This webinar will discuss appropriate quality attributes for different raw material uses, present strategies to support identification, selection and risk assessment of raw materials, and highlight the importance of regulatory documentation. Recent and continuing regulatory improvements require drug manufacturers to assess and mitigate risk throughout their entire processes. This includes raw materials used at every stage of manufacturing and clinical phases. Current regulatory guidelines and industry standards clearly define quality requirements for raw materials that are incorporated into, or used close to, final drug product, for example active ingredients and excipients. However, no such clear standards are defined for chemicals used earlier in the process, such as in upstream bioprocessing, early chemical synthesis stages, or clean-in-place. The absence of such standards presents a challenge to efficiently and effectively source raw materials with appropriate supply chain transparency and control, accompanied by the necessary supporting documentation. In this webinar, you will learn: • Strategies to support identification, selection, and risk assessment of raw materials throughout the manufacturing process • Appropriate quality attributes for different raw material uses • The importance of quality and regulatory documentation provided by the supplier

1. Merck KGaA
Darmstadt, Germany
January 18, 2018
Douglas Bowman
Identifying Appropriate-Quality
Pharmaceutical Raw Materials in an
Evolving Regulatory Environment

2. 2 Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 2018
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.

3. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 20183
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

4. Raw Materials Challenges
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 20184
 Raw materials inherently introduce risk
 Bioprocesses sensitive to variability and present different risks
 Traceability and control of raw materials through entire supply chain

5. Raw Materials Challenges
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How do we identify
”““appropriate quality”?
Regulations require drug manufacturers
to assess and mitigate risk throughout
their entire processes, including raw
materials
No clear, prescriptive quality definitions
exist for “non-regulated” raw materials

6. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 20186
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

7. Constantly Evolving Regulations and Guidance
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aceuticalExcipients
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8. ICH Q11:
•Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities)
•Clarifies and explains ICH Q8, Q9, Q10 & CTD
•Describes the need for comprehensive risk assessment of the entire drug product
manufacturing process, defining critical control parameters, quality by design
•Specifically states the need to include raw and starting materials in this assessment,
highlighting biological processes, but does not set specific quality standards for raw
materials
Guidelines For Raw Materials - Example
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9. EUDRALEX Vol 4, Part 1, Chapter 5:
•Revision to the EU Rules Governing GMP for Medicinal Products – Production
•Two major changes: one was the addition of qualification of suppliers of starting materials
•Introduces strict requirements for the selection, qualification, approval and maintenance
of suppliers of starting materials
Guidelines For Raw Materials - Example
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10. EMA/CHMP/BWP/187338/2014:
•Guideline on process validation for the manufacture of biotechnology-derived active
substances, and data to be provided in the regulatory submission
•Risk assessment, supported by documentation, to control raw material impact on quality
of drug substance
•This should be evaluated already at the stage of manufacturing process development and
validation
Guidelines For Raw Materials - Example
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11. EU 2015/C95/02:
•Guideline on the formalized risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use
•The manufacturing authorization holder to define appropriate GMP for their specific use
and then ensure the excipients are suitable for use.
•Risk assessment/management documentation should be available on site for review by GMP
inspectors.
•Relevant information from the risk assessment should be shared with the excipient
manufacturer to facilitate continuous improvement.
 This risk assessment guideline for excipients could play a useful role in the
selection of other raw materials
Guidelines For Raw Materials - Example
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12. Risk Assessment for Excipients: (Useful for other raw materials?)
Guidelines For Raw Materials - Example
12 Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 2018
Drug Product ManufacturerDrug Product Manufacturer
Determine and assess the risks for each materialDetermine and assess the risks for each material
Consider the Application
of the Material
Consider the Application
of the Material
• Dosage form & Route of administration
• Functionality
• Potential impact on critical quality
attributes
• Quantity, daily intake
• Dosage form & Route of administration
• Functionality
• Potential impact on critical quality
attributes
• Quantity, daily intake
Consider Risks from
Manufacture / Supply
Consider Risks from
Manufacture / Supply
• Quality Management System
• Contamination potential
• Impurities
• TSE, viral safety
• Microbiological / endotoxin
• Equipment / facilities
• Supply chain complexity
• Quality Management System
• Contamination potential
• Impurities
• TSE, viral safety
• Microbiological / endotoxin
• Equipment / facilities
• Supply chain complexity

13. Regulatory Considerations - Summary
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201813
Risk Assessment and Quality By Design are important focus topics for
regulatory agencies, includes raw materials
Control of manufacturing process parameters and raw material quality is
necessary to mitigate risks
Demands a deep understanding by the drug manufacturer of raw material
attributes and supply chains.
Bioprocess technologies further drive the need for higher supply chain
transparency and standardization.
General guidance is given for “non-regulated” or “evolving regulation” raw
materials, but no detailed quality attributes are described.
1
2
3
4
5

14. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201814
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

15. Drug Manufacturing Process Steps
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201815
LARGE
MOLECULE
SMALL
MOLECULE
“Evolving Regulation”
Raw Materials:
Upstream & Process
“Regulated” Starting
Materials:
Downstream &
Formulation

16. Complex Manufacturing Systems Need Detailed Risk Assessment
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201816
Impurities From
Input Materials
Drug Product and
Manufacturing
Process Dependent

17. Transparency of supply chain and quality system
• Visibility of supply chain to original manufacturer
• Quality system information for qualification
• Complete documentation package, ideally readily available
Consistency of product
• Robust, controlled manufacturing processes and analytical
methods
• Change management, change notifications
• Fit-for-purpose testing and release specifications
• Shelf-life information
Not over-engineered
• Reduce complexity
“Evolving Regulation” Raw Material Needs
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Reminder: Usefulness of risk assessment for
excipients principles

18. Proposed Quality Attributes: Summary Table I
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19. Proposed Quality Attributes: Summary Table II
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20. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201820
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

21. Sourcing GMP and compendial chemicals should ensure high levels of product quality and control, but they
are not always the perfect fit for processing use:
•Using APIs and Excipients as process chemicals might add unnecessary complexity and cost.
•Compendial specifications are not designed for processing applications; many suppliers are not equipped
to develop new analytical methods to support these needs
•Compendial and GMP compliance claims are not always clear
•Focusing only on GMP suppliers and products limits choice
 Work with specialized life science suppliers who understand different technologies and applications and
offer a range of relevant quality standards.
GMP/Compendial Grades
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22. Suppliers From Emerging Markets
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Approaches to suppliers from emerging markets can be extreme; finding the correct balance is critical:
•A strategy for these regions is important since they represent a high percentage of global capacity of
many essential product groups.
•Supply chains are often difficult to penetrate, so regional QA and Procurement presence is a strong
advantage.
•Further processing and purification of raw materials can mitigate risk.
•Working with a large specialized supplier who has this regional presence and capability can be an effective
approach.
 Handled correctly, suppliers and raw materials from emerging markets are an important component of
the supply chain.

23. Drug manufacturers are encouraged to procure starting materials from the original manufacturer wherever
possible (e.g., EU GMP Guide, Part 1, Chapter 5.)
However, it is not always practical or even possible to buy from the original manufacturer:
•In particular, large industrial manufacturers will often not entertain the quality needs of pharma
customers.
•Their distributors are not always set up to properly handle requests and provide documentation.
•Site audits, quality agreements and change notifications are difficult to establish.
 Regulations do not insist on procurement from original manufacturers, as long as full traceability is
available.
 Specialized suppliers actively qualify and audit original manufacturers, and additionally offer
reprocessing, repackaging, QC and documentation.
Original Manufacturer Requirement
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24. Collecting documents and information from suppliers is one of the biggest causes of delay in raw material
qualification.
•Target suppliers within the life science industry.
•Make clear at the start what documentation you will need for qualification and ongoing material
management, get the supplier's commitment.
•One-off questionnaires are relatively easy to complete; make sure there is a sufficient quality system in
place to support the documents and manage change.
•Start discussions on quality agreements as early as possible in the qualification process
 Facilitate the qualification process and save time by working with a supplier who already has detailed
documentation packages prepared and readily available
Documentation
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25. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201825
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

26. Emprove®
Evolve
Non-GMP, but with GMP concepts and
elements
Evolving regulatory needs
NEW Emprove®
Chemicals category to
be added in 2018
SAFC PharmaGrade™
(~120 products)
Integration 2018-2020
Emprove®
Essential
GMP (IPEC)
Moderate risk applications
Emprove®
Expert
GMP (IPEC)
Higher risk applications
Emprove®
API
GMP (ICH Q7)
Existing Emprove®
Chemicals categories
(~400 products)
Emprove®
Program – Chemicals Categories
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201826

27. Emprove®
Chemicals Dossier Library
Emprove®
Documentation
Operational Excellence Dossier
Product quality report
Elemental impurity information
Analytical procedure
Supports process optimization
Material Qualification Dossier
In line with CTD chapter 3 quality
(adapted for excipients)
General information
Manufacture
Characterization
Control of drug substance
Reference standard
Materials
Container closure system
Stability
Information to start a material
qualification
Quality Management Dossier
Quality Self Assessment
Audit report summary
Supply chain Information
Stability data
Answers questions during risk
assessment
free of charge
charged charged
Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201827
Emprove®
Suite: Full online access to all dossiers

28. PharmaGrade™ Product Regulatory Datasheet
− Product Name, Part Number, CAS No., MW
− Specifications
− Product Origin
− Site of Manufacturing
− Process Information
− Risk Statements
− Shelf-life/Stability Statement
Site Quality Overview
Site and Supply Chain Security Overview
Certificates (ISO, GMP, etc.)
PharmaGrade™ Documentation
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Direct web access to documentation for in-house manufactured products
Controlled access to third-party manufactured products (under CDA)

29. Webinar: Raw Materials in Evolving Regulatory Environment | D Bowman | January 18 201829
Agenda
Regulatory considerations for raw materials
Raw material quality attributes for different applications
Strategies/tips for selection of suppliers and raw materials
Emprove®
Program
Summary
Introduction

30. • Regulations require drug manufacturers to perform significant risk assessment and mitigation strategies
for raw materials.
• Supply chains and manufacturing technologies are increasingly complex.
• Evolving regulations and technologies are driving the need for greater transparency and
standardization.
• No clear quality standard exists for many raw materials.
• Up-to-date, accurate information in a convenient format is crucial.
 Working with an expert partner can help you speed your way through the regulatory maze.
Summary
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31. Thank You
Questions?

32. Douglas Bowman
douglas.bowman@sial.com
Contact