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GUERBET MISSION
Guerbet’s men and womenare committed to offering
health professionals contrast
agents, medical devices
and innovative solutionsindispensable to diagnostic
and interventional imaging to
improve patients’ prognosis
and quality of life.

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TABLES OF CONTENTS

1 Introduction
1.1
1.2
1.3
1.4
1.5
1.6

Executive Summary – P5
Scope – P5
About Guerbet – P5
Guerbet Products and Services – P6
Our Guerbet Quality Vision – P7
Our Guerbet Quality Policy – P8

Responsibilities
2 Quality
and Organisation
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10

Responsibilities – P9
Organisational Charts – P10
Site Quality Operations – P12
Quality Technical Operations Group – P12
Senior Management – P13
Responsibilities for Third Parties(Services Providers, Suppliers) – P13
Responsibilities for Contract
Manufacturers (CMOs) – P14
Responsibilities for Supply Chain – P14
Development, Medical andRegulatory Affairs Organisation
and Quality Assurance – P15
Affiliate Quality Management – P15

3 Management Responsibilities
3.1
3.2
3.3
3.4

Management Review – P16
Planning – P17
Measurement – P17
Communication – P17

6 Group Quality Audits
an Inspections – P20

7 Group Quality Documentation
System and Data Control
7.1
7.2

Documentation Overview – P21
Records Management – P22

8 Product Realisation
8.1
8.2
8.3

8.4
8.5
8.6
8.7
8.8
8.9
8.10

Research and Innovation – P23
Design and Development – P23
Design changes / Change Management
System (Management of
Change - MoC) – P24
Purchasing – P24
Product Identification and Traceability – P25
Control of Monitoring and
Measuring Devices – P25
Customer Related Processes – P25
Pharmacovigilance Processes – P25
Medical Devices Vigilance Processes – P25
Information Systems Processes – P26

9 Measurement, Analysis
and Improvement
9.1
9.2
9.3
9.4

Monitoring and Measurement – P27
Non-conforming Product Control – P27
Data Analysis – P27
Improvement – P28

4 Our Quality Culture – P18

10 Document History – P29
5 Knowledge Management andQuality Risk Management

5.1
5.2

Knowledge Management – P19
Quality Risk Management – P19

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1
INTRODUCTION
We are pleased to share with you the first Guerbet Group Quality Manual!
Guerbet is a leader in medical imaging worldwide, offering a wide range of pharmaceuticalproducts, medical devices, software and services for diagnostic and interventional imaging, toimprove the diagnosis and treatment of patients.
Our Quality Management System is based upon our strong commitment to offering healthprofessionals contrast agents, medical devices and innovative solutions indispensable todiagnostic and interventional imaging to improve patients' prognosis and quality of life. It is our
Quality System applied to ensure the quality of all the Guerbet products, services and solutions
throughout their life-cycle from discovery to development, manufacturing, distribution anddiscontinuation for established and innovative products & services. It is operated in a flexible
and adaptable model to include quality standards specific to each profile class of the Guerbet
portfolio. It is constantly evolving to anticipate regulatory developments and to support theneeds of our three franchises: Diagnostic Imaging, Interventional Imaging and Digital
Solutions, as well as our Global Functions.
In line with our Guerbet objective of focus and simplification, the Quality Manual provides to
all Guerbet personnel as well as to external partners and regulators a concise and useful
overview of our Quality System structure and related key processes. Our Guerbet Quality
Vision, Quality Policy and Quality Manual constitute the hallmarks of our Quality
Documentation pyramid and serve as vectors to ensure a full deployment of our Quality
management principles across the organization. They are an important part of our desired
Quality Culture focused on patient safety centricity and contribute to our innovation andcontinuous improvement strategic goals.
We are convinced that, thanks to the commitment to this Quality Manual of each individual at
all levels of Guerbet, we will be improving diagnosis, prognosis and quality of life for patients.

David HALE
Chief Executive Officer

Q020326, GBT-DMS-Quality-10000110 V1.0

Pierre ANDRE
Vice President, Quality Technical Operations
Chief Pharmaceutical Officer

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1.1 EXECUTIVE SUMMARY
This Quality Manual provides specifics on the policies and procedures Guerbet uses to meet cGXPs
Quality Management System requirements.
The intent of these policies and procedures is to demonstrate Guerbet’s ability to consistently provide
products & services that meets our patients, customers and applicable regulatory requirements and toenhance our patients & customers’ satisfaction through the effective application of the quality system,
including processes for continual improvement of the system and the assurance of conformity to ourpatients & customers and applicable regulatory requirements.

1.2 SCOPE
The Quality Manual applies to all Guerbet sites including all activities related to research, development,
manufacturing and distribution of all Guerbet products & services.

1.3 ABOUT GUERBET
Guerbet is a Global Pharmaceutical and Medical Device group founded in France and supporting
healthcare professionals specializing in diagnostic and interventional medical imaging. We provide themwith contrast media, injection systems, medical devices and related solutions adapted to their needs.
It all began with Marcel Guerbet’s discovery of the first iodinated organic contrast medium in 1901. The
company was later founded in 1926 by André Guerbet. Guerbet’s innovative workforce has since left
its mark on medical imaging technologies and contrast media, taking the company to the next level.
Every second, somewhere in the world a patient undergoes an imaging procedure with a Guerbet
product. More than 60,000 health professionals rely on our contrast agents to diagnose disease andassess treatment efficacy.
Guerbet is listed in Euronext Segment B, and a majority of its shares are owned by the Guerbet family.
> For more info about Guerbet, visit www.guerbet.com

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1.4 GUERBET PRODUCTS AND SERVICES
Guerbet offers a comprehensive range of imaging products, solutions, and services for Diagnostic
Imaging (MRI, CT, Cath Lab, Digital Solutions, Interventional Imaging, Interventional Radiology) and
Women’s Health to enhance clinical decision-making at each point of the patient journey fromdiagnosis, to treatment and follow-up, in order to efficiently improve patient outcomes.
Our products and services are available in more than 80 countries through our affiliates and networkof distributors.

DIAGNOSTIC IMAGING (DI)CT&
Cath Lab

Magnetic
Resonance
Imaging

Optiray®

Dotarem®

Digital& AI
solutions

Xenetix®

Illumena Neo®

OptiStar
Elite®

OptiVantage®

Flowsens®

OptiOne®

INTERVENTIONAL IMAGING (II)Interventional
Imaging

Lipiodol® Ultra-Fluid

Patent Blue V

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Microcatheters
SeQure® and DrakinTM

Vectorio®

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1.5 OUR QUALITY VISION

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1.6 OUR QUALITY POLICY

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2
QUALITY RESPONSIBILITIES AND ORGANISATION
2.1 RESPONSABILITIES
Quality Technical Operations Vice-President (QTO VP) & Chief Pharmaceutical Officer
The Quality Technical Operations VP & Chief Pharmaceutical Officer is responsible and has theauthority:
 For the implementation of the quality system. The QTO VP delegates to others various aspectsof the system but retains the responsibility and accountability,
 To establish a system, which will ensure the flow and further communication of the required
information on current regulatory requirements.

Quality Assurance Manager of Departments
The Quality Assurance Manager of departments are accountable for:
 For ensuring compliance of its Department activities to regulatory and internal requirements;
 For monitoring the accurate application of the quality management system of its Department; For establishing an audit plan and conducting such audits, based on a risk analysis;
 For representing its department towards competent / regulatory authorities during inspections.

Quality Organisation (Sites, group)
The Quality Organisation is responsible for:
 Recommending strategies to management for meeting quality objectives and monitoring theeffectiveness of the quality system,
 Establishing and monitoring suitable audits on products, processes, and systems to ensure that
all established quality criteria are met prior to release to the market.

All Departments
The responsibility for attainment of the established quality levels is shared by all departments. The
quality system includes an environment that encourages continuous improvement by everyone – Allof management is committed to this and all employees are involved.
Each individual employee is responsible for performing assigned functions or task assignments inaccordance with established procedures and guidelines, so that the defined standards of quality areachieved.
Department Managers are responsible and have authority for creation and implementation of all
required procedures.

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2.2 ORGANISATIONAL CHARTS
Within the Quality Technical Operations (QTO) there over 300 people. The Quality Technical
Operations VP & Chief Pharmaceutical Officer reports into the Chief Technical Operations
Officer:

Quality Manager LanesternQuality Manager DublinnQuality Manager MaransnQuality Manager MontrealnQuality Manager RaleighnQuality Manager Aulnay
Executive
Assistant
Quality Technical
Operations VP / Chief
Pharmaceutical OfficernQuality Manager Lyonn

Quality Manager RionQuality Manager
Cincinnati

Quality Manager St LouisnGlobal Medical Devices Quality Manager

Medical Devices
Quality Expert
MDS&T Medical
Device SMEnGlobal QMS ManagernGlobal Distribution Quality ManagernQuality Manager
IsraelGlobal Quality Supplier ManagernGlobal QC Program Manager

nGroup Sterile & Microbiology QA Managern

CMO Quality ManagernPharmaceutical Compliance SI and Laboratory expertnQ020326, GBT-DMS-Quality-10000110 V1.0

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2Within the Development, Medical and Regulatory Affairs group there are over 100 people.
The Medical Affairs and Regulatory Affairs VP has the following direct reports:

Within the Audit and Compliance group there are about 8 people. The CI audit and ComplianceDirector reports into the Chief Executive Officer and has the following direct reports:

Pharmaceutical Affairs Compliance ManagernDirector Audit CI
and Compliance

RESP Group Internal Auditsn

RESP Internal Control

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2.3 SITE QUALITY OPERATIONS
At each manufacturing site there is one Site Quality Manager (SQM) with the mission to leadand coordinate quality and compliance in their sites to ensure that all products and services
are designed, developed, manufactured and distributed in compliance with the applicableregulatory and Company requirements.
This includes the following responsibilities, as a minimum:
 Accountable for cGxP compliance and quality performance for products and services attheir sites, Ensure and harmonize consistent implementation of the Guerbet QMS at their sites, Ensure continuous improvement of the quality concepts, promote innovation and systems
performance, Integrate risk management principles into Quality Systems,
 Ensure inspection readiness and strictly follow-up to GxP regulatory inspections.
The SQM in the Active Pharmaceutical Ingredients (API) and Fill / Finish sites report
operationally to the Chief Pharmaceutical Officer, with a dotted line to the Plant Directors.

The Heads of the Operational Quality Units in the Medical Device sites report operationally to
the Global Medical Devices Quality Manager, with a dotted line to the Plant Directors.

2.4 QUALITY TECHNICAL OPERATIONS GROUP
The Quality Technical Operations (QTO) group report into the Quality Technical Operations
VP & Chief Pharmaceutical Officer.
This group consists of the following: Quality Manager for CMOs,
 Global Medical Devices Quality Manager
 Global Distribution Quality Manager, Global Quality Management Systems Manager,
 US Quality Technical Operations Manager, Global Supplier Quality Manager, Pharmaceutical Compliance SI and Laboratory expert, Group Microbiology & GMP Compliance,
 Computer System Validation Manager, Executive Assistant to Vice President, Global Quality Technical Operations & Chief
Pharmaceutical Officer.

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2.5 SENIOR MANAGEMENT
Senior Management is the team of individuals at the highest level of authority in theirrespective organisation who have the day-to-day task to manage that organisation. They
have the ultimate responsibility for the overall effectiveness of the QMS. Senior
Management ensures that roles, responsibilities and authorities related to the QMS are
defined, communicated and implemented throughout the company.
In practice, Senior Management: Participates in the design, implementation, monitoring and maintenance of the QMS
throughout their organization,
 Demonstrates strong and visible commitment to the QMS,
 Ensures a timely and effective communication and escalation process exists to raise
quality issues to the appropriate levels of management, Conducts management reviews of process performance, product quality and the QMS
effectiveness,
 Supervise relevant staff in their respective field of operation and adherence to Quality
principles, Advocates for continuous improvement, determining and ensuring adequate
resources to implement, maintain and continuously improve the QMS.

2.6 RESPONSIBILITIES FOR THIRD PARTIES (SERVICESPROVIDERS, SUPPLIERS)
The responsibility for service providers and suppliers is with the Global Supplier Quality
Manager and with each site Quality Manager. This includes;
 The overall quality and compliance of supplier quality and oversight responsibility forpurchasing controls as to relates to quality, The assurance of consistency for supplier audits, supplier statuses, supplier selection,
monitoring practices, metrics and field action prevention,
 Compliance to GMP, deployment of best practices including developing operating
philosophies, establishment and maintenance of a Quality culture and establishingquality systems in alignment with Guerbet Global standards and international GMP
regulations.

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2.7 RESPONSIBILITIES FOR CONTRACT MANUFACTURERS
The contract manufacturing organization (CMO) team is composed of individuals thatmanage the day-to-day tasks to ensure production at CMOs sites are effectively performed
according to cGXP. They have the responsibility to ensure the Guerbet Group policy are
efficiently applied.
In order to ensure an adequate surveillance of the operations performed at CMO sites andquality system is in place, regular governance meetings are organized to review therequirements defined in relevant quality agreements.
Finally, an annual evaluation of each CMO performance is established.

2.8 RESPONSIBILITIES FOR SUPPLY CHAIN
The Quality Supply Chain ensures the control of the distribution chain and consequently
maintains the quality and the integrity of medicinal products and medical devices.
In order to guarantee the quality and the integrity of the products, the quality supply chain
is responsible for:










Developing and maintaining a quality system setting out responsibilities, processes
and risk management principles in relation to the distribution activities,
Conducting Quality risk management and ensuring that the evaluation of the risk
to quality is based on scientific knowledge, experience with the process andultimately links to the protection of the patient,
Defining the shipping lanes and qualify them prospectively or retrospectively,
Qualifying the transporters and maintain their qualification (Audit and Quality
agreement),
Qualifying the distributors partners (Third Party Logistic and distributors) andmaintain their qualification (Audit, Quality Agreement and Quality Review Meeting),
Tracking and assessing all deviations noted during the distribution activities,
The training of auditors and other teams involved in the distribution quality
activities,
Managing complaints, returns, suspected falsified medicinal products and recalls
and define appropriate action plan to avoid recurrences.

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2.9 DEVELOPMENT, MEDICAL AND REGULATORY AFFAIRS (DMRA)ORGANISATION
The main activities covered by the departments of the DMRA Division are described in the chart
below:DMRA

Regulatory
Affairs

Pharmaceuticals &Medical Devices• Operations• CMC• Compliance & Data
• Management

Vigilances &MedicalInformation

Medical Affairs &ClinicalDevelopment

Pharmaceuticals &Medical Devices• Operations• Excellence &Innovation PV• System & Processes• Materiovigilance

Pharmaceuticals &Medical Devices• Clinical Projects• Medical Biometrics• IIS• Imaging Expert• Medical Writing& ScientificDocumentation

Quality
Assurance

Pharmaceuticals &Medical Devices• Regulatory Affairs• Vigilances & Medical
Information• Medical Affairs &Clinical Development

Computerized Systems Validation for DMRA
Administration of QMS, Key User for Compliance Wire at DMRA level

The Quality Management System is structured so as to reflect the organization described above.

2.10 AFFILIATE QUALITY MANAGEMENT
At each Commercial Affiliate office within Guerbet, a Quality Manager is appointed to define, implement,
manage and control the Affiliate Quality Systems, in order to ensure the quality of products and services
at market level and to guarantee compliance with applicable regulatory requirements and the Guerbet
Quality Management System. The Affiliate Quality Manager reports to the Affiliate General Manager aswell as, in some regions, to the Regional Distribution Quality Manager. In countries where local regulations
require a Responsible / Qualified Person (QP) for commercial activities, the Affiliate Quality Manager isthe Qualified Person or delegates this responsibility to a designated person.

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MANAGEMENT RESPONSIBILITIES
Senior Management has the responsibility to demonstrate a strong commitment to thequality management system and share the responsibility and authority for overall
administration of quality management system activities. They are responsible for ensuring
the implementation and maintenance of the QMS within their respective areas.
Guerbet has provided evidence of its commitment to the development and implementationof the quality management system and continually improving its effectiveness by:
 Communicating to the organization the importance of meeting customer as well as
statutory and regulatory requirements,
 Establishing the quality policy,
 Ensuring that quality objectives are established, Conducting audits and management reviews; andEnsuring the availability of resources.

3.1 MANAGEMENT REVIEWTechnical Operations
Guerbet reviews the quality management system at planned intervals to ensure its
continuing suitability, adequacy and effectiveness. This review includes assessing
opportunities for improvement and the need for changes to the quality management
system, including the quality policy and quality objectives. Records of management reviews
are maintained.
Management Review is organised and performed as follows: Quarterly Business Quality Management Reviews attended by the Quality Technical
Operations VP / Chief Pharmaceutical Officer and the SVP, Technical Operations at aminimum, Site level Quality Management Reviews (at least three times per year), Monthly Cluster calls to review the months activities by groups (API, Fill & Finish andMedical Device).
Business Quality Management regularly reviews the quality system, as implemented in thesite, to assure its effectiveness in meeting current requirements and company needs.
These reviews are physically conducted at the sites with the relevant site leadership team.

Development, Medical & Regulatory Affairs (DMRA)
The management review is organized yearly, based on QMS update plan – established at
the beginning of a given year for the subsequent two years between QA, Compliance andOperations. In addition, a monthly review of deviations and action plans is organized
between QA and compliance. Finally, monthly indicators are established following the
conduct of audits and planning of corrective / preventive actions.
References: EMA/CHMP/ICH/135/1995 Guideline for Good Clinical Practice (GCP) E6(R2)
EMA/541760/2011 Guideline on Good Pharmacovigilance Practices (GVP)

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3.2 PLANNING
The Quality Policy is supported by Quality Objectives that have been established by thesites and the VP, Quality Technical Operations / Chief Pharmaceutical Officer, the SVP,
Technical Operations and the CEO. Quality is fully integrated into Guerbet’s strategic andoperational planning and business processes.

3.3 MEASUREMENT
Quality performance and reporting are completed for key performance indicators (KPIs),
Quality issues (both product and system) to the appropriate levels within the organisation.
These also include areas for continuous improvement.

3.4 COMMUNICATION
Effective communication is used to promote the Quality Policy and objectives to ensure
there is awareness, engagement and involvement of all personnel at every level. In
addition, Quality Alerts are shared at and between sites to ensure learnings and escalation
occurs within the organisation.

Quality KPIs and key communications are shared and reviewed during the Monthly Tech
Ops T/C by clusters, Monthly QTO T/C by clusters, Quarterly Reviews and Annual Tech
Ops & QTO meetings.
Note:
Reference Quality Management Policy (QMR), (Q019016, GBT-DMS-Quality-Quality
Systems-10000008).
Reference Escalation Policy, (Q019706, GBT-DMS-Quality-Quality Systems-10000062).

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OUR QUALITY CULTURE Creates an environment where Quality is owned by all, so that every employee can adopt
the right behavior and make the right decisions, Includes Patient at the center of our vision, of our thoughts and our acts,
 Encourages continuous improvement and emphasizes Simplicity (Keep It Simple & Smart- KISS), Pragmatism & Entrepreneurial attitude, Develop the right sense of urgency, pay attention to the right things,
 Execute and live Gemba, observe, feed-back and partner with production teams – QuEnSH,
 Take visible actions to simplify processes and systems,
 Includes Quality Risk Management (QRM) in all our decisions, Reinforces our Priorities:

The basics = Permit to Operate

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KNOWLEDGE MANAGEMENT ANDQUALITY RISK MANAGEMENT
Use of Knowledge Management and Quality Risk Management will facilitate achievement of the following
objectives by providing the means for science and risk-based decisions related to product quality: Achieve product realization,
 Establish and maintain a state of control, Facilitate continual improvement.
The Manufacturing Development, Science and Technology (MDS&T) group plays an important role in
Knowledge Management by providing technical and scientific support with the sites, global functions and third
parties to introduce and maintain commercially viable and robust products and services. It helps to ensure
effective product/service development, scale up, technology transfer, process validation, continual
improvement and post-approval change management that meet all the applicable regulatory and Guerbet
requirements. MDS&T is involved as well in new technology surveillance process.

5.1 KNOWLEDGE MANAGEMENT
Product and process knowledge should be managed throughout the product lifecycle from development
through the commercial life of the product up to and including product discontinuation.
Knowledge management is a systematic approach to acquiring, analysing, storing and disseminating
information related to products, manufacturing processes and components.
Sources of knowledge include, but are not limited to: Prior knowledge, Pharmaceutical research and development studies – MDS&T…
 Technology transfer activities,
 Process validation studies, Manufacturing experience, Innovation and Continual improvement, Management of Change activities,
 Pharmacovigilance / Material vigilance.

5.2 QUALITY RISK MANAGEMENT
Quality Risk Management (QRM) is integral to an effective quality management system & supports a scientificand practical approach to decision-making. It provides documented, transparent and reproducible methods toaccomplish steps of the quality risk management process based on current knowledge about assessing theprobability, severity and sometimes detectability of the risk.
It can provide a proactive approach to identifying, scientifically evaluating and controlling potential risks toquality. It facilitates continual improvement of process performance and product quality throughout the productlifecycle.
QRM is integrated into the quality management system including areas such as auditing / inspection program,change management, continuous improvement, quality defects, CAPA and deviation management.
Note: Reference Quality Risk Management Policy (QRM), (Q019219, GBT-DMS-Quality-Quality Systems10000026)

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GROUP QUALITY AUDITS AND INSPECTIONS

Guerbet sites and functions are periodically audited to verify compliance with Guerbet’s
QMS. These audits are managed by the Quality Technical Operations group and the audit
teams include personnel from other sites and functions. These audits facilitate readinessof the sites and functions for regulatory authority inspections, ensuring that Guerbet ismeeting all regulatory obligations and commitments. The audit frequency, duration andnumber of auditors is determined using analysis based on risk.
To ensure on-going inspection readiness the following tools and support are provided: Mock Audits can be performed by Quality Technical Operations group at request of thesite, Unannounced audits are also used to assess the state of compliance and associatedrisks,
 Inspection Preparation can be provided from the Quality Technical Operations groupand site Quality departments. This support is provided both prior to and during
regulatory inspections, Quality Management Review and Monthly Performance Review with Senior
Management.
When deviations from internal or external requirements are identified during audits or
regulatory inspections, corrective and preventive action plans are put in place andmonitored until resolution.
Also, prior to the decision to enter a partnership or purchase of a new product, the Quality
Technical Operations group is involved in the evaluation and selection of the company(depending on the criticality / risk of the product being supplied) through a due diligenceprocess, to assess the state of compliance and associated risks to Guerbet.

Note: Reference Quality Audits (Q018966, GBT-DMS-Quality-Quality Systems-10000001)

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7
GROUP QUALITY DOCUMENTATIONSYSTEM AND DATA CONTROL
Guerbet considers data generated as being a company asset and therefore ensures that data
integrity is fundamental within the quality system to guarantee the safety, efficacy and qualityof Guerbet products.
Guerbet protects the maintenance and assurance of the accuracy and consistency of dataover its life-cycle and ensures that data integrity is critical to the design, implementation anduse of a system that stores, processes or retrieves data.
Data should be reliable and accurate and apply equally to manual and electronic data.
Data governance is integral to the quality system allowing for a flexible and risk-based
approach to prevent and detect data integrity issues.

7.1 DOCUMENTATION OVERVIEW
Quality system is documented at 4 levels to ensure planning and integration of quality into
Guerbet products.
Basic Structure of the Quality Management System Documentation:QUALITY
POLICY ANDOBJECTIVESGBT POLICIES &PROCEDURES

SITE PROCEDURESWORKING INSTRUCTIONS & FORMS

The process to establish, review, approve and distribute global quality policies andprocedures is detailed in the policy for issuing global quality polices referenced below. Global
Quality documents are developed for each type of GxP and public health-related regulation.
Note: Reference Good Data and Records Management (Q019032, GBT-DMS-QualityQuality Systems-10000014)

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7.2 RECORDS MANAGEMENT
Quality records are documents that indicate compliance with the Quality System procedures andprovide evidence of a controlled system. Records define and establish the evidence ofconformity to requirements and effective operation of the Quality Management System.
Quality records will also include computerised systems data that generate GxP data. The use ofvalidated, effective, GxP controlled computerized systems provide enhancements in the quality
assurance of all operations (manufacturing, quality control, release and distribution) related withregulated materials/products and associated data / information management. The extent andtype of validation necessary will be based on the assessment of the criticality of operations
handled through the specific computerised system.
The requirements for identification, storage, protection, retrieval, retention time and dispositionof records are defined.
Note:
Reference Policy for the Control and Issue of Quality Technical Operations Policies,
Guidelines and Procedures (Q018924, GBT-DMS-Quality-Quality Systems-10000000).
Reference Policy for Good Data and Records Management (Q019032, GBT-DMS-QualityQuality Systems-10000014).
Reference Data Integrity Management and Remediation Policy (Q019034, GBT-DMS-QualityQuality Systems-10000013).

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8
PRODUCT REALISATION
8.1 RESEARCH AND INNOVATION
In accordance to Guerbet defined strategy, Research and Innovation objectives are the exploration of new concepts
leading to technological innovations to improve overall patient care through advances in medical imaging with new
products or the development of new applications and processes for existing products in line with regulatory quality andenvironment requirements. Products are either pharmaceuticals, medical devices or software.
Guerbet devotes signification resources to research and innovation including about 9% of revenue and 4 R&D centres.
There is scientific partnership with public and private players worldwide for the development of contrast media andartificial intelligence.

8.2 DESIGN AND DEVELOPMENT
New contrast media or new chemical entities (NCEs) are developed in several successive phases:Phase I to study the clinical and biological tolerance in healthy volunteers and the pharmacokinetics (how the
product is distributed, metabolized and eliminated within the organism) of increasing doses of the product, andthereby determine the maximum tolerated dose,
Phase II to compare the diagnostic effectiveness on patients of several doses of the product usually with aleading product on the market,
Phase III to confirm, for a large cohort of patients, the diagnostic effectiveness and tolerance profile of the productcompared with a leading product or technique.

The main objective of Life Cycle Management (LCM) activities is to manage the changes made on products that are
already approved and sold. Typical LCM activities include obtaining approval for new indications, the development of
new formulations or presentations, securing registrations in new geographic regions, and the clinical studies that takeplace after approval (phase IV).
Medical Device Product design and development activities are accomplished as a planned, controlled, maintained, anddocumented activity. The design and development activities are planned by and assigned to qualified personnel equippedwith adequate resources.
Design input requirements (including functional, performance, usability, and safety requirements, previous designs,
output of risk management) are documented, as detailed in an approved design procedure. Applicable statutory andregulatory requirements are considered and included in design and development inputs. Design input specifications
relating to the product requirements are identified, documented and reviewed for adequacy. Design and development
input activities should also address packaging requirements. Design output specifications defining identified productrequirements are documented in a form that enables verification against the design and development input and isreviewed for adequacy. Design reviews will be conducted by a cross functional team as required. Such reviews will be
documented.
Design verification establishes that design output meets the design input specification by means of design control
measures, as specified in approved design control procedures. Design validation is conducted after Design Verification
activities and shall ensure that product specifications and product performance will meet the specified requirements ofthe product definition as per product dossier. Design transfers are to occur per an approved engineering procedure. This
procedure ensures that design and development outputs are verified and suitable for manufacturing, and production
capability can meet production requirements.
Design History File. This record is of the design and development process and is maintained for each product. This
design history file contains or references the records that demonstrate fulfilment of design control requirements.

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88.3 DESIGN CHANGES / CHANGE MANAGEMENT SYSTEM (MANAGEMENT OFCHANGE – MoC)
Changes, modifications, or revisions are controlled and distributed through the Change Management
System (Management of Change - MoC).
Innovation, continuous improvement, the outputs of process performance and product quality monitoring
and CAPA drive change. In order to evaluate, approve and implement these changes properly, Guerbet
has an effective change management system.
The change management system ensures continuous improvement is undertaken in a timely and effective
manner. It provides a high degree of assurance there are no unintended consequences of the change.
The change management system should include the following, as appropriate for the stage of the lifecycle:
 Quality Risk Management should be utilized to evaluate proposed changes. The level of effort andformality of the evaluation is commensurate with the level of risk,
 Proposed changes are evaluated relative to the marketing authorization, including design space, where
established, and current product and process understanding. There is an assessment to determine
whether a change to the regulatory filing is required under regional requirements. From a
pharmaceutical quality system standpoint, all changes should be evaluated by a company’s change
management system, Proposed changes are evaluated by expert teams with the appropriate expertise and knowledge fromrelevant areas (e.g. Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs) toensure the change is technically justified, After implementation, an evaluation of the change is undertaken to confirm the change objectives wereachieved and that there was no deleterious impact on product quality.
Note: Reference Policy Quality and EHS Management of Change (MOC) (Q019479, GBT-DMS-QualityQuality Systems-10000057)

8.4 PURCHASING
Purchased materials and services from suppliers must conform to requirements established by Guerbet.
Supplier selection, supplier process control, receiving, and testing are methods to provide purchasedmaterial control.
Suppliers are selected on the basis of their ability to meet specified requirements (quality, delivery, service,
and cost). Qualified suppliers are on an Approved Suppliers List (ASL) controlled locally at site level.
Critical suppliers and Guerbet work closely together to identify and target areas for improvement, both at
the supplier and at Guerbet. Establishing process controls, reducing variability, and accomplishing process
improvements, allow both parties to make improvements in terms of quality and service.

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88.5 PRODUCT IDENTIFICATION AND TRACEABILITY
Where appropriate, procedures are established and maintained for product and material identification andtraceability. Procedures and methods are established that identify materials and products during all stagesof delivery and production. These procedures and methods are documented and maintained. When
traceability requirements have to be met, individual materials and products will have unique identification
assigned and will be recorded.

8.6 CONTROL OF MONITORING AND MEASURING EQUIPMENT
Quality and Site management is responsible for establishing and maintaining a system for the control of all
measuring and test equipment used by each site in all phases of product development, inspection, testing,installation, servicing and product acceptance. Designated instruments and equipment are calibrated andtraceable to recognized standards.

8.7 CUSTOMER RELATED PROCESSES
Guerbet establishes and implements procedures for the review of contract requirements, sales contracts,
customer orders and contract compliance in supplying products and services to customers. Customer
complaint communications are handled through the Global Quality Technical Operations group with theProduct Monitoring team based in Saint Louis, USA and in Villepinte, France. Customer complaints arehandled in accordance with local procedures and in partnership with Pharmacovigilance & Medical Devices
Vigilance.

8.8 PHARMACOVIGILANCE PROCESSES
Pharmacovigilance relates to the science and activities ensuring the detection, assessment, understanding
and prevention of adverse effects or any other medicine-related problem [Definition by the WHO].
Guerbet has set up a pharmacovigilance system and a quality system dedicated to pharmacovigilance, as
specified in the guidelines on Good Pharmacovigilance Practices (GVP). The organization and theprocesses of pharmacovigilance are described in quality documents (procedures, instructions and forms)
and in the Pharmacovigilance System Master File (PSMF) of the Group. Pharmacovigilance activities are
performed by some qualified personnel working at headquarters and at partners’ level under the oversightof the European Union Qualified Person for Pharmacovigilance (EU-QPPV). Safety Data Exchange
Agreements (SDEA) stating the roles and responsibilities in pharmacovigilance have been signed between
each partner (affiliate or distributor) and the Pharmacovigilance department of Guerbet.
The pharmacovigilance system is designed to monitor the safety of Guerbet’s authorized medicinal products
and detect any change to their risk-benefit balance.

8.9 MEDICAL DEVICES VIGILANCE PROCESSESThe purpose of the Medical Device Vigilance System (Materiovigilance) is to improve the protection ofhealth and safety of patients, healthcare professionals, and other users by reducing the likelihood ofreoccurrence of incidents related to the use of a medical device.
The Medical Devices regulations states that adverse incidents are evaluated and, where appropriate,
information is disseminated in the form of a National Competent Authority Report (NCAR).

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8
8.10 INFORMATION SYSTEMS PROCESSESThe Information Systems (IS) department of Guerbet Group has set up a quality system (“Qual-IT”)
ensuring the compliance of the group's Information Systems and Information Technologies with
global pharmaceutical requirements and Information Systems good practices. Most of the activities
run by Guerbet Group are critically dependent on Information Systems, which are hosted onpremises or in the cloud. They are made up of a complex worldwide network of interrelated systems,
involving a great variety of stakeholders such as institutions, clients, suppliers and even more.
A dysfunction or cyberattack in the way Information Systems operate can therefore lead to problems
that could be severe with possible consequences on product quality, patient safety, our image,turnover, employees, customers, shareholders and environment. IS has issued policies andprocedures that govern all our IS processes.
The IS Quality Policy is based on two main pillars:

Information Security,
IS Validation.

Information Security Policy is driven by the Chief Information Security Officer who oversees
managing IS security. He reports to the Chief Information Officer (CIO). The Chief Information
Security Officer (CISO) leads 2 committees: Security committee (Quarterly with CIO), Security
report (Monthly with Local Security Officer). Information Security aims at taking adapted measures
to ensure the protection of data and Information Systems and compliance with regulations by
establishing and implementing the appropriate principles:

Availability to ensure that authorized users have access to information, application andservices when needed,
Integrity to safeguard the accuracy and completeness of information and processing
methods,
Confidentiality to ensure that information is not made available or disclosed to unauthorizedindividuals, entities, or processes,
Auditability which refers to the capability of a system to keep relevant tracks and proofs ofwhat was done and by who.

IS Validation Policy is driven by the IS Validation Engineer who oversees validating Information
Systems used for decision making related to product quality or patient safety. The IS Validation
Engineer reports to the IS organization & Methods manager with a dotted line to the Chief
Pharmaceutical Officer. The Validation Engineer participates to GxP project committees, Change
Advisory Boards (CABs) and Quarterly Validation Reviews with the Chief Pharmaceutical Officer.
The purpose of IS Validation is to implement measures to ensure that Information Systems are fit
for intended use and compliant with healthcare industry regulations all over their life cycle fromconception to retirement. Those measures aim to safeguard product quality and patient safety by
reducing the risk to an acceptable level of undermining the integrity of the data and the Information
Systems.
Validation consists in obtaining and maintaining compliance with healthcare industry regulations by:Organizing qualification activities as part of plans and reports,
Applying appropriate controls during operation phase of Information Systems in periodic
reviews.

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9
MEASUREMENT, ANALYSIS AND IMPROVEMENT
9.1 MONITORING AND MEASUREMENT
The effectiveness of quality management system and the overall quality performance of
manufacturing, distribution, development operations must be continuously monitored andassessed in order that opportunities for improvement and elimination of defects be provided.
Customer satisfaction
Guerbet aims at not only to meeting proactively, but exceeding, if possible, customers’ needs
and expectations.
Internal inspection / audits
Planned and documented internal site inspections / audits verify the implementation andeffectiveness of the quality system and provides self-improvement objectives. Audits are
conducted by qualified personnel independent of those having direct responsibility in the area
being audited and examine the processes, procedures, systems and premises. They are
conducted following a written procedure or plan. Results of audits are used to evaluate theimplementation and effectiveness of the quality system. Audit reports are reviewed by sitemanagement.

9.2 NON-CONFORMING PRODUCT CONTROL
Guerbet has established and maintains procedures that prevent the inadvertent use of nonconforming material or product. Identification, documentation, evaluation, segregation (wherepractical), and disposition of non-conforming material or product is controlled. The procedures
define the responsibility for reviewing product found to be non-conforming and ensuring thecorrect disposition authority.

9.3 DATA ANALYSIS
Quality data is collected and analysed to determine the effectiveness of the Quality
Management System and to identify areas for improvement. Key Performance Indicators(KPIs) are collected each month for the sites and reported with to the Technical Operationsgroup.

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99.4 IMPROVEMENT
Guerbet improves the effectiveness of the Quality Management System by reviewing the
Quality Policy, objectives, audit & inspection results, analysis of data/KPIs, and CAPAs.
CAPA:
A planned and documented program for corrective and preventive actions is established toensure that conditions which adversely affect quality are promptly identified. The causes of
discrepancies are determined, and positive steps are taken to prevent recurrence. Changes
in procedures resulting from corrective and preventive actions are implemented anddocumented.
Corrective and preventive actions are reviewed and identified Root Causes are tracked bymanagement as part of the Management Review Process in order to evaluate the Corrective
and preventive actions effectiveness.
Note: Reference Policy for the Corrective Action / Preventive Action (CAPA) Management(Q018958, GBT-DMS-Quality-Quality Systems-10000004)

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10
DOCUMENT HISTORY

Issue date & version

Comment

April 2020 - V 1.0

First version - Global Quality Manual

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