer’s quality function.
This should be addressed in the PQP of the project.

Defects resulting from mistakes and errors (typical punch list items) should preferably be corrected
during the review, inspection and test activities. For deviations it should be agreed between
pharmaceutical customer and supplier how deviations and changes will be managed, especially if they
involve scope changes and approvals.

Appendix 5 includes a template example regarding Change Management and Deviation Management.

6.5 Design Activities, Engineering Activities

Engineering is the phase in technical projects, where work on the design and technical details is done.
A number of design documents are prepared based on the URS and discussed among pharmaceutical
customers, suppliers and engineering companies, if involved. The creation of the design drawings,
specifications, component lists and other design documents is the initiation of a system with quality
built in.

The cooperation between supplier and pharmaceutical customer during the design phase can be
described as a combination of engineering activities (where initial functional specifications, P&IDs etc.
are developed by the supplier or the engineering company and subjected to internal Design Reviews)
and design qualification activity (where the initial engineering documents are reviewed and approved
by the pharmaceutical customer).

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The agreement between supplier and customer with the approval of the design is very important for
both supplier and pharmaceutical customer since it is the basis for consecutive supplier activities such
as detail design, procurement, assembly, software development etc. and particularly the mutual basis
for the Design Qualification (see section 5.6).

Larger engineering projects typically follow three stages of design: Conceptual design, Basic design and
Detailed design or a variation of these. Conceptual Design is a very general summary of the overall
layout, design principles and project scope, Basic Design handles the overall equipment or system
level, whereas during the Detailed Design, all parts, components, modules, and programming details
are specified.

In the cooperation between the pharmaceutical customer and supplier the supplier typically has a
number of activities that does not involve the pharmaceutical customer, but the joint activities and
decision points should be described in the PQP. Figure 7 illustrates a cooperation example where
activities of Specification & Design and Construction/ Assembly are described in more detail from a
supplier perspective with the link to the customer’s Design Qualification (DQ).

Figure 7 Activities of Specification & Design and Construction/Assembly phases from a supplier perspective.

As soon as a design document is completed and the requirements of the URS and the other
requirements have been considered and there is a common understanding between pharmaceutical
customer and supplier, the design is considered “frozen”. This implies that design documents are
approved and released within the supplier’s organisation for subsequent detail design, procurement,
manufacturing etc. Individual design documents may have their own individual design freeze. The term
“design freeze” is typically a project milestone, the action related to this milestone is the document
approval and the documents related to this milestone are the “approved design documents”.
There are many types of design documents, e.g., Functional Specifications, Software Design
Specifications, Technical Design Documents, P&IDs, Component Specifications etc. They should
document the intended design and function of the relevant manufacturing system and should contain

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enough details to form the basis for Design Review activities. They must be version controlled,
reviewed and agreed as outlined in the PQP. Updates of requirement and design documents and their
intervals should be agreed beforehand between pharmaceutical customer and supplier and
documented in the PQP. Changes should be managed as agreed.

The Functional Specification is one important document among many others that a supplier will
develop during the design & engineering phase where pharmaceutical customer, supplier and possibly
an engineering company typically collaborate. It describes the detailed functions of the manufacturing
system, i.e., ‘what the system will do’.

In general, it is helpful to use suppliers’ standard design documents, test documents etc. to make best
use of the supplier’s capabilities.

In case the supplier involves any engineering company as a third party, the tasks and responsibilities
of the third party shall be described in a contract and PQP respectively to ensure that information and
knowledge are made available in the same way as between the client and supplier.

6.6 Design Review and its Link to Design Qualification (DQ)

Technical and compliance reviews of the engineering documents, called Design Reviews, are important
elements in the design process, especially when they are used for the pharmaceutical customer’s
Design Qualification as described in Section 5. Design Review and review meetings should be planned
into the design process and typically includes both internal supplier reviews and review meetings with
the pharmaceutical customer.

6.7 Activities during Assembly/Construction

Depending on the manufacturing system in scope, the pharmaceutical customer’s knowledge
concerning the supplier and the supplier’s capabilities, a pharmaceutical customer may want to carry
out inspections during the assembly activities. Sometimes it is appropriate and important to perform
testing activities during the building or assembly of the manufacturing system. Activities such as
verification of material certificates, instrument certificates, welding, surface treatment, gaskets, piping
drainability, and other technical solutions can be done effectively and efficiently at this phase of the
project. Their documentation, including certificates, photos and other inspection documents is an
important part of the documentation of the verification and qualification activities.

It is expected that the supplier performs necessary checks or testing activities during the assembly and
construction to ensure that the design is realized with the right level of quality. This is especially
important when using sub‐suppliers for significant parts of the work. The pharmaceutical customer
may also like to perform supervision in key stages or for specific elements like welding, material
selection, calibration etc.

6.8 Commissioning and Qualification Testing

6.8.1 Introduction
Most suppliers have developed or adapted specifications, drawings, material management
procedures, testing and inspections in acceptable formats and methods as agreed with the

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pharmaceutical customer to make the supplier documentation useful for the qualification activities.
The purpose for testing is to identify errors and correct them as soon as possible. Overall, the testing
should confirm that the system is implemented as designed and performs as intended so that it may
be concluded that it is fit for intended use. Particularly when engineering and pharmaceutical activities
overlap, it must be clear which tests are to be carried out and documented in accordance with EU‐
GMP‐Guidelines. This can be described in the PQP.

Some companies use the term commissioning for these activities to emphasize that they are
engineering activities in the meaning “a planned, managed and documented approach to the setting
to work, start‐up, regulation and adjustment, and installation/operation/performance verification
necessary to bring equipment, automation and systems to a fully operational state meeting safety and
end‐user requirements.” (ASTM E2500). These activities may include acceptance testing, especially
Factory Acceptance Test (FAT) and Site Acceptance Test (SAT). Before this testing and qualification, the
supplier may conduct internal tests, some of which may go beyond the tests that the pharmaceutical
customer has specified.

6.8.2 Installation Testing and Qualification

The installation testing follows the installation and assembly of the manufacturing system and verifies
that all parts of the manufacturing system, such as components (e.g., valves, pumps, pipes etc.),
software modules, wires, etc. are mechanically and electrically installed and connected as specified.

These activities depend very much on the type of manufacturing system and include both technical
and GMP‐related aspects such as material types, piping slope, drainability, airlocks, dead‐legs,
cleanability of surfaces and many other technical aspects that are covered in several industry standards
and guidelines related to Good Engineering Practice of pharmaceutical manufacturing systems.
Generally, installation testing is a prerequisite for operational testing and for some activities, for
example input/output testing and calibration of instruments.

Some of the installation tests are typically part of the Factory Acceptance Test (FAT), especially for
those parts of manufacturing systems that are not disassembled for transportation to the
pharmaceutical customer’s site. Installation tests where components, have to be dismantled after FAT
due to transportation, as well as other tests, which could have been influenced by transportation, have
to be repeated. Such repetitions may be described in the Test Matrix, see Appendix 1.

Site Acceptance Test (SAT) is performed after the manufacturing system has been installed in the
pharmaceutical customer’s facility. FAT and SAT typically address both the installation and the function
of the manufacturing system, and they should be executed and documented as agreed.

The documented tests may be used by the customer to support Installation Qualification (IQ), as
mentioned in some GMP regulations, e.g., EU GMP Annex 15 on Qualification and Validation.

6.8.3 Operational Testing and Qualification

Operational testing is focusing on functional aspects and is intended to demonstrate that the
manufacturing system’s functions are performing as specified in URS or design documents such as
functional specifications and/or software design specifications.

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Some of the operational tests may be performed as part of the Factory Acceptance Test (FAT),
especially for those parts of manufacturing systems that are not disassembled for transportation to
the pharmaceutical customer’s site.

The documented functional tests may be used by the customer to support Operational Qualification
(OQ), as mentioned in some GMP regulations, e.g., EU GMP Annex 15 on Qualification and Validation.

6.8.4 Remote Testing

Travel rules during, e.g., pandemic restrictions have increased acceptance of remote testing without
physical presence at, e.g., the suppliers’ premises during FAT. Also, broad experience with on‐line video
conferencing tools has increased the understanding that remote testing offers saving resources and
cost and can be a good contribution to limit travel and improve sustainability.

When using this for e.g., FAT, the customer can participate in a test execution even when not being at
supplier’s site. Since this is a rather new approach it requires upfront preparation, such as checking of
the IT Infrastructure on both ends, enhanced communication and common understanding of the limits.
A risk assessment should be performed and documented as basis for the decision of using remote
testing in each case.

A description of activities that can contribute to a successful remote testing is included in Appendix 8.

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7 Support by Categorisation

7.1 Introduction
When planning the qualification approach in a project, it has proven useful to use a simple equipment
categorisation approach. Similar approaches are used for software categories according to GAMP 5
and to analytical equipment according to USP <1058>, which distinguish between standard systems,
configurable systems, and customised systems.
In short, a standard system is used without modifications, a configurable system is set up for each
specific application (e.g., an autoclave sterilisation program) and a customised system is built for its
specific purpose (e.g., a bioreactor). See more examples below.
The categorisation approach should be used with caution and should also take other aspects into
consideration, e.g.

a) The manufacturing system is sourced by a supplier, who

 Has established processes and follow them (e.g., ISO 9000ff)
 Is using well known supportive standards or guidelines (e.g., from ASTM, ECA, ISPE)
 If software is involved Is following the GAMP Approach
 Is open for audits and accepts them as a possibility for continual improvement
 has a fundamental understanding of “GMP Thinking”
b) the pharmaceutical customer
 knowing the processes and defines the critical aspects
 listens to the suppliers, be open for widely used solutions and does not want to
reinvent the wheel
 does not force the supplier into not engineer to order (ETO) solutions (unless this is
clearly communicated and mutually agreed)
 has a focus on the mandatory requirements (GMP)

Categorisation can only be applied as critical aspects are identified. The process for categorization
should be thoroughly described, e.g., in a SOP

7.2 Starting Point for Categorisation of Manufacturing Systems

A categorisation approach may start with a first decision, whether a manufacturing system needs to
be subject to qualification or not. This may be done via a system impact assessment where non‐direct‐
impact systems, which have no direct impact on process or product quality, will not need any
qualification, but only commissioning activities. Direct impact systems need qualification and for this
can undergo categorization.

7.3 Categorization of direct Impact Manufacturing Systems

7.3.1 Categorization for Qualification Activities
What is the purpose and expected benefit of categorisation of direct impact systems? The aim is to
reduce the time and effort of related qualification activities. The EU GMP Guide Annex 15 is providing
a mandatory frame of the qualification approach but has to be also based upon the individual GMP
risk of each system and there is a huge variation among the variety of the used equipment and systems.

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Within these Guide, we have defined the following describes 3 main categories of manufacturing
systems with regards to their complexity:

A. Standard (Commercial off‐the‐shelf systems (COTS))

B. Configured (COTS with customer specific configuration of, e.g., sequence, setpoints, timers,
etc.)

C. Customised (designed for the specific customer with specific requirements, that is not
available commercially, due to a special application, technology innovation etc.)

The categorisation has an impact on the entire equipment life cycle and even though it seems in most
cases obvious to which category a system belongs to, this should be analysed very carefully. Of course,
other categorization models with a different number of categorization classes are possible.

For categories A and B, the customer may reduce some activities such as:

 The supplier assessment or audits may be reduced or a documented justification might be

sufficient if the supplier is well‐known to the industry and has manufactured the said chosen
system for several years in higher numbers.

 Every qualification activity according to Annex 15 must be conducted, such as the DQ. In most
cases, the DQ will be done after purchasing by a dedicated group and in accordance with the formal
DQ approach. Category A and B system purchase requirements and commercial technical
descriptions (or even catalogue information) might be sufficient to decide on the equipment's
suitability for intended use. This should be documented in a simplified approach into the life cycle
documentation. No dedicated additional DQ phase needs to be performed.

 The supplier provides technical documentation for that type of equipment (e.g., functional
specification, conformity certificates, risk analysis etc.) and the related quality department of the
pharmaceutical customer accepts the supplier standard as long as all GMP aspects are covered.
No customization of design documents is necessary in terms of layout or preferred structure.

 Customer test activities including Factory Acceptance Test might be done by physical
presence of the customer, hybrid or remotely.

Other simplifications can be done based on a case‐by‐case risk‐based decision.

With regards to quality or qualification related activities at least the following activities should be
done for any of the direct impact systems:

 Risk assessment, possibly supported by equipment‐based supplier risk assessment

 Performance Qualification (PQ) to ensure that the manufacturing system as installed

operates as intended in the integrated environment (see also section 5.7 Integration
Testing)

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All other qualification activities as per Annex 15 must be considered. For category A and B systems a
risk‐based rationale might allow for reduced verification for IQ or OQ. Properly documented supplier
verification of non‐customized features or functions might be considered as sufficient as proof for
intended use.

In any case, decisions on reduced testing need to be justified, documented and should be part of the
systems life cycle documentation.

For customised manufacturing systems (category C) where the reduced approach does not apply, the
full approach of this guide should be applied.

For all categories, tests focusing on critical aspects always involve the customer’s SMEs and Quality
Function.

7.3.2 Additional Points to consider

A system categorisation approach is often useful but should be combined with an assessment of the
criticality of the system, e.g., the technology complexity, the specific application criticality and the
supplier capabilities. Here are some points to consider:

System criticality, considering:

‐ system complexity
‐ grade of automation
‐ grade of standardisation

Usage criticality, considering:

‐ impact on product quality and process
‐ ease of operation
‐ interaction with other systems
‐ knowledge and experience of the pharmaceutical manufacturer

Supplier criticality, considering:

‐ experience with pharmaceutical customers and GMP requirements, history, quality
‐ system experiences (number of systems produced)
‐ standardised manufacturing process

7.3.3 Examples for categorized Systems

The following table provides some examples for categorization including the proposed verification
procedures. The table considers the system’s complexity as well as the other critical attributes as
outlined in section 7.3.2

Table 2 includes examples of the 3 categories:

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 Good Practice Guide Qualification and Validation

Category Name Verification Approach Typical example

A Standard Typically verified by commissioning Refrigerator
Non‐complex based on GEP, typically supervised or Mobile tanks
system (few executed with the customer. Stand‐alone transfer pump
functions), low Qualification (IQ/OQ) reduced to
impact on process income checks and/or onsite as built
and product checks.
quality, long term
supplier If the system includes Critical Aspects
the testing typically involves the
(Also called customer’s quality function (PQ).
Commercial off‐
the shelf – COTS)

B Configured Verified as A, but the systems have to Filter Unit

Low complexity, undergo special verification for its Blender
with essential specific configurations and finally has Stand‐alone CIP System
influence on to pass Performance Qualification to
process and ensure that it is fit for its intended use
product quality,
well known, long The PQ involves the customer’s quality
term supplier function.

C Customised Typically verified by commissioning Bioreactor

Complex with and qualification, supplemented by WFI distribution systems
essential specific testing of customized Purification Column
influence on components and functionalities, Integrated CIP system
process and working closely together with the
product quality. customer within several areas.
Supplier is known
but it is not a fully The project involvement typically
standardized includes close cooperation and
system for him< approval of the customer’s quality
function, not only on PQ.

Category A manufacturing systems are typically standard systems that are sold many times (COTS) and
they are to be tested by well‐known suppliers using GEP principles. Suppliers often provide a range of
different products, systems and services, so it must be ensured that the selected equipment meets the
specific customer requirements for the application. Nevertheless, such systems can become critical in
the sense of the categorisation, when they are complex and are intended for use in a process with high
influence on product quality. Also, in case the supplier is a new one, newly started a business, even a
standard system may become critical and will be categorised as B or C.

For Category B manufacturing systems, customers and suppliers are encouraged to cooperate on the
relevant qualification approach to reach a common understanding of the parts where GEP testing is
sufficient and the parts where more in depth verification and documentation is needed. It is
recommended to use supplier’s standard solutions, when possible, to save time and minimize the risk.
Also, it is recommended to use supplier’s standard documents for design and verification activities

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thus limiting the number of new documents to be developed. It is still the responsibility of the
customer to review the supplier’s standard documents and test procedures and approve the
documents as applicable for the manufacturing system. The number of review and approval cycles for
documents should be appropriate to risk and limited. It is recommended to focus on critical aspects.

Category C is to be selected when the customer requirements cannot be fulfilled by a standard

manufacturing system, equipment, or function. This category is also to be selected for standardized
systems when the system is complex with a high influence on process and product quality or the
interaction with other systems leads to a high influence on process and product quality. Critical
Category (C) may also be the category selected when the system itself is standardized but there is
doubt about the quality of the supplier and there is no other choice. Customised equipment is designed
specifically to the customer needs, but if the same partners (pharmaceutical company and supplier)
using similar design and functionality in follow up projects, the criticality maybe lower, and the systems
may be transferred into category B.

7.3.4 Possible Life Cycle Approach for Defined Categories

Appendix 9 provides examples on how to do a risk‐based categorisation keeping the system, usage,
and supplier criticality in mind. It also provides examples on the resulting and qualification related
activities.

Figure 8 illustrates the typical project quality activities that should be considered for the three main
categories of manufacturing systems. Boxes with grey text indicate an activity that may be omitted
depending on the project. The planning of activities should reflect the risk assessment for the
manufacturing system and its application. The assessment, decision and planning in specific projects
should be documented.

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Figure 8 Typical project quality activities for the three main categories

Explanation: grey font indicates that extent of testing activities should be based on risk

The herein suggested approach is just one possibility of categorisation. The categories and the
belonging life cycle activities might not fit for all pharmaceutical companies. The intention of this
section is to provide guidance and suggestions, which must be adapted to the own needs. Anyway,
categorisation provides a pathway to reduce qualification effort. This is beneficial for each project and
each company.

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8 Support by Use of Electronic Documentation

The use of Electronic Documentation (ED) offers benefits for a qualification/validation project when
implemented upfront. The general expectations for Good Documentation Practice should be followed,
as described in section 3.2 for both the pharmaceutical customer and the supplier. The pharmaceutical
customer should manage the ED according to the requirements in EU GMP Annex 11 Computerised
Systems so that technical solutions and technical documentation can be used in the pharmaceutical
company’s final qualification and validation documentation. The integrity of the qualification and
validation data and documentation must be ensured by all participants independent on whether they
are on paper or electronic. Basis for data integrity activities are reflected by ALCOA++ principles
(attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring and
traceable).

For data integrity aspects please refer to authority guidance, e.g., PIC/S PI‐041 and FDA guidance Data
Integrity and Compliance with Drug cGMP Questions and Answers Guidance for Industry.

These agreed preconditions should be described in the PQP or contract as described in sections 4 and
6.2. For further description, see EU GMP volume 4, Part 1, Chapter 4 Documentation.

For the life cycle of the documents the pharmaceutical customer has to decide how data storage and
archiving should be done.

There are many advantages by following paperless qualification and validation execution by faster and
more efficient workflow.

Standardization of processes, templates and documents is a key to success for electronic qualification
and validation tools. Documented evidence should be available, that the system is suitable for
intended use before implementing.

It may be useful to distinguish between two types for Electronic Documentation: The traditional
approach, where handwritten qualification and validation documentation is scanned, or using an
eDMS (electronic Documentation Management System)/VLMS (Validation Life Cycle Management
System).

Traditional approach: Scanned, paper‐based qualification/validation documentation

Customer and supplier need to agree on the format of digitalized qualification documentation. Since
various systems and software packages are on the market, it is recommended to agree on “pdf/A” as
the common file format. Customer and supplier may agree on additional formats (e.g., for drawings),
but this is not the focus of this section.

During the scanning process it has to be ensured that the paper original and the scan have identical
content, in particular that colors (e.g., spectra, plots) are maintained. The scanning and verification
process should be described in an instruction, which should include the verification of
the compliance of the electronic file with the paper original. This is recommended to be verified using

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an electronic signature. After scanning, the document may be uploaded to an eDMS for subsequent
processing (e.g., approval).

Advanced approach: Documents are being created, test executed and approved in electronic format
Software tools or comprehensive software solutions are available to facilitate the life cycle of
qualification and validation information. If a software tool or solution is applied, it needs to be
validated for its intended use.

Paperless qualification and validation documentation can be designed to be more efficient and
effective in project execution and later‐on managing the documented evidence for the system over its
life cycle. If the engineering data base is connected to qualification and validation data base/software,
there may be automatic linking to the correct design documents used as test‐ and reference
documents.

It is preferable to use a validated VLMS of the customer as the repository for all types of documents
created during the qualification and validation process.

This approach can range from single event digital documented evidence creation (e.g., video, pictures)
closely linked to the qualification and validation documentation over Validation Life Cycle
Management Systems for drafting, sharing, executing and approving of documents further on to
systems for handling all qualification and validation activities.

When applying any kind of electronic documentation, the interface for data exchange (original data
plus related meta data (e.g., audit trail, dates, …) between customer and supplier is key. Therefor all
involved parties should discuss and agree upfront, how this should be implemented and maintained.
If data are kept in the cloud (e.g., by a subordinated SaaS service provider) such CSP (Cloud Service
Provider) must be audited in order to verify the GxP compliant handling of data and validation of the
cloud application.

ED offers benefits when the following points are addressed:

 Transparency for involved parties (incl. easy navigation): A validated software tool (preferrable
VLMS of the customer) might be useful to enable a good overview on stored documentation and
status (such as in draft, under revision, for approval, under execution)

 Allow monitoring and oversight for ongoing testing activities

 Allow attaching and incorporation of files (e.g., pdf files, pictures, videos, trend curves) in test
plans as documented evidence during test execution or reports using modern digital equipment
(smart phones, tablets, laptops).

 Approach shall comply with data integrity requirements at the start and in the life cycle.

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ED also offers quick and efficient interfacing. To facilitate this collaboration, it should be clearly
outlined and agreed before implementation. This includes

 a listing of all documents that need to be handled or exchanged electronically

 data format

 name/file conventions, if applicable

 Change Management

 Deviation Management

 Upload and download procedures

 Approval of documents.

It must be agreed (e.g., via data flow map, quality agreement, Project Quality Plan) how data exchange
is handled.

ED can also be applied in remote testing (see 6.8.4).

It is important to mention, that ED in a larger project offers full benefit only, if all suppliers are included.
It might be appropriate to compromise on the scope for ED for the sake of 100 % completeness for
defined items. The suitability of the supplier’s Document Management system should be checked
during supplier qualification, in case GMP relevant documents are created and stored for the
customer.

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 Good Practice Guide Qualification and Validation

9 Abbreviations

Abbreviation Definition
ASTM American Society of Testing and Materials
C&Q Commissioning and Qualification
CA Critical Aspects
CDE Critical Design Element
CARA Critical Aspects Risk Assessment
cGMP Current Good Manufacturing Practice
CIP Cleaning in Place
CMA Critical Material Attribute
COTS Commercial off‐the‐shelf (system)
CPP Critical Process Parameter
CPV Continued Process Verification (FDA Process Validation Guidance)
CPV Continuous Process Verification (EU GMP Annex 15)
CQA Critical Quality Attribute
CSV Computerized System Validation
CTQ Critical to Quality
DQ Design Qualification
ED Electronic Documentation
EHS Environment, Health and Safety
EMA European Medicines Agency
EU European Union
FAT Factory Acceptance Test
FDA Food and Drug Administration (US)
FMEA Failure Mode and Effects Analysis
FMECA Failure Mode, Effects and Criticality Analysis
FS Functional Specification
GAMP Good Automated Manufacturing Practice
GDP Good Documentation Practice
GEP Good Engineering Practice
HMI Human Machine Interface
ICH International Council on Harmonisation
IQ Installation Qualification
ISO International Standardisation Organisation
N/A Not applicable
NOR Normal Operating Rage
OPL Open Point List
OPV Ongoing Process Verification (EU GMP Annex 15)
OQ Operational Qualification
PAR Proven Acceptable Range
PAT Process Analytical Technology
P&ID Piping & Instrumentation Diagram

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 Good Practice Guide Qualification and Validation

Abbreviation Definition
PFD Process Flow Diagram
PPURS Product and Process User Requirement Specifications
PPQ Process Performance Qualification (FDA Process Validation Guidance)
PQ Performance Qualification (EU GMP Annex 15)
PQ Process Qualification (FDA Process Validation Guidance)
PQP Project Quality Plan
PV Process Validation
PVP Project Verification Plan
Q Quality
QAA Quality Assurance Agreements
QA Quality Assurance
QRA Quality Risk Assessment
QRM Quality Risk Management
QTPP Quality Target Product Profile
RACI Responsible, Authorise, Consult and Inform (Chart)
RFP Request for Proposal
RTM Requirement Traceability Matrix
RTR Real Time Release
SARR System Acceptance and Release Report
SAT Site Acceptance Test
SDS Software Design Specification
SIP Sterilisation in Place
SME Subject Matter Expert
SOP Standard Operating Procedure
SW Software
TM Test Matrix
URS User Requirement Specifications
USP United States Pharmacopeia
VLMS Validation Life Cycle Management System
VMP Validation Master Plan
VTOP Vendor Turn Over Package (aka Supplier Turn Over Package)

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 Good Practice Guide Qualification and Validation

10 Bibliography

1. ASTM E2500: “Standard Guide for Specification, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems and Equipment”, ASTM, 2020
2. ICH Q8 (R2): “Pharmaceutical Development”, ICH Harmonised Tripartite Guideline 2009
3. ICH Q9: “Quality Risk Management”, ICH Harmonised Tripartite Guideline 2005
4. ICH Q10: ”Pharmaceutical Quality System”, ICH Harmonised Tripartite Guideline 2008
5. ICH Q11: ”Development and manufacture of drug substances (chemical entities and
biotechnological/biological entities)”, ICH 2012
6. ICH Q12: “Technical and Regulatory Considerations for Pharmaceutical Product Life cycle
Management” ICH 2020
7. EU GMP Part I Volume 4 Chapter 7 “Outsourced Activities”, 2012
8. EU GMP Annex 11 “Computerised Systems”, Eudralex 2011
9. EU GMP Annex 15 “Qualification and Validation”, Eudralex 2015
10. PIC/S GMP for Medicinal Products Annex 15 “Qualification and Validation” PE009‐14
(Annexes) 2021
11. US FDA Guidance for Industry: “Process Validation: General Principles and Practices, 2011
12. ZLG Aide Memoire: ”Inspektion der Validierung von Herstellprozessen (Prozessvalidierung)”,
Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten, AiM
07122901, ZLG, 2015
13. USP 43: “Analytical Instrument Qualification”, (section 1058), The United States
Pharmacopeial Convention, 2016
14. ISPE GAMP® 5 Guide: “A Risk‐Based Approach to Compliant GxP Computerized Systems”, ISPE
2008
15. ISPE Baseline Guide Volume 5: “Commissioning & Qualification”, Second Edition, 2019
16. PDA Technical Report 60: “Process Validation: A Life cycle Approach”, 2017
17. PDA Technical Report 54‐5: “Quality Risk Management for the Design, Qualification, and
Operation of Manufacturing Systems”, PDA 2017
18. ECA Good Practice Guide on Validation, 2015
19. VDI 6305: “Technical good manufacturing practice ‐ Application guideline for requests in the
GMP environment”, VDI 2018
20. FDA US CFR 21 part 11 Electronic Records; Electronic Signatures 2003
21. Good Practices for Data Management and Integrity in regulated GMP/GDP environments
PICS: PI 041‐1 2021

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Integrated Qualification and Validation Guide

Appendices
Table of Content
Appendix 1: Explanation of the Integrated Qualification Core Concept ................... 2

Appendix 2: User Requirement Specification (URS) Template .................................. 6

Appendix 3: Supplier Evaluation ................................................................................ 17

Appendix 4: CARA and Verification Planning Tools Templates .............................. 18

Appendix 5: Change Management and Deviation Management Template .............. 22

Appendix 6: Project Quality Plan (PQP) Template .................................................... 26

Appendix 7: Qualification Documentation Template ................................................ 41

Appendix 8: Remote Testing of GMP Manufacturing Systems ................................ 50

Appendix 9: Categorisation of Manufacturing Systems: Template ......................... 54

Appendix 10: Pharmaceutical Customer and Supplier Contract Checklist............. 58

Appendix 11: Electronic Documentation (ED) ........................................................... 60

Appendix 12: Technical Glossary ............................................................................... 61

 Integrated Qualification and Validation Guide

Appendix 1: Explanation of the Integrated Qualification Core Concept

Here is a brief explanation of the core concept of the ECA Q&V approach of this guide. The purpose is to
integrate customer and supplier activities for effective and efficient qualification and validation of
manufacturing systems. Basis for that approach is a common understanding of “Critical Aspects” and
Quality Risk Management as well as the use of Good Engineering Practice. It can be applied to small or
large projects containing other types of manufacturing systems in both new and existing facilities.

A tablet press has been selected as manufacturing system to explain this Integration Core Concept. As a
starting point the pharmaceutical customer is performing an initial Quality Risk Assessment (QRA0) of
the relevant tablet production process; he knows the Critical Quality Attributes (CQA) and the Critical
Process Parameters (CPP). Besides he drafts a User Requirement Specification (URS).

Some companies use an overall document for the whole manufacturing process from formulation to final
package, e.g., called a Product and Process User Requirements Specification (PPURS) to develop the URS
for each equipment, as illustrated in figure 1.

Figure 1 Project scope overview of the manufacturing systems used for tablet production related to the PPURS

The tablet press machine feeds powder to pistons that compresses the tablet and the product and
process development determines the relevant process parameters. In this example the customer’s
product and process development has identified the compression force of the tableting piston as a CPP.

The Quality Risk Assessments during this project is documented in a CARA Matrix (Critical Aspects Risk
Assessment) which also includes the possible failure modes of the equipment that can affect the
compression force. Each failure mode is listed in the table, as illustrated below (table 1) and includes:
 cause of the failure mode related to the compression (machine parts: die cavity, punches, cam
truck and tablet adjuster),

 related measures to prevent the failure from affecting the product (risk control), and

 related measures to detect the failure (risk detection).

 Integrated Qualification and Validation Guide

Appendix 1: Explanation of the Integrated Qualification Core Concept

Table 1 Link between CQA, CPP and Critical Aspect (CA) for a tablet product produced on tablet press

Critical Aspect (CA)

Quality risks /
CQA CPP Cause of the quality
Failure mode Risk control Risk detection
risk / Failure mode
Tablet hardness Compression force Wrong compression Failure of Compression control Alarm Indicated and
(CPP) forces compression station, (In process control) recorded on Control
System
die cavity,
punches,
cam truck,
tablet adjuster

Table 2 shows an extract of the first CARA step (QRA1) for a tablet press example with only one CQA and
one CPP, based on the data in Table 1. The example shows the failure mode of the critical aspects as well
as the cause of the failure mode, the risk control and possible risk detection measures, for example the
failure mode “Wrong compression force”. The risk score scale for Severity, Probability and Detectability
is described in more details in Appendix 4.

Table 2 Extract of QRA 1 for tablet press ‐ Critical Aspects/CPPs Risk Assessment [CARA]

The CARA matrix is a useful tool for Design Qualification, where the URS and the design documents are
discussed between customer and supplier and the conclusion for each Critical Aspect may be
documented. The use of the CARA matrix is described in further details in appendix 4.

In this way the CARA matrix serves as an overview document which keeps track of all critical aspects
during the life cycle of the project.

To summarize, the commissioning and qualification activities for the manufacturing systems, incl. the
DQ, FAT, SAT etc., shall ensure that the design, installation and operation of the manufacturing systems
are as intended, meets good engineering practice and relevant GMP requirements and the
documentation of the commissioning and qualification activities meets good documentation practice, so
they correctly describe the commissioning and qualification activities, with conclusions on that all
requirements are met. The CARA documents these activities related to the critical aspects of the
manufacturing systems. In many companies the quality organization is deeply involved in the
qualification activities related to the critical aspects whereas other commissioning and activities may be
delegated to relevant subject matter experts (e.g., process, automation etc.) with oversight from the
quality organization but without detailed involvement, unless deviations or other concerns are found.

The “red thread” of the activities with the CARA matrix can be summarized as follows:
 Integrated Qualification and Validation Guide

Appendix 1: Explanation of the Integrated Qualification Core Concept

1. User Requirements and quality risk assessment:

The URS for each manufacturing system is stating the requirements including both the Critical Aspects
and other user requirements. The CARA typically summarizes only requirements related to the Critical
Aspects.

2. Requirement design review and design qualification:

During the project the supplier will deliver design documents (drawings, functional specifications etc.)
and the design qualification (DQ) involving both customer and supplier ensures that all user
requirements and respective design documents are discussed and accepted by both customer and
supplier. The CARA is used to document the DQ activities for the critical aspects whereas all other
requirements not related to critical aspects can be documented elsewhere.
In some companies the quality function is only involved in discussions about the design of Critical Aspects
(together with other subject matter experts) whereas other technical components and solutions are
reviewed and accepted by subject matter experts only.

3. Verification:
After design reviews and based on design specifications the verification activities should be outlined. It
is recommended to clearly distinguish between commissioning activities and GMP related qualification
activities. Both should be linked to the URS either by an RTM or CARA.

The relation of the life‐cycle CARA matrix (QRA1, QRA2 and QRA3), URS and verification (Commissioning
and Qualification) activities is illustrated in Figure 2.

Figure 2 Critical Aspects Risk Assessment matrix, engineering, and verification activities for a tablet press

The Figure 3 illustrates how user requirements are carried over into subsequent documents. The red text
is related to Critical Aspect requirements and black text to other requirements.
Integrated Qualification and Validation Guide

Appendix 1: Explanation of the Integrated Qualification Core Concept

Figure 3 Project document flow example of Critical Aspects requirements (in red) for a tablet press

When all manufacturing systems used for tablet production have been commissioned and qualified and
relevant interim release reports are available for each system, the overall production system is subjected
to an integrated Performance Qualification to confirm that all the manufacturing systems have been
installed as specified, operate as required, and are fit for the intended use when operating together. In
this case where the pharmaceutical company has a PPURS for the tablet product, the acceptance and
release report documents that the manufacturing systems overall can produce the tablet product in
accordance with the relevant PPURS.
 Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template

The User Requirement Specification (URS) should reflect the pharmaceutical customer requirements for
the manufacturing system in scope of the project. There may be an initial URS issued by the
pharmaceutical customer and a final URS supported by and agreed with the supplier. An agreed URS is
the starting point for the supplier activities in order to ensure a successful project. The URS is further
described in sections 5 and 6 of this guide.

Typically input from the suppliers is important as they may have significant expertise within their scope
of delivery, e.g. types of equipment and systems, and they may be able to provide useful URS examples
or templates that may be used to provide useful input to the pharmaceutical company’s user
requirements.

The URS may include several documents describing the manufacturing system for a specific
pharmaceutical application as well as more general, technical document. A clear, well‐structured URS
document may also be achieved an indication of where each URS requirements origins (e.g., quality
related, GMP‐related, HSE‐related, business‐related, Technical and others). For each requirement it may
be stated whether this should be tested and documented or not. If relevant the reference for each
requirement may be marked too.

The URS should be written in accordance with an initial Quality Risk Assessment that identifies the Critical
Quality Attributes (CQA), Critical Process Parameters (CPP) which are input to Critical Aspects of the
manufacturing system together with other requirements that are Critical to Quality (CTQ) of the
pharmaceutical product, see section 5.4.

The following template example illustrates the structure and content of a URS from a project.
Suggested content is described in brackets < > and data entry examples are indicated as "xyz”.
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

User Requirement Specification

Project name

Document number
Revision

Approval Table
Signs for Role Name Date Signature

Finished Author <name> <date> <signature>

Document
…
…

Table of Content

1.0 Objective
2.0 Scope
3.0 Reference/Related Documents
3.1 Reference documents
3.2 Related documents
4.0 Definitions
5.0 Project Introduction
5.1 Project Description
5.2 Process Description
5.3 System Description
6.0 User Requirements
6.1 Process Requirements
6.2 Installation Requirements
6.3 Operational Requirements
6.4 Other Requirements
7.0 Appendices/Attachments
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

1.0 Objective
1.1 This document summarizes the User Requirement Specification (URS) of the project,
equipment or system xyz

1.2 The URS is a summary of the company xyz requirements and description of their requirements
for the single equipment or system

1.3 The xyz URS focuses in what is needed for a system and which requirements are set to the
system. The xyz URS requirements are the basis for the further development of the system
documentation and shall provide a list of design objectives and criteria for the testing of the system
xyz

2.0 Scope
2.1 This document states the requirements for project xyz and for the system xyz which will be
operational in facility xyz

Limitations: This document does not cover …

3.0 References/Related Documents

3.1 Reference documents

<This section summarizes reference documents for the URS, e.g. project scope, product and process
specifications (or PPURS) etc.>

3.2 Related documents

<This section summarizes other documents related to the URS, e.g. technical requirement documents
etc.>

4.0 Definitions

4.1 References documents

<This section summarizes the abbreviations and definitions used in the document>

5.0 Project Introduction

5.1 Project Description

<This section is a brief description of the goals and limits of the project, incl. location,
systems and activities involved>
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

5.2 Process Description

<This section summarizes at a very high level the process associated with the project, equipment or
system. This section should include inputs to the process, description of process steps, output from
process. Required equipment automation systems, Building Management System and/or
environmental management system. It is recommended to keep the description at a higher overall
level. A flowchart may be used to complete this description. Add diagrams such as process diagrams,
context diagrams or others useful illustrations>

5.3 System Description: <Context diagram of systems around this equipment>

<This section summarizes the systems involved in the project and its system boundaries to other
manufacturing systems, including the main components, the operation and the location. This includes
automation systems, Building Management Systems and utilities that are shared with other parts of
the facility. Possibly supplemented with drawings or schematics that illustrates the scope of the project
and its boundaries>

6.0 User Requirements

6.1 Process Requirements

< This section gives an overview of the process parameters for each process step including the operation
range and tolerances of the general process parameters including quantities of materials, sequence of
additions/operations, Critical Quality Attributes (CQA), Critical Process Parameters (CPP), other
requirements Critical to the Quality (CTQ) of the product, Critical Aspects (CA), non‐critical process
parameters, heating/cooling rate as well as control, monitoring and alarm functions associated with
each parameter. The URS may include general project reference documents, e.g. media list, approved
list of materials, preferred components etc.>

6.1.1 Product Volume / Equipment Capacity

Requirement ID Requirement Type of requirement

xyz The Filling System should be able to run continuously at Business‐related

xyz per hour (Minimum Effective Output)
xyz The Filling System shall be able to process various Critical Aspect
Product and Sizes as described in Section …
…
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.1.2 Process Parameters

Requirement System Operating Accuracy Unit Type of

Monitored
Controlled
ID Parameters Range requirement

Alarmed
(Min‐Max)

xyz Line Speed X X X Business‐related

xyz Temperature X X Critical Aspect

6.1.3 Process Constraints and Limitations

< Some steps in the process may limit the design, type, dimensions or arrangements of the
systems or auxiliary equipment. Examples:
‐ Input conditions (number, pressure, temperature, etc.) of the incoming flows.
‐ Open and/or closed systems, risk of cross‐contamination, from a facility
viewpoint etc.>

Requirement ID Requirement Type of requirement

xyz Potable Water is supplied at a minimal pressure of xyz bar GMP‐related

… Ambient temperature is xyz °C Operation related

6.1.4 Production Period

< What is to be produced in what period, e.g. 24 hours day, day shift, night shift…
What is the required availability of the product, the guaranteed throughput rate etc.>

Requirement ID Requirement Type of requirement

xyz The xyz water production is a continuous process Business‐related

(24h/day)
…
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.1.5 Other process requirements

< Other requirements for the manufacturing system>

Requirement ID Requirement Type of requirement

xyz xyz

6.2 Installation Requirements

6.2.1 Material Requirements

<Specify adequate construction materials, or to know compatibility / incompatibility for

construction materials (including seals) for the system components>

Requirement ID Requirement Type of

requirement
All lubricants and fluid utilized on process equipment shall be Critical Aspect
identified and confirmed as Food Grade Quality
…

6.2.2 Construction Requirements

<Specify construction requirements such as gravity flow, slopes, no dead spaces, no dead legs
(design according to the 6‐D rule), heat tracing, etc. >

Requirement ID Requirement Type of

requirement
xyz Dead spaces shall be avoided at critical locations GMP‐related

Process piping is installed according to standards of sanitary GMP‐related

design
…

6.3 Operational Requirements

<The operational and functional requirements specify the way the equipment, the automation and the
system should perform. The sequence and correlation between the process functions can be illustrated
with a diagram. The process steps with acceptance criteria, actions in case of failure or exceeding of
the limits, quantities, and frequency of a process are items can be added in this section if not in a
separate functional specification>
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.3.1 Operation & Functional Requirement

<Special operational and functional requirements that applies>

Requirement ID Requirement Type of requirement

xyz xyz

6.3.2 Automation and Records (DCS, SCADA, PLC…)

<Special automation requirements, control system requirements etc. >

Requirement ID Requirement Type of requirement

xyz Language: The SCADA/HMI Interface shall support the Operation‐related

following languages: xyz and xyz. languages. All Graphic
Labels and Operator messages shall be switchable between
the languages
…

6.3.3 Building Management System

<similar to 6.3.2>

6.4 Other Requirements

6.4.1 Facility/Room Classification and Environmental Conditions Requirements

Requirement ID Requirement Type of requirement

xyz All production suites shall meet class ISO <…> in operation Critical Aspect

Core production area shall meet class ISO <…> in operation Critical Aspect

…
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.4.2 Cleaning/Sanitization/Sterilization Methods, Products and Limits/Visual Inspection

Requirements

<Cleaning/sanitation/sterilization methods and their specific products and specifications may influence
the design of systems (e.g. manual, automatic, CIP, combined cleaning) and the design of system
components (e.g. required finishing.). The requirement for visual inspection of the equipment or
components should also be mentioned>

Requirement ID Requirement Type of requirement

xyz The production system and storage shall be drainable and Critical Aspect
chemically cleanable
…

6.4.3 Utility Requirements

Requirement ID Requirement Type of requirement

xyz Compressed air coming in contact with product must be Critical Aspect
filtered (Type xyz filter)
…

6.4.4 Personnel/Material/Waste Movement Requirement

< Specific requirements related to the building layout and movement of personnel, materials, and
waste are mentioned here >

Requirement ID Requirement Type of requirement

xyz The building layout must include areas for receipt, GMP‐related
identification, sampling, and quarantine of incoming
materials, pending release or rejection
…
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.4.5 Environmental, Health, and Safety (EHS) Requirements

< Specific requirements related to aspects of operational safety, industrial health and hygiene, and
environmental discharges, permits, etc. are mentioned here. These can be grouped together or
segregated into separate subjects>

Requirement ID Requirement Type of requirement

xyz The noise level generated during operation of the <…> Safety‐related
equipment shall not exceed <…> dBA.
…

6.4.6 Ergonomic (Accessibility, Maintainability) Requirements

< This section may include requirements such as: the space required around equipment for operability
and maintenance, accessibility to the equipment and components for maintenance activities and
normal operation, etc. >

Requirement ID Requirement Type of requirement

xyz All components shall be located at an accessible place. A

platform shall be provided around the <…> tank
…

6.4.7 Maintenance Requirements

< specific requirements related to the preventive maintenance of processes and systems are mentioned
in this section, e.g. information required to establish a preventive maintenance program,
recommended spare parts requirement, etc. >

Requirement ID Requirement Type of requirement

xyz All Lubricating Points must be Registered, Shown and clearly

Labeled in an overall Plan. Inaccessible Lubricating Points must
be made Accessible by installing Corresponding Lines without
opening the Protective Doors. It must be guaranteed that no
Lubricants entering the Production
…
Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

6.4.8 Training Requirements

< Specific training requirements of personnel for processes and systems are covered in this section >

Requirement ID Requirement Type of requirement

xyz The training material must be delivered in paper and

electronic version in advance <…>
…

6.4.9 Documentation Requirements

< Specific documentation requirements for templates, document control etc. >

Requirement ID Requirement Type of requirement

xyz All documents from Vendors shall follow these Requirements:

- They shall be Approved and Provided with the latest
Revision
- Language for Document and Drawing shall be <…>
- Units in Documents and Drawings shall be International
Unit, such as m for Length, kg for Weight, m/s for Velocity
and so on
- All Documents must be provided in Hard Copy and
Electronic in advance for Review
- All Description shall be Microsoft Word Version,
preferable Word version <…> or pdf.
…

7.0 Appendices/Attachments

7.1 Drawings or diagrams, context diagrams, photos, other illustrations relevant for
specifying the URS requirements.

8.0 Template for History of Change

< Should be required for all documents >

Version Change Section Reason for Revision (Description of Remarks

Number Control Change)
Number
xyz

(End of template example)

Integrated Qualification and Validation Guide

Appendix 2: User Requirement Specification (URS) Template Example

About Product and Process User Requirement Specification (PPURS)

In some pharmaceutical companies the URS documents refers to a so‐called “Product and Process
User Requirement Specification” (PPURS) for the pharmaceutical product in scope for the project.
The PPURS document typically contains the specific process requirements for each process step and
area of the facility, based on the so‐called Control Strategy for the pharmaceutical product. Both the
PPURS and the Control Strategy are internal and confidential document for the pharmaceutical
company and includes process requirements and the initial Quality Risk Assessment for the product
and processes. An example of PPURS content is shown at the end of this Appendix.

If a PPURS does not exist in a project an initial Quality Risk Assessment (QRA 0) should summarize the
CQA, CPP and other CTQ requirements.
As illustrated in figure 6 the scope of the PPURS is typically the whole process whereas the scope of an
URS is typically one manufacturing system within the overall process flow.

Figure 6 PPURS document for the overall process and URS documents for each of the manufacturing systems

Content example for a PPURS:

1. Objective
2. Scope
3. References/Related Documents
4. Definitions
5. Product and Process Description
5.1. Product Description (main stages)
5.2. Process Description (main process steps with input and output, required equipment)
6. Product and Process related User Requirements
6.1. Product: Critical Quality Attributes (CQA)
6.2. Process: Critical Process Parameters (CPP)
6.3. Additional Requirements
7. Control Strategy
7.1. Process Step 1 (including process operations, CPP and In‐Process ‐Controls (IPC)
7.2. Process Step 2, etc.
7.3. …
8. Appendices/Attachment
 Integrated Qualification and Validation Guide

Appendix 3: Supplier Evaluation

The supplier management may be organized as lifecycle management process of e.g. five stages of
supplier evaluation: Selection, Qualification, Performance Evaluation, Development and Termination.
They often involve both the sourcing (e.g. procurement) and the business organisation (e.g.,
production, quality, engineering etc.), typically as a cross‐functional evaluation team. The depth and
frequency of supplier evaluation depends on the importance and the risk of the system and should be
based on a documented risk assessment.

Pharmaceutical customers typically have a questionnaire or similar tool for the evaluation, and it may
include several focus areas such as Quality, Technical capability, EHS (Environmental, Health & Safety),
Financial performance etc.

Questionnaires may be used instead of an audit for less critical equipment and systems. Questionnaires
may also supplement audit(s) as a preliminary assessment (initial evaluation) to gather information
relevant for the audit planning.

Depending on the order and magnitude of the delivery the following point should be considered in the
supplier evaluation:

 Size of supplier, business track record and customer references, especially within the
pharmaceutical industry
 Mutual history between the customer and supplier
 Technical capabilities,
 Assessment of the supplier’s quality management system (QMS) and its implementation
 GMP capabilities and knowledge of regulatory requirements, including Good Engineering
Practice (GEP)
 Project Management up to on‐site installation of the system
 Process and procedures for design and construction, and inspection (for intermediate steps
and finished goods
 Procedure(s) implemented for Change Management
 Procedures for management (incl. calibration) of measuring devices and their use
 Documentation management incl. version control, especially for design and test
documentation
 Management of materials and related certificates
 Use of sub‐suppliers, incl. track record and follow‐up
 Use of software, including software development procedures and control
 Capabilities and capacity for planned verification activities (e.g. resources, procedures,
documentation of results, …)
 Integrated Qualification and Validation Guide

Appendix 4: CARA and Verification Planning Tools Templates

The Critical Aspects Risk Assessment (CARA) matrix is a useful tool to manage the critical aspects during
design qualification and verification.

1. Critical Aspects Risk Assessment Matrix (CARA)

The Critical Aspects Risk Assessment matrix (CARA) is used for the risk management of Critical
Aspects. There may be a CARA matrix for each manufacturing system.

The CARA matrix is made before Design Qualification to identify the critical aspects of the
manufacturing system and their failure modes as well as agreed risk mitigations and
verification activities for each critical aspect.

The CARA is based on the initial Quality Risk Assessment (QRA0), based on the Critical Quality Attributes
of the product, the Critical Process Parameters (CPP) of the process and other aspects that are critical to
product quality.

The CARA includes the following main sections (QRA 1‐3) for the project life cycle:
 QRA 1 is used for identifying and assessing the Critical Aspects of the URS requirements and
potential risk mitigations.
 QRA 2 is used for Design Qualification of the Critical Aspects as seen in the design documents.
 QRA 3 is used for planning the qualification activities for each Critical Aspect to ensure acceptance
criteria are met and traceability is given.
The documentation of QRA 1‐3 in the CARA matrix is illustrated in Figure 1.

Figure 1 CARA matrix steps

QRA 1 Section QRA 2 Section QRA 3 Section

After the completing of a project, CARA matrix may be considered a life cycle living document and
updated with the related URS in case of important changes.

The CARA matrix may also be useful during a regulatory inspection of the factory to explain the
management of the Critical Aspects of the manufacturing system.
Integrated Qualification and Validation Guide

Appendix 4: CARA and Verification Planning Tools Templates

The following CARA example is based on a FMECA risk management tool (Failure Mode, Effects and
Criticality Analysis) with Severity, Probability and Detectability of each failure mode. The risk of each
Critical Aspect’s failure mode is calculated as a Risk Priority Number (RPN) by multiplying S x P x D.

(Please note that Severity is linked to a product risk and can normally not be modified. Risk mitigations
can decrease occurrence and increase detectability and may be changed by design or operating
procedures to an acceptable residual risk)

The CARA example is based on the following company example of a risk score:

Severity (S)
Score Description Definition
10 Catastrophic Product CQA affected and OOS
8 Critical Product CQA affected but no OOS
3 Minimal Cosmetic defect
1 Negligible No defect
Probability (P)
Score Description Definition
10 High Failure is almost inevitable
8 Moderate Repeated failures
3 Low Occasional failures
1 Negligible Failure is unlikely
Detectability (D)
Score Description Definition
1 Almost certain Existing controls will almost certainly detect a failure
3 High High chance that existing controls will detect a failure
8 Low Low chance for detection of a failure
10 Negligible No possibility of detection of failure

The overall Risk Priority Number (RPN) is evaluated with following action levels:

RPN (S x P x D) Action level

Unacceptable if no risk reduction measures are feasible
[Individual risk may be accepted on a case‐by‐case by
Intolerable (red)
proving that the risk/benefit ratio is favorable, once all
reasonable reduction measures have been taken]
Tolerable only if further reduction is not possible and
As low as possible (ALAP) (yellow)
benefits outweigh the residual risk
Broadly accepted (green) Accepted. No further risk control measures needed
 Integrated Qualification and Validation Guide

Appendix 4: CARA and Verification Planning Tools Templates

Table 1 QRA1 template

Table 2 QRA 2 and QRA 3 templates

Integrated Qualification and Validation Guide

Appendix 4: CARA and Verification Planning Tools Templates

1. Requirement Traceability Matrix

Some companies use a Requirement Traceability Matrix (RTM) for each URS to demonstrate how the user
requirements are addressed in the design documentation.

The RTM is useful for the Design Qualification and may be combined with the CARA into one combined matrix.

2. Design Qualification Report

CARA is used during Design Qualification to confirm, that critical aspects are sufficiently covered and risks are
mitigated to an acceptable level.
The output of CARA step 2 is often captured in a Design Qualification report.

Design reviews for the requirements not linked to a critical aspect/CPP can be documented in a separate report
containing the design discussions and agreements between customer and supplier for these requirements.
Integrated Qualification and Validation Guide

Appendix 5: Change Management and Deviation Management Template

The templates in this section can be used to facilitate Change Management (see section 6.4) and
Deviation Management (see section 6.5). It is important, that the way, how these templates are used,
is agreed and documented upfront (e.g. in the PQP).

The Change Management form is mainly intended to stipulate change proposals to approved
documents in the area of scope (adding or deleting of verifications), acceptance criteria, procedures or
test situations, if applicable. It similarly can be used to stipulate changes to agreed design (“engineering
change request”).

Non‐conformities during inspection and verification can be captured either in the Deviation Form or
the Punch List. It might be helpful to use the Deviation Form for tests related to critical attributes (CQA,
CPP, CTQ) to allow orchestrated corrective action.
Integrated Qualification and Validation Guide

Appendix 5: Change Management and Deviation Management Template Examples

Change Request Form

Title:

Change # ID:

Project Name:

System reference:

Activity:

Observation (actual situation):

Should be (planned situation)

Proposed action (proposed change)

Risk from the change (to previous tests/qualifications or to product quality)

Risk Mitigation (suggested actions to minimise or eliminate the risk)

Author: Signature: Date:

Name:
Function:
Reviewer: Signature: Date:
Name:
Responsible User:
Approved: Signature: Date:
Name:
Quality Responsible
Integrated Qualification and Validation Guide

Appendix 5: Change Management and Deviation Management Template Examples

Deviation Registration Form

Deviation No.: Project Activity: Date/ initials creator:

Test:

Deviation:

Responsible for solving: Name/ department:  Critical

 Uncritical
Deadline for solution: Date:

Planned and agreed measures:

Results:

Deviation solved/ closed Name/ department/ date Signature:

 Yes
 No
Approved Name/ department/ date Signature:

Approved Name/ department/ date Signature:

Integrated Qualification and Validation Guide

Appendix 5: Change Management and Deviation Management Template Examples

Punch List

Project ID: Project Name:

Customer: System ID:

Open issues Closed issue

Punch Test Corrective Critical?

Description Date Responsible Reference Responsible
ID ID action (Y/N)

Remarks Closeout (date, sign)

 Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template

A Project Quality Plan should be the basis for the cooperation between customer and supplier and
regulate important aspects during the project. All verification activities, responsibilities and applicable
procedures should be covered.

The following template example is based on a project where it was used as the joint Project Quality
Plan (PQP) between customer and supplier throughout the project. This PQP example does not
distinguish between the terms Installation Qualification vs. Installation Verification and Operation
Verification vs Operational Qualification since the use of these terms depends on the pharmaceutical
customer company’s terminology.

Test activities are outlined in clause 5 and the scope of them should be described as agreed in the
contract. It is up to the author if they are grouped, put in logical order, or follow a timeline.

Project Management activities may be added or outlined in depth as agreed in the contract.

The use of appendices is highly recommended, since the documents out of standard applications can
be attached without reformatting.

A Project Quality Plan should be the basis for the cooperation between customer and supplier and
regulate important aspects during the project. All verification activities, responsibilities and applicable
procedures should be covered.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

Project Quality Plan

Project name xyz

Document number
Revision

Customer xyz

Project ID …

Project Name

Site

Unit/Equipment

Project Quality Plan approval by <Supplier>

Signs for Name Department Date Signature
Title Company
Created by Name xyz Qualification Dept …
<supplier)

Reviewed by Project Manager

<supplier>

Approved by … Qualification
Project Manager
<supplier>

Project Quality Plan approval by <customer>

Signs for Name Department Date Signature
Title Company
Approved by Name xyz … …

Approved by

Approved by
 Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

Change log

Revision Date Responsible Change description

xyz dd‐mmm‐yyyy Removal of xyz

Adding of xyz
…

Table of Content

1. References
2. Introduction
3. Scope
4. Overview
5. Qualification Plan Section
5.1. Qualification/Validation Management
5.2. Planning Phase
5.3. Design Phase
5.4. Risk Analysis
5.5. Testing Phase
5.6. Requirement Traceability Matrix
5.7. Training
6. Project Plan Section
6.1. Project Organisation
6.2. Scope of Documentation
6.3. Project Activities
7. Glossary
8. Appendices

1. References

No. Reference title

[1] Confirmation of order xyz date dd‐mmm‐yyyy

[2] EC machinery directive 2006/42/EC
[3] <supplier> Quality Management System
[4] SOP‐AG‐06.012e: Qualification deviation procedure
[5] SOP‐AG‐24.005e: Procedure for change control
[6] SOP‐AG‐23.006e: Hand‐written documentation for qualification
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

No. Reference title

[7] Department handbook: Electro design and software

development
[8] GAMP Guide for Validation of Automated Systems in
Pharmaceutical Manufacture 5
[9] US 21 CFR Parts 11 & 210 & 211
[10] EU GMP Annex 1 “Manufacture of Sterile Medicinal
Products”
…

2. Introduction
This document forms the plan for the <supplier> (in the following named <supplier>) qualification and
validation related activities for development, manufacturing and testing of the manufacturing system
xyz for customer xyz (in the following named <customer>) in project xyz…

The line will be manufactured at <supplier> facility in xyz and installed at <customer> in site xyz.

This plan has been produced according to reference [1] with reference to [9] by the <supplier>
Qualification and Validation Department on behalf of <customer>. The document is part of the overall
<customer> qualification activities for project xyz.

3. Scope
This document consists of
 a qualification plan section with qualification and validation related activities in combination
with
 a project plan section, which includes details about the <supplier> project team, the
deliverable documentation, and the planning activities with milestones. Time schedule
changes will not lead to an update of the PQP. Further plans are issued by the project
manager.

According to the agreed scope of supply (see reference [1 Confirmation of order]), the qualification
and validation activities defined in this plan include a planning phase, a specification & design phase,
and a testing phase.

4. Overview
The xyz line consists of the following types of machines:
<List all the machines, types and machine numbers of the line>
‐ Machine xyz type xyz
‐ Machine …
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

The design of these machines complies with reference [2] EC Machine Directive. <supplier> is working
with an internal quality assurance system that has been ISO 9001 certified/recertified (certificate is
included in appendix 1). The ISO 9001 system with reference [3] forms the basis for all quality
assurance activities of planning, development, design, manufacturing, assembly and testing for the
<supplier> supply. Special GMP/cGMP requirements (references [10], [11]) requirements are taken
into consideration and reflected in this plan.

The internal activities of <supplier> (producing internal specifications, reviews for the electrical and
pneumatic drawings and the detailed machine layout reflecting the purchase order) and the definition
of <supplier> internal work orders are not subject to customer approval.

The computer software development will be done according to the <supplier> internal development
process [8], based on reference [9] GAMP.

5. Qualification Plan Section

5.1 Qualification and Validation Management

5.1.1 Good Documentation Practices

All documents from <supplier> related to qualification and validation documentation (project quality
plan, qualification reports, specifications, test protocols and handwritten test results [6]) which
includes also documentation version control, will be produced according to <supplier> internal SOPs

5.1.2 Deficiency and Deviation

Non‐conformities, which will be found during qualification & validation testing, will be reported
according to <supplier> SOP (see [4]) and classified as “Deficiencies” or “Deviations”. Installation‐
related non‐conformities are labelled “Deficiencies” whereas operational non‐conformities are
labelled “Deviations”.

<Supplier> will make a proposal for the solution of a deviation in the <supplier> deviation sheet. If
<customer> does not approve within 5 working days, <supplier> will continue with the qualification
activities by using the proposed solution to finish the work in the given time schedule. In case that the
approval cannot be given after these 5 days by <customer>, any additional testing needs to be ordered
separately.

5.1.3 Changes during the Project Change Control

Changes during the qualification and validation testing shall be treated according to <supplier> QMS
and SOP [5]. In the change control form the change has to be evaluated, whether a
re‐qualification will be necessary or not.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.1.4 Personnel
The execution of the qualification and validation tests will be done only by trained and instructed
personnel.

5.1.5 Standard Operating Procedures

The qualification and validation tests will be executed by <supplier> according to supplier QMS.
The SOPs used are specified in the activity list (see Appendix 2).

5.2 Planning Phase

The planning activities are executed as follows:

Activity Responsibility Supplier Responsibility Customer

Produce Project <supplier> Qualification

Quality Plan Dept.
Review Project <supplier> <customer> Quality Dept.
Quality Plan
Approve Project <supplier> <customer> Quality Dept.
Quality Plan

The planning of other supplier‐internal activities and the definition of <supplier> internal work
orders are based on the DIN EN ISO 9001 system and / or < supplier > internal procedures and not
subject to customer approval.

5.3 Design Phase

5.3.1 Mock‐up Meeting

The machines will be modelled with customized equipment in a wooden model.
Based on this wood model, an ergonomics study and process simulation will be carried out to define
physical design and work positions. It should be noted that the mock‐up meeting is not part of the
qualification, but how the design review meeting serves to determine the design and is thus assigned
to the engineering phase.

Activity Responsibility Supplier Responsibility Customer

Execution Mock‐up <supplier> Engineering Dept. <customer>Technical Dept.

Produce Mock‐up <supplier> …
summary
Approve Mock‐up <supplier> <customer>
summary
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.3.2 Design Qualification

The Design Qualification (DQ) will be exercised during a DQ workshop at <supplier> site. The suppliers
design documents will be reviewed against the customer URS. A Design Qualification summary will be
issued after the meeting, documenting the design documents used, the personnel involved, the
decision‐making process used, the open points and the result of the workshop.

Activity Responsibility Responsibility Customer

Supplier
Execute DQ <supplier> Dept. <customer>
workshop (Engineering,
Qualification dept...)
Produce DQ <supplier> …
summary Qualification
Dept.
Approve DQ <supplier> <customer>
summary Qualification
Dept.

5.3.3 Requirement Traceability Matrix (RTM)

After issuing the Functional Specification, a draft version of a Requirement Traceability Matrix (RTM)
will be written for each machine, showing the conformity of the specified functionality with the
confirmation of order and the specification of <customer>.

After OQ testing these documents will be issued as final version.

5.4 Risk Analysis

After issuing the process flow diagrams, a draft version of a risk analysis (RA) will be written for each
machine and will be sent to <customer>. Subsequently there will be a workshop with <customer> at
<supplier> site. According to the critical points, necessary installation tests (IQ), functional tests (OQ),
and integration tests will be identified.

5.5 Testing Phase

5.5.1 General
All single machines, their parts, and the complete line as well as the software will be part of a detailed
test program during manufacturing and assembly at Supplier xyz’s site, and after commissioning at
<customer> site.

The test program includes the following

- <Supplier> Internal Testing for the complete line at <supplier> site consisting of:
‐ Safety verification of mechanical items
‐ Safety verification of electrical items
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

‐ Installation verification of documentation

‐ Installation verification of mechanical items
‐ Installation verification of electrical items
‐ Operational verification of mechanical items
‐ Operational verification of electrical items
- Internal hard‐ & software testing
- Disaster Recovery Testing at < supplier > site
- Customer Specific Factory Acceptance Test (CFAT): Testing of machine performance according to
requirements (focus: technical & commercial) at supplier’s site.
- Alarm and Function Testing for PLC & PC systems
- Commissioning Phase
- Customer Specific Site Acceptance Test (CSAT): Testing of machine performance according to
requirements (focus: technical & commercial) at customer’s site
- Calibration at <customer>
- Operational Verification (or OQ) at <customer>:
o Alarm and Function Testing (controls testing): part of the GMP compliant
Operational Verification (or OQ) of the line with focus on software functions of the
line. Scope of testing will be based on the risk analysis results for the GMP critical
functions only
o Operational Verification Testing of the line with focus on the unit functions of the
line
at <customer>

5.5.2 Disaster Recovery Tests (DR)

Prior to the Factory Acceptance Test, the Disaster Recovery Tests (DR) will be executed.
The DR is the verification of the description on how the machine and line functions need to be
recovered after terminal hardware failure has occurred.

Activity Responsibility Supplier Responsibility Customer

Produce DR plan <supplier>

Qualification Dept.
Approve DR plan <supplier> …
Qualification Dept.
Perform DR <supplier>
Qualification Dept.
Document DR <supplier>
Qualification Dept.
Approve DR results <supplier> <customer>
Qualification Dept.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.5.3 Customer Specific Factory Acceptance Test (CFAT)

Prior to commissioning the <supplier> machines will be tested during Factory Acceptance Test (FAT)
at <supplier> premises.

The final FAT‐activities will be agreed and fixed with <customer>. The tests will be executed according
to <supplier> SOPs.

The FAT plan must be approved prior to testing cf. the time schedule in Appendix 4. The test results
will be documented and handed over to <customer> for approval at the end of FAT. After FAT the line
will be delivered to < customer>.

The FAT activities are executed as follows:

Activity Responsibility Supplier Responsibility Customer

Produce FAT plan <supplier>

Qualification Dept.
Review FAT plan <customer>

Approve FAT plan … <customer>

Execute and
document FAT
Approve FAT <customer>
results

5.5.4 Commissioning Phase

During the commissioning phase at <customer>, the complete line will be assembled and
connected to the site services (electricity, pressured air, etc.). At the installed machines informal
start‐up tests will be done to show that they are installed correctly and work properly.

5.5.5 Customer Specific Site Acceptance Test (CSAT)

The final Site Acceptance Test (SAT) activities will be agreed and fixed with <customer>. The tests
will be executed according to <supplier> SOPs.
The SAT plan must be approved prior to testing (cf. the time schedule in Appendix 4). The test
results will be documented and handed over to <customer> for approval at the end of SAT.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

The SAT activities are executed as follows:

Activity Responsibility Supplier Responsibility Customer

Produce SAT plan <supplier>

Qualification Dept.
Review SAT plan <supplier> <customer>
Qualification Dept.
Approve SAT plan <supplier>

Perform SAT <supplier>

Document SAT <supplier> <customer>

Approve SAT <supplier> <customer>

results Qualification Dept.

5.5.6 Installation Verification (Installation Qualification, IQ)

The Installation Verification will be executed at the completely installed line according to < supplier >
SOPs at < customer >. The activities with the corresponding <supplier> SOPs are listed in Appendix 2.
The Installation Verification plan must be approved prior to testing cf. the time schedule in Appendix
4. The test results will be documented and handed over to <customer> for approval.

Activity Responsibility Supplier Responsibility Customer

Produce IQ plan <supplier>

Qualification Dept.
Review IQ plan <supplier> <customer>
Qualification Dept.
Approve IQ plan <supplier> <customer>
Qualification Dept.
Perform IQ testing <supplier>
Qualification Dept.
Produce IQ Report

Approve IQ report <supplier> <customer>

Qualification Dept.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.5.7 Calibration
After commissioning of the machines and prior to Operational Verification (OQ) all process critical
sensors and measuring loops will be calibrated according to <supplier> SOP for the different
equipment.
The calibration results will be documented and handed over to <customer> for approval

Activity Responsibility Supplier Responsibility Customer

Produce Calibration plan <supplier>

Qualification Dept.
Review Calibration plan <supplier> <customer>
Qualification Dept.
Approve Calibration plan <supplier> <customer>
Qualification Dept.
Perform calibration <supplier>
Qualification Dept.
Document calibration <supplier>
Qualification Dept.
Produce calibration <supplier>
report Qualification Dept.
Approve calibration <supplier> <customer>
report Qualification Dept.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.5.8 Operational Verification Phase (OQ)

5.5.8.1 Alarm and Function Testing for PLC & PC Systems (AFT)
The Alarm and Function Testing for PLC & PC systems shows that all alarms of the machine and
important system functions work properly with the correct machine/system reaction. The tests
package is comprised of all of the alarms of the control system and includes also a set of standard
checks of single system / machine functions.

It will be executed at the completely installed line according to <supplier> SOPs at <supplier> site.
The test results will be documented and handed over to the < customer > for approval.

Activity Responsibility Supplier Responsibility Customer

Produce AFT plan <supplier>

Qualification Dept.
Review AFT plan <supplier>
Qualification Dept.
Approve AFT plan <supplier>
Qualification Dept.
Perform AFT testing <supplier>
Qualification Dept.
Produce AFT Report <supplier>
Qualification Dept.
Approve AFT report <supplier> <customer>
Qualification Dept.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

5.5.8.2 Operational Qualification (OQ)

The Operational Verification (OQ) will be executed according to <supplier> SOPs at the completely
installed line at <customer> The OQ activities with the corresponding <supplier> SOPs are listed in
Appendix 2.

The IQ testing and calibration must be finished, except the customer agrees to another proceeding.
The OQ plan must be approved prior to testing. The test results will be documented and handed
over to <customer> for approval.

Activity Responsibility Supplier Responsibility Customer

Produce OQ plan <supplier>

Qualification Dept.
Review OQ plan <supplier>
Qualification Dept.
Approve OQ plan <supplier> <customer>
Qualification Dept.
Perform OQ testing <supplier>
Qualification Dept.
Produce OQ Report <supplier>
Qualification Dept.
Approve OQ report <supplier> <customer>
Qualification Dept.

5.6 Requirement Traceability Matrix (RTM)

After issuing the Functional Specification, a draft version of a Requirement Traceability Matrix
(RTM) will be written for each machine, showing the conformity of the specified functionality
of the confirmation to order and the specification of <customer>.

After OQ testing these documents will be issued as final version.

5.7 Training
As part of the <supplier> supply staff training will be supplied at <customer> site. After the
training will be completed, all participants will receive a training certificate.
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

6 Project Plan Section

6.1 Project Organisation

The following personnel form the project team:

Responsibility Name Department

Project Manager Name xyz PM Dept

Project Manager … Qualification Dept.

Qualification
Mechanical design

Electrical design

Software PLC

Software HMI

Documentation

Assembly

As a standard <supplier> sub‐contractor for the software application, < sub‐supplier 1> will also
be involved in this project. <Sub‐supplier 1>, located in < sub‐supplier 1 site >, has a formal
quality management system and is audited periodically by < supplier >.

6.2 Scope of Documentation

The documentation to be delivered according to the order confirmation (ref. [1]) is listed in
Appendix 3.

6.3 Project Activities

The project activities will be listed in a time schedule (see Appendix 4), issued by the <supplier>
project manager. This schedule will be produced using project software xyz (Gantt Chart) and
updated following the project progress. It will include
- Project milestones
- Timelines
Integrated Qualification and Validation Guide

Appendix 6: Project Quality Plan (PQP) Template Example

7 Glossary.
Abbreviation Definition

CFAT Customer Specific Factory Acceptance Test

CSAT Customer Specific Site Acceptance Test

… …

8 Appendices.
Appendix Content

Appendix 1 ISO 90001 Certificate (2 pages)

Appendix 2 IQ/OQ/AFT ‐ Activity Listing (xy pages)

Appendix 3 Deliverable Documentation (xy pages)

Appendix 4 Project Time Schedule (xy page)

 Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template

The following section contains one test example from Operational Verification (or OQ) from a project
where the testing is done by the supplier with approval by the customer.

In general, the test sheets contain the following sections:

 Title of test
This should be unique and unambiguous and allow tracing back to TM (and Qualification
Plans, if used)

 Test number
This is typically a consecutive numbering within a defined activity (e.g. within a FAT)

 Test run no.

In case that multiple runs are foreseen, a numbering (or any other ID) should be used to
identify them

 Test objective
Short description on what is intended with the test (might be solely mentioned in the
template or taken from a previously issued document (e.g. Test Matrix or Qualification
Plan))

 Test prerequisites
Lists items or conditions that need to be available to allow a successful execution of the test

 Test procedure
Description on how to perform the test. This can either be done in the template or a
reference to a SOP can be given
It should be noted, that the procedure should be written (and verified upfront) to allow a
knowledgeable (SME) and trained person to achieve equal results when repeating the test

 Acceptance criteria
Precise and unambiguously with respect to scope and test procedure; if multiple acceptance
criteria are part of the test, they should undergo an individual assessment

 Test result(s)
Foreseen to capture the test results (handwriting or prints of electronically captured data,
that belongs to the test); requires multiple lines, if several acceptance criteria are in scope
of the test

 Comments section
Open space that can be used to record things that happened during the test execution; if
not used it needs to be crossed out (oblique stroke)

 Final test assessment

This is for the assessment for the performed test and related tests and includes a review
that the procedures has been followed, compliance to Good Documentation practice, and
meeting the acceptance criteria
Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

 Test result raw data

The test sheet should also have a defined area for recording of test results, this could be a
blank sheet (also for attaching print outs) or better predefined to guide the tester on what
to record and how

In addition, all test documentation contains the following

 Customer
 Page numbering (page x of y)
 Doc ID

Notes:
Coloured boxes on the test example sheets are for explanation and reference only. They are not in the
real project example documentation.
The example is dual language English/German. It is from a German supplier and the project language
is English.
Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

Test Plan

<customer> Page
Test of xyz xyz of xyz

Test Procedure SOP xyz Test number

Test (mark with X or N/A) Test [ ] Retest [ ]

identification
Test xyz
Objective
Machine Type xyz
Machine no xyz
Test
Prerequisites Test location (e.g. factory or customer site location)

Format xyz

Number of xyz
items tested

Test Results Yes/No

Acceptance xyz
Criteria
Comments

Yes/no Date Initials

Results xyz xyz
comply
Results xyz xyz
approved

Comments
Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

Electronic documentation of test and qualification activities may be executed similar to paper‐based
execution of tests, but on a digital media, e.g., a tablet computer. Some companies have started to use
the electronic documentation more integrated with images, recordings and other types of
documentation that supports the test documentation. For example, the use of electronic tablets
enables attachment of images of an inspection or video of a test run.

The qualification activities can be streamlined significantly with such tools and the following example
is from a project where an iPad‐based application using Adobe Acrobat as the software tool was used
to plan, execute and document the testing of a machine for pharmaceutical application, both during
Factory Acceptance Test (FAT) and Site Acceptance Test (SAT).

There are many benefits of using digital electronic test descriptions and documentation and the
following examples serves as inspiration from projects that used these tools. The examples are
performed with a simple Adobe Acrobat based tool that has been used by both, pharmaceutical
customers and suppliers. Requirements related to data integrity and regulations may apply,
depending on the specific application.

Appendix 6 Product Quality Plan (PQP) includes an example of a project test plan with paper‐based
test results and here is an example of the same test using an electronic recording method. Although
the two formats look comparable, the electronic version enables a number of automatic recordings
on e.g., the date, time, user ID etc. as desired. None of this is possible with traditional paper‐based
test and qualification activities.
Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

Paper‐based test execution Electronic test execution

Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

During test execution the digital document can be expanded for the specific test details, acceptance
criteria, signatures etc. as illustrated below:

Validation function for actions performed

within electronic qualification record pairs
actions with their executor.
This feature is intended to check if
actions/records were created in the
correct order and signed by the correct
personnel.

During the execution, digital images and other recordings may be added as follows:

Attaching of raw data (e.g.

pictures, audio, video files or
recordings of various
measuring devices) in their
original format to the
electronic record is another
advantage that leads to
increased transparency and
efficacy during qualification
execution.

The addition of files also enables a ‘hybrid’ approach where some of the documentation is paper based.
In this example the documents are stored in an electronic document management system that keeps
track on the progress, the records and the approvals associated with the test and qualification activities.
Integrated Qualification and Validation Guide

Appendix 7: Qualification Documentation Template Example

The electronic completion and signatures of a set of test activities is illustrated below:

Use of commenting/release functions

eases the user traceability, readability of
records and together with the e‐signature
provides requested level of reliability in
terms of who its author/reviewer is.

The figure shows current practice, when

attaching paper attachments with the
arrow pointing to an electronic solution ‐
the predefined electronic stamp equipped
with the e‐signature.

The electronic tools can be enhanced with several more options as illustrated below:

Function for signature validation to

determine the authenticity of the
signature’s digital ID certificate status and
document integrity.
A valid document gives you assurance, that
content was not manipulated after being
signed.
 Integrated Qualification and Validation Guide

Appendix 8: Remote Testing of GMP Manufacturing Systems

Introduction to Remote Testing
For interaction between customer and supplier in the engineering phase and for testing activities, the
physical presence at the supplier’s plant or the customer’s site may require significant resources on
travel and time for the involved teams on both customer and supplier side.

Therefore, based on a trustful relationship between customer and supplier, it can make sense for
activities to be carried out remotely rather than in person, at least for part of the teams. The remote
activities can be combined with IT tools like video link, teleconference etc. so that only some of the
customer representatives are present, and others are only connected. There are many different tools
commercially available and the exact approach must be discussed and clarified in advance by all
parties involved. If at least one person is not participating in an onsite joint activity and must be hosted
remotely to the rest of the party, this condition is called “hybrid situation”. Hybrid situations are more
difficult than remote situations because all requirements to a joint communication and common
understanding need to be considered.

During the coronavirus pandemic several remote activities were the only way out of the traveling
restrictions. Since then, the use of remote activities such as supplier audit, Design Qualification
workshop, factory acceptance tests (FAT), site acceptance tests (SAT), IQ tests, OQ tests and many
others, can be planned case to case as a supplement to physical presence and the exact approach
should be decided from a risk‐based perspective.
Legally there are no formal requirements on physical presence, but inspectors expect detailed planning
and documentation of remote activities. This is unlike formal regulatory inspections (e.g., GMP
inspections by regulatory authorities or audit of suppliers of pharmaceutical product ingredients)
where physical presence is the regulatory necessity.

The purpose of this chapter is to list advantages, disadvantages and prerequisites, to raise the
acceptance of organizing remote and hybrid remote activities in a project. It is the goal to enable
remote activities ‐if properly prepared, executed and documented – to be fully accepted by all parties.

Checklist for planning Remote or Hybrid Remote Testing

As stated in the introduction, there are many forms of remote or hybrid remote activities. The
following “points to consider” have been collected to help customers and suppliers finding the
most suitable way to perform successful remote or hybrid testing activities. These points can be used
as inspiration for other remote or hybrid activities.

Before Remote Testing

Before starting the activity, the following points should be considered:
 Definition of a clear program including planning, duration, way of interaction during the remote
testing execution
 Discuss which tests can be performed in advance and which results can already be derived from
this testing
 Who will participate (assembly engineers, software engineers, mechanical engineers, etc. need to
be available during the remote test duration); time difference between customer and supplier
Integrated Qualification and Validation Guide

location must also be considered

 Scope of the remote testing; 100% remote, partly remote or partly in physical presence
 Which documented evidence is needed
 Define IT‐platform and IT exchange and communication tools
 Training or presentation of the technical infrastructure and telecommunication devices
 At least one pre‐test is recommended prior remote follow‐up for testing of all technique,
connections, etc. (avoid hick‐ups when start of remote testing execution)
 Level of interaction between supplier and customer– ranging from customer only getting test
results and documentation presented by supplier up to fully witnessed tests by customer via video
feed
 In case of video‐feed, clarification of how many cameras, in which positions, and for which tests
should be used
 Confirmation if according to local supplier country regulations staff executing the tests must sign
a declaration accepting that they are being video recorded (General Data Protection Regulation),
 For each test at least one acceptance criterion (according to agreed testing protocol) needs to be
defined
 Discussion and agreement on how to show and view the actual execution results
 Integrated Qualification and Validation Guide

Appendix 8: Remote Testing of GMP Manufacturing Systems

 Discussion and agreement how documentation should be reviewed

o Which documents (incl. technical documentation, certificates & specifications) should be
reviewed and in which format and maturity level?
o Whether to send all documents by scan to the client before or during remote testing or
whether to use an agreed electronic way of reviewing (see chapter electronical
documentation in this guideline)
o how are supplier internal testing results documented and in which way will these be part of
the testing
o How often should (intermediate) test result forwarded to the customer
o How to handle test results approval, when supplier or customer representatives are
witnessing the test especially when contemporaneous signature is expected
o Discuss and agree between customer and supplier how raw data generated during remote
testing is treated.
 Discussion how to clarify content questions during test execution (normally conversations on the
sidelines)
 Clarification of possible language issues upfront
 Having an alternative plan in hand in case of technical difficulties
 Clarification in advance how to handle deviations and changes during test execution
 Discuss and agree on the staff that is performing the tests, personnel of the customer following and
reviewing the performance as well as experts jumping in, in case of deviations or questions
 A system should be discussed and agreed on for indicating items having passed the test and for
listing deviations
 Management of deviations should be described and approved by customer before the testing
starts.
 Prepare the story book for each single day
In case video‐feed throughout testing has not been chosen or is not possible, consider in the
beginning of day 1 to execute a virtual “tour” of the equipment even if no actual testing is done
during this event.
 It should be discussed between customer and suppliers how tests should be executed to make
leveraging possible (e.g. from FAT to IQ) regarding possible limitation due to remote testing

Starting and Progress of Remote Testing

 Fill in the story book for each day
 The testing should start with a common web conference where the agenda for the day(s) is
presented, players are introduced, and timelines are discussed. Dependent on the agreed process
this may be a daily agenda item.
 Use of supplier’s protocol approved by customer (early integration of the customer into the process
is very helpful).
 Make customer familiar with the manufacturing system(s) and all the details ‐ live demonstration
of the running system(s).
 Run remote testing by teleconference using webcam if agreed.
 Review tests executed by supplier (protocol can be executed by supplier before the remote testing
 Integrated Qualification and Validation Guide

and then a spot check – for which the methodology must be defined in advance ‐ should be done
by customer during remote testing). Alternatively, execute all tests directly during remote testing).
 Review of test documentation at the end of each day in a daily wrap up meeting.
 Consider live feed giving customer team access to HMI child monitor – i.e. all HMI communication
directly visible to customer.
 All generated test proofs must be attached to the protocol by the supplier.
 Raw data generated during remote testing must be scanned and sent to the customer. The original
paper or raw data should be sent, the latest, at the same time of manufacturing system delivery.
 Alternatively, an agreed way of electronic testing could be used to avoid paper and accelerate the
advantages of remote testing (see also Chapter electronic documentation of the Guide)
 Microphones should be muted. Only the speaker should be unmuted otherwise there will be too
many side noises. Noise cancelling would be desirable maybe using headphones.
 Check the possibility to use reality devices (bodycam, integrated webcam and glasses).

End of Remote Testing

 Questions & Answers session with the customer.

 Approval by the customer of all registered deviations and changes detected during remote testing.
 Executive summary report reviewed and approved/signed by customer.
 Authorization (or not) by customer for manufacturing system(s) shipment to customer’s facility.
 Integrated Qualification and Validation Guide

Appendix 9: Categorisation of Manufacturing Systems: Template

As described in Section 7 some pharmaceutical companies use a categorisation of manufacturing systems

not only to standardise the qualification approach for certain system types but also to reduce the
qualification efforts in case of simple and/or less quality critical systems. There are several possibilities on
how to do the categorisation and definition of the work scope. In this appendix, one method is shown,
but other methods, like a matrix approach or a decision tree approach can be applied too. This is based
on the individual needs and preferences. The example is based on the three categories as introduced in
section 7:

A. Standard (Commercial off‐the‐shelf systems (COTS))

B. Configured (COTS with specific configuration of, e.g., sequence, setpoints, timers, etc.)
C. Customised (designed for the specific customer with specific requirements, that is not available
commercially, due to a special application, technology innovation etc.)
On top of these three categories the dimensions related to the intended use of the system and knowledge
on the supplier should be considered, e.g., as described in the example below.

For a tabular approach, the three aspects of “system criticality”, “Intended use criticality”, and “supplier
related criticality” are assessed in combination as typically done in the qualitative risk assessments. Each
of three aspects are first classified as “High”, “Middle” or “Low”‐critical dependent on the following
aspects:

 System criticality, considering:

‐ system complexity (e.g. customised systems)
‐ grade of automation (e.g. configured systems)
‐ grade of standardisation (e.g. standardised systems)
 Intended use criticality, considering:
‐ impact on product and process
‐ ease of operation
‐ interaction with other systems
‐ knowledge and experience of the pharmaceutical manufacturer
 Supplier related criticality, considering:
‐ experience, history, quality
‐ system experiences (numbers produced)
‐ standardised manufacturing process

Each single item is classified individually for the system using the terms “low”, “medium” or “high” for
assessing the overall criticality. The level of effort, formality, and documentation should be commensurate
with the level of risk.

Additionally, it is possible to categorise each manufacturing system into a superordinate system group
like A, B and C. It leads to a superordinate and harmonized categorisation within the company, as
manufacturing systems of the same intended use and supplier will be handled similar.

After qualification and release of a system the categorisation could also be used for the periodic
evaluation of qualification status and if necessary, the determination of the frequency for requalification
 Integrated Qualification and Validation Guide

Appendix 9: Categorisation of Manufacturing Systems: Examples

e.g., category C = each year, category B = every 2 – 3 years, category A = every 5 years, for practical
requalification the same extent of OQ / PQ could be used. The approach could also be used ongoing if
changes are initiated impacting the intended use or causing modifications (life cycle approach).

The example shown in figure xx gives a deep insight into the attribute‐specific criticalities and can be used
to get a better overview of the criticality of a specific system and what kind of qualification activities must
be performed. Also, you can justify your decision and use the detailed format to generate specific test
plans covering those parts that are relevant for the intended use.
Integrated Qualification and Validation Guide

Appendix 9: Categorisation of Manufacturing Systems: Examples

Direct Impact
Equipment

System Criticality T1

Usage Criticality T2

Supplier Criticality T3
 Integrated Qualification and Validation Guide

Appendix 9: Categorisation of Manufacturing Systems: Examples

In addition to the system criticality, this example considers the criticality associated with intended use
and supplier as well. Every company must decide whether these items will be taken into consideration or
not. They can have an impact on a project, e.g. after several projects with the same (known and
experienced) supplier, the risk decreases.

The final average evaluation may be done in a simple list, like shown below:

System Risk (T1) Usage Risk (T2) Supplier (T3) Total Risk Result
Cat A (low) Simple (low) Well known (low) Low Use standard test template xxx for
qualification
Cat B (medium) With Cal. (middle) Famous and certified, Middle Use standard test template for
but not known here standard system parts. Develop a
(middle) system specific protocol for
configured options
Cat C (high) CPPs (high) Unknown (high) High System specific test protocol
 Integrated Qualification and Validation Guide

Appendix 10: Pharmaceutical Customer and Supplier Contract Checklist

This appendix is to cover the quality related aspects of a contract, which is normally done in writing before
a project starts. Details and extent of a contract between pharmaceutical customer and supplier should
be adapted to the complexity and the scope of supply. Duplications or repetitions within the contract or
with other related documents should be avoided. When the contract has the status of a Quality Assurance
Agreement (QAA), commercial aspects ‐ such as prices, payment terms, delivery times, etc. – should
whenever possible not be covered in the same document.

Regarding details and extent of the contract, following could be a first basic rule, when using the
categorization system as proposed in chapter 4.2 of the main guide:

The contract details and extent for the supply of equipment category A (not‐critical, typically highly
standardized COTS systems, no critical process function) shall be minimal. In such a case, studying the
contract documents should not cause more effort than studying the purchase documents or brochures.

The contract details and extent for the supply of equipment category B (low criticality, typically configured
COTS systems with some influence on processes and product quality) shall be adapted to the specific risks
and the ultimate impact of this manufacturing system to patient safety.

The contract details and extent for the supply of equipment category C (critical systems, customized and
designed for the specific customer with specific requirements, having considerable influence on processes
and products) has to be specific and detailed enough to mitigate or minimize the risks on processes and
products and has to consider all relevant additional services in relation with the supply. Risks must be
considered in connection with the ultimate impact of this manufacturing system to patient safety.

The contract details and extent for the supply of equipment category A, B or C depends very much on
whether the services related to the supply are to be performed on site within the GMP‐production
environment or not. If such services on site are included, the contract has to consider this in all details –
following a risk‐based approach and keeping the impact of this service to patient safety in mind.

It is strongly recommended that before contract implementation the pharmaceutical manufacturer–‐

performs process, product and project related risk analysis respectively from which the level of
supervision including life cycle activities are derived, forming the basis for the later contracts with the
suppliers. This includes but is not limited to the definition, which GMP‐tests and documents should be
prepared by the supplier, where and when the customer will witness tests or will review test‐protocols
and many more. This can also be an advantage for the pharmaceutical manufacturer, as unnecessary
repetition of tests can be avoided (“single‐test‐approach”).
 Integrated Qualification and Validation Guide

Appendix 10: Pharmaceutical Customer and Supplier Contract Checklist

The following list shows contract contents which ‐ depending on the result of the risk analysis ‐ should be
part of the contract and which considers not only the one‐time delivery but also the life‐cycle related
services as far as appropriate:

(1) Responsibilities and demarcation of tasks, to ensure:

1.1. that effective process is available for maintaining and calibrating critical equipment
1.2. Appropriate reviewing and approving of validation protocols and reports, if agreed as part
of the scope of services
1.3. Deviation and escalation management is in place and followed
1.4. Delimitation of responsibilities/ tasks/ functions for all individual activities
(2) Equipment deliverables and scope of services, also considering in the life cycle of the system
(3) Timelines and frequencies especially for life‐cycle deliverables and activities
(4) Scope of documentation of the supplier’s QMS
(5) The obligation to permit supplier audits
(6) Requirements & documentation on subcontracting and subcontractor’s QMS (for critical parts, if
applicable)
(7) Information exchange management
(8) Languages, versioning, general review and approval process of all kinds of documents
(9) General work conditions
(10) Provision of materials, devices, work facilities
(11) Environmental, Health and Safety aspects
(12) Contact information
(13) Organization charts
(14) Training requirements
(15) List with definition of terms and abbreviations used in common documents
(16) Confidentiality obligations, performance and guarantee values
(17) Raw data handling practices including recording and storage
(18) Regulations in force and marketing authorization details as far as relevant

In general, suppliers shall be aware of the principles and guidelines of good manufacturing practice as far
as applicable and should support inspections carried out by the competent authorities as far as needed;
arrangements for audits should be agreed upon if applicable, including permission to audit outsourced
activities, performed by the Contract Acceptor and his mutually agreed subcontractors.
 Integrated Qualification and Validation Guide

Appendix 11: Electronic Documentation (ED)

Aspects to be considered when implementing electronic documentation (ED)

1. GMP & Good Documentation Practice

Legal

Legal stakeholder requirements to be heeded. 2. Legal requirements

3. Local (e.g., company or country specific)
4. Understanding & willingness
Various feasibility aspects between supplier and 5. Adaptability
Supplier‐Customer Interfaces

customer to be considered. 6. Customer‐Supplier management (e.g., audits)

User management to be defined for processes and 7. User groups definition/agreement/assignment
flows, systems, etc. 8. User rights definition/agreement/ assignment
9. Email correspondence
Interfaces between customer and supplier to be 10. Online cloud solutions
checked for feasibility and agreed. 11. External drives
12. Using same system (VLMS/eDMS)
13. Raw Data (e.g., video, pictures, device logs)
Possible Data types intended for exchange to be
14. Documents: Scans/Originals
checked for feasibility and agreed.
15. Using same system (VLMS/eDMS)
Workflows based on the intended use & 16. Uni‐ / multi‐directional
circumstances to be checked for feasibility and 17. Conditional
agreed. 18. Registered/Monitored

19. Electronic signatures

Workflows

Review & approval, to be checked for 20. Standard/built in application

feasibility and agreed. 21. Qualified/ validated
22. Commercially available third‐party applications
23. Editing protection when signed
Protection of approved content and possible 24. Signature revocation/invalidation function or other means
correction of previously entered content to be of entry correction
thought through. 25. Data Integrity and ALCOA++ principles
26. Capacity of handling
Capacity & robustness of the system to be 27. Processes & various qualification/validation steps
considered for intended use. 28. Stability
29. Accessibility
30. Modularity
Scalability & modularity of the system to be
31. Downsize scope for smaller projects (e.g., complex line vs.
considered to fit for purpose.
laboratory equipment)
Use of computerized systems with all its aspects to 32. Hardware (Laptops, tablets, smart phones)
System Lifecycle

be considered if feasible for all involved parties. 33. Software (availability, compatibility, protection)
(even sub‐suppliers)
34. Interactive forms
Advanced automatic functions with intuitive tools 35. Use of templates
and operations might be considered to ease and 36. Pre‐defined content
improve content creation. 37. Execution of tests in the system
38. Data Management
39. Physical /Digital /Dual
Archiving requirements of the created records, logs, 40. Definition of retention period
flows, etc. must be considered. 41. Automatic Deletion after retention period
Backup of archived but also “in use” data to be 42. Data Back‐up Routine
considered.
43. System needs to be validated (eDMS/VLMS)
Qualification / Validation

44. Data Integrity and ALCOA++ requirements should be

Qualification & Validation of relevant aspects for tested prior use
GMP industry to be considered. 45. Personnel training, equipment, IT infrastructure should be
also qualified/validated

46. Project Management Lifecycle:

Management of qualification & validation activities 47. Initiating/ planning/ executing/ monitoring controlling/
with all its constraints to be considered within the closing
whole project management lifecycle. 48. Project Management constraints:
49. cost/ time/ scope/ quality/ resources/ risk
 Integrated Qualification and Validation Guide

Appendix 12: Technical Glossary

Term Explanation

Calibration The set of operations which establish, under specified conditions, the
relationship between values indicated by a measuring instrument or
measuring system, or values represented by a material measure, and
the corresponding known values of a reference standard (EU GMP)
Commissioning A well‐planned, documented and managed engineering approach to the
start‐up and turnover of facilities, systems, utilities and equipment to the
end‐user that results in a safe and functional environment that meets
established design requirements and stakeholder expectations. (ISPE
C&Q Baseline Guide version 2)

Critical Aspects (CA) Functions, features, abilities and performances or characteristics

necessary for the manufacturing process and systems to ensure
consistent product quality and patient safety (ASTM E2500‐20)

Critical Design Elements (CDE) Design functions or features of an engineered system that are necessary
to consistently manufacture products with the desired quality attributes.
Examples of automation design functions include alarms and data
management. Examples of engineering design features include
components, instruments, and materials of construction. CDEs are
identified and documented based on technical understanding of the
product CQAs, process CPPs and equipment design/automation. CDEs are
verified through C&Q (ISPE C&Q Baseline Guide version 2)
Critical Process Parameter (CPP) A process parameter whose variability has an impact on a critical quality
attribute and therefore should be monitored or controlled to ensure the
process produces the desired quality (ICH Q8)
Critical Quality Attribute (CQA) A physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range or
distribution to ensure the desired product quality. CQAs are generally
associated with the drug substance, excipients, intermediates (in‐process
materials) and drug product. (ICH Q8)
Design Qualification (DQ) The documented verification that the proposed design of the facilities,
systems and equipment is suitable for the intended purpose (EU GMP
Annex 15)
Design Review(s) Planned and systematic reviews of specifications, design, and design
development and continuous improvement changes performed as
appropriate throughout the life cycle of the manufacturing system. Design
reviews evaluate deliverables against standards and requirements,
identify problems, and propose required corrective actions (ASTM E2500‐
20)
Factory Acceptance Test (FAT) An Acceptance Test in the Supplier’s factory, usually involving the
Customer (IEEE).

Functional Specification or A document that specifies the functions that a system or component
Functional Design Specification (FDS) must perform (often part of a requirements specification) (ISO/IEC/IEEE
24765‐2010)
 Integrated Qualification and Validation Guide

Term Explanation

Good Engineering Practice (GEP) Engineering and technical activities that ensure that a company
manufactures products of the required quality as expected (e.g., by the
relevant regulatory authorities). Good engineering practices are to ensure
that the development and/or manufacturing effort consistently generates
deliverables that support the requirements for qualification or validation
(Wikipedia)
Human Machine Interface Mostly touch screens or any other kind of monitor connected to a control
system or computer to provide the needed information to the user

Installation Qualification (IQ) The documented verification that the facilities, systems and equipment,
as installed or modified, comply with the approved design and the
manufacturer's recommendations (EU GMP Annex 15)

Manufacturing System(s) Elements of pharmaceutical and biopharmaceutical manufacturing

capability, including manufacturing systems, facility equipment, process
equipment, supporting utilities, associated process monitoring and control
systems, and automation systems, that have the potential to affect
product quality and patient safety (ASTM E2500)

Operational Qualification (OQ) The documented verification that the facilities, systems and equipment,
as installed or modified, perform as intended throughout the anticipated
operating ranges (EU GMP Annex 15)

Performance Qualification (PQ) The documented verification that systems and equipment can perform
effectively and reproducibly based on the approved process method and
product specification (EU GMP Annex 15)

Process Qualification (PQ) Confirming that the manufacturing process as designed is capable of
reproducible commercial manufacturing (FDA Process Validation
Guidance)
Process Performance Qualification The process performance qualification (PPQ) is the second element of
(PPQ) Stage 2, process qualification. The PPQ combines the actual facility,
utilities, equipment (each now qualified), and the trained personnel with
the commercial manufacturing process, control procedures, and
components to produce commercial batches. A successful PPQ will
confirm the process design and demonstrate that the commercial
manufacturing process performs as expected (FDA Process Validation
Guidance)
Qualification Action of proving and documenting that equipment or ancillary systems
are properly installed, work correctly, and actually lead to the expected
results. Qualification is part of validation, but the individual qualification
steps alone do not constitute process validation (EU GMP, ICH Q7)
SAT An Acceptance Test at the Customer’s site, usually involving the Customer
(IEEE)
Subject Matter Expert (SME) Individuals with specific expertise in a particular area or field (for example,
quality unit, engineering, automation, development, operations and so
forth) (ASTM E2500)
Supplier Organisation that provides a product or a service (ISO 9001:15)

Quality Risk Management A systematic process for the assessment, control, communication and
review of risks to the quality of the drug (medicinal) product across the
product lifecycle (ICH Q9)
 Integrated Qualification and Validation Guide

Term Explanation

Subject Matter Expert(s) (SME) Individuals with specific expertise and responsibility in a particular
area or field (for example, quality unit, engineering, automation,
development, operations, and so forth) (ASTM E2500)
User requirement specification (URS) The set of owner, user and engineering requirements necessary and
sufficient to create a feasible design meeting the intended purpose of the
system (EU GMP Annex 15)

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 (EU
GMP)
Verification A systematic approach to verify that manufacturing systems, acting singly
or in combination, are fit for intended use, have been properly installed,
and are operating correctly. This is an umbrella term that encompasses all
types of approaches to assuring systems are fit for use such as
qualification, commissioning and qualification, verification, system
validation, or other (ASTM E2500)