817058_QMD_1.2

Emprove Quality ®
Management Dossier
Documentation to support risk assessment
817058
Maleic acid EMPROVE® ESSENTIAL Ph Eur,NF
Not appropriate for regulatory submission as active pharmaceutical

ingredient. The use of this dossier shall be subject to the terms of
use that can be found at Emprove.de
The life science business

of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the
U.S. and Canada.
Version: 1.2 Status: Approved
817058 Maleic acid EMPROVE® ESSENTIAL Ph Eur,NF
Table of Contents
version history report.................................................................................................2
Introduction.................................................................................................................3
Chapter 1: Supply Chain Information........................................................................4
Chapter 2: Statement on Good Distribution Practices............................................6
Chapter 3: Product Quality Self-Assessment.........................................................10
Chapter 4: Site Quality Self Assessment................................................................19
Chapter 5: Supplier Audit Report Summary...........................................................34
Chapter 6: Quality Risk Management Process Summary.....................................36
Chapter 7: Change Management Process Summary.............................................38
Annex.........................................................................................................................40
©2014-2020 Merck KGaA, Darmstadt, Germany Status Date: 04/07/2023 Page 1 of 40

and/or its affiliates. All Rights Reserved.
Version History Report

Chapter Name Statement Type New Version Number Old Version Number Replacement Reason
Chapter 1: Supply Chain D_Supply Chain Editorial/Formatting
1.1 1.0
Information Information Change

Introduction
The Emprove® dossiers are designed to enable our customers to respond to the regulatory
recommendations/requirements easily, quickly, and adequately. As a result of the Emprove®
qualification processes, we offer the Emprove® Material Qualification Dossier (in line with CTD format).
This dossier is designed to facilitate qualification of material for application in the pharmaceutical
industry. With the Emprove® Quality Management Dossier, we assist in conducting the required risk
assessments. With the Emprove® Operational Excellence Dossier, we provide supporting information
to optimize processes according to the relevant regulations.
Version history
The dossier version number is indicated in the header of every page. Product quality-relevant content
changes result in a full-version increase, for example version 1.0 to 2.0. Editorial or formatting
changes result in a sub-version increase, for example 1.0 to 1.1.
Additionally, the Version History Report provides an overview of components which have been
updated in this version.
Regulatory Framework
Regulatory agencies expect a risk-based approach to managing a drug’s quality throughout its
lifecycle: from early development through commercial manufacturing. These concepts are clearly
articulated in ICH Q8-Q11, for example ICH Q10 chapter 2.7 addresses the responsibility of the drug
product manufacturer to evaluate and qualify purchased materials.
The US Food and Drug Administration Safety and Innovation Act (FDASIA) introduces similar
requirements, with FDASIA Title VII Section 711 indicating the need for oversight and controls to
ensure quality. This includes managing the risk of, and establishing the safety of, raw materials and
materials used in the manufacturing of drugs. European Commission Guideline 2015/C 95/02
describes the requirements for excipient GMP risk assessment in the EU as mandated by Directive
2001/83/EC.
With our Supply Chain Information and Quality Self Assessments we provide transparency on the
manufacturing steps, facilities and quality systems applied to support our customers risk assessment
needs.
European Commission Guideline 2015/C 95/01 describes the requirements for GDP for active
pharmaceutical ingredients in the EU. The principles of this guideline can also be applied to excipients
for which no specific guidelines exist in the EU.
The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients provides guidance on the
application of GDP to steps in the distribution/supply chain.
The risk-based approach on how storage and distribution conditions are defined for our
pharmaceutical starting and raw materials is described in our Statement on Good Distribution Practice.
With the Quality Risk Management Process Summary, we provide an overview of our approach to
identify and adequately assess potential risks related to manufacture and distribution of our products.
This is in line with ICH Guideline Q9 Quality Risk Management and ISO 31000 Risk Management
Principles & Guidelines.
The Change Management Process Summary describes the process of evaluation, implementation and
notification of changes, considering the impact of the change on the product quality in line with the
overall Risk Management Process. The Change Management process allows changes to be managed
in compliance with competent authority requirements.

Chapter 1: Supply Chain Information


Chapter 2: Statement on Good Distribution Practices




Chapter 3: Product Quality Self-Assessment









Chapter 4: Site Quality Self-Assessment















Chapter 5: Supplier Audit Report Summary


Chapter 6: Quality Risk Management Process Summary

In our Life Science (LS) business, Quality Risk Management is an integral part of our manufacturing
and distribution Quality Management System. All functions, responsible for the manufacture and
handling of our product offerings, are effectively and consistently evaluating and controlling identified
risks, governed by an effective Quality Risk Management process. The LS Quality Risk Management
process is aligned with ICH Guideline Q9 Quality Risk Management and ISO 31000 Risk
Management Principles & Guidelines.
Figure 1: Overview of LS Quality Risk Management process (adopted from ICH Q9):
Quality Risk Management at LS uses process and scientific knowledge for the identification and
evaluation of risk to product quality. The level of effort, formality and documentation of the quality risk
management process is commensurate with the level of risk identified.
A Quality & Regulatory Risk Register is mandatory for all LS manufacturing sites and distribution
centres. This is designed to identify and evaluate, through an annual risk planning cycle based on the
Quality Risk Management process described above, Quality and/or Regulatory risks that have the
potential to impact product quality or the application of our products for our customers.
In addition to the Risk Register, Risk Management, using tools such as FMEA and HACCP, is an
integral part of routine manufacturing and product realization and supply processes and as such is
incorporated into the Change Management, New Product Introduction, Supplier Management, Non-
Conformance / Deviation & CAPA, Out of Specification and Complaint Investigation processes of LS.
For some identified risks, even the best Quality Risk Management practices might not entirely
eliminate all risk. In cases where risks are not fully mitigated, residual risk will be re-assessed and
may be accepted, with appropriate documentation and approval by responsible stakeholders.

Actions to mitigate risks are documented and communicated appropriately, for example through
CAPAs, Change Controls and Objectives for the next planning period. These processes and regular
risk reviews are then used as tools to track and trend the effectiveness of these actions.
While we strive to continuously identify and manage any risks associated with the manufacture,
testing, release, and distribution of our product offerings, it is ultimately our customers’ responsibility
to perform their own risk assessment for their individual use or application. Any additional risk
identified during our customers’ use or application of our products should be assessed by the
customer and notified to us as appropriate.

Chapter 7: Change Management Process Summary

In our Life Science (LS) business, Change Management is an integral part of our manufacturing and
distribution Quality Management System (QMS). Our LS Change Management process allows
changes to be managed in compliance with competent authority requirements. Internal procedures
and applicable industry guidance provided by organizations such as BioPhorum or IPEC federation,
define the responsibilities for the various roles involved in the Change Management Process.
Our LS Risk Management process ensures that all potential risks are identified and adequately
assessed, mitigated, and managed to closure. The LS Risk Management process helps the Change
Team to define activities that reflect the magnitude of change, where the level of effort and formality of
any the proposed Implementation Action Plan is commensurate with the level of identified risk.
The main phases of our Change Management process are outlined in Figure 1.
Our obligations and processes for Customer Notifications, that may arise from any change
implementation, are also integrated into the overall Change Management Process at LS. Customer
Notification is not a requirement for all Change Controls. The LS Change Management process
includes consideration for changes which should be notified to relevant customers, who have opted-in
to our change notification program for their products, depending on the type of change, the product’s
MQ level as defined by the M-Clarity™ program, the intended application of the product or service
and the potential Quality Agreement between LS and the customer. During the ‘Assess Change’
phase of the Change process, it will be determined by the Change Team and relevant customer
facing functions if Customer Notification is required. As well the need for authority notifications is
determined. Changes impacting Emprove® Dossier content are also reflected in the post-change
updated version of the Dossier.

Phase 1: Evaluation
• High level Stakeholder review of
Proposed Change.
• Decision, to progress with change or
not (guided by key stakeholders).
Phase 2: Change Assessment
• Complete detailed Risk Assessment of
the proposed Change (e.g. through a
Process FMEA).
• Identify products, processes, and
customers (internal & external)
impacted by the change.
• Document Quality & Regulatory impact
on product and intended customer
application of the product.
• Develop Implementation action plan
guided by completed risk assessment.
Considerations may include but are
not limited to:
o Product specifications
o Extractables
o Shelf life
o Material evaluation
o Material declarations
• Determination of Customer Notification
Strategy.
Phase 3: Change Approval
• On completion of Risk Assessment
and development of the
Implementation Action plan, the
Change is routed for approval by
relevant Stakeholders, Subject Matter
Experts (SME) and functions.
Phase 4: Implementation
• Execute the Action plan.
• Document results, which may include,
but are not limited to:
o Validation/Qualification as
applicable
▪ IQ / OQ / PQ
▪ Sterilisation
▪ Test Method
Qualification
▪ Software Validation
▪ Cleaning Validation
o Test results
o Trainings
o Procedural updates
• Execute the Customer Notification
Strategy as applicable.
• Inventory Management.
Phase 5: Monitoring
• Incorporate a Post-Implementation
Monitoring plan to monitor consistency
and Quality of the product / process
post change, if applicable.
• Review of completed change details
and change closure.
Figure 1: Overview of LS Change Management Process

Annex
References:
ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL DEVELOPMENT Q8

Current version
ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9

Current version
ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL QUALITY SYSTEM Q10

Current version
ICH HARMONISED TRIPARTITE GUIDELINE DEVELOPMENT AND MANUFACTURE OF DRUG

SUBSTANCES Q11
Current version
Code of Federal Regulations, TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG
ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER C—DRUGS: General Part
211: Current Good Manufacturing Practice for Finished Pharmaceuticals
Food and Drug Administration Safety and Innovation Act FDASIA Title VII Drug Supply Chain
Provisions
EudraLex
The Rules Governing Medicinal Products in the European Union Volume 4
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use,
Chapter 1 Pharmaceutical Quality System, Chapter 5 Production
EU Guidelines of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate
good manufacturing practice for excipients of medicinal products for human use (2015/C 95/02)
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL

of 6 November 2001 on the Community code relating to medicinal products for human use
EU Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for
medicinal products for human use (2015/C 95/01)
IPEC Federation: The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients
Current version
International Organization for Standardization: ISO 31000 Risk Management - Guidelines

Current version
IPEC Federation: The IPEC Significant Change Guide

Current version
Raw Materials: Supplier change notifications: change areas and requirements

BioPhorum Operations Group Ltd and Bio-Process Systems Alliance

For additional information,

please visit
Emprove.de
We provide information and advice to our customers on application technologies and regulatory matters to
the best of our knowledge and ability, but without obligation or liability. Existing laws and regulations are to
be observed in all cases by our customers. This also applies in respect to any rights of third parties. Our
information and advice do not relieve our customers of their own responsibility for checking the suitability of
our products for the envisaged purpose.
© 2020 Merck KGaA, Darmstadt, Germany and/or its aﬃliates. All Rights Reserved. MilliporeSigma, the vibrant M, SAFC
and Emprove are trademarks of Merck KGaA, Darmstadt, Germany or its aﬃliates. All other trademarks are the property
of their respective owners. Detailed information on trademarks is available via publicly accessible resources.
©2014-2020 Merck KGaA, Darmstadt, Germany Status Date: 04/07/2023


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Emprove Quality ®

Not appropriate for regulatory submission as active pharmaceutical

The life science business

817058 Maleic acid EMPROVE® ESSENTIAL Ph Eur,NF

version history report.................................................................................................2

Chapter 1: Supply Chain Information........................................................................4

Chapter 2: Statement on Good Distribution Practices............................................6

Chapter 3: Product Quality Self-Assessment.........................................................10

Chapter 4: Site Quality Self Assessment................................................................19

Chapter 5: Supplier Audit Report Summary...........................................................34

Chapter 6: Quality Risk Management Process Summary.....................................36

Chapter 7: Change Management Process Summary.............................................38

©2014-2020 Merck KGaA, Darmstadt, Germany Status Date: 04/07/2023 Page 1 of 40

817058 Maleic acid EMPROVE® ESSENTIAL Ph Eur,NF

Version History Report

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Chapter 1: Supply Chain Information

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Chapter 2: Statement on Good Distribution Practices

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Chapter 3: Product Quality Self-Assessment

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Chapter 4: Site Quality Self-Assessment

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