The Emprove® Program: an introduction focussing on the Emprove® Suite and Emprove® Chemicals content

Merck KGaA
Darmstadt, Germany
Anne Knauer and Dr. Torsten Schadendorf
An introduction focusing on the Emprove® Suite and
Emprove® Chemicals content
The Emprove®
Program

2
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.
The Emprove® Program for Chemicals | Nov 10th 2020

0
0
0
0Agenda Emprove® Program in general
1
Emprove® Suite Demo
2
Emprove® Chemicals with focus on
recent content updates such as TUPPs &
nitrosamine declarations3
Q&A
4

... Convenient
Access ...
... for a Broad
Portfolio.
... to reliable
information ...
The Emprove® Program
at a glance…

Chemicals Expanding content
PharmaGradeTM Integration in progress
Filters & Single use Constant portfolio expansion, supporting launches
Chromatography Launched Q2/2020
Cell Culture Media Launched Sept 2020
Emprove® Material Qualification Dossier
Emprove® Quality Management Dossier
Emprove® Operational Excellence Dossier
Emprove® Program
Portfolio, Dossiers, Suite
Emprove® Suite

Days….Weeks
Non-Emprove® Products:
Emprove® Products:
Emprove® Program
Fulfilling the promise on speed to regulatory filing.
Log in to
Local
Website
Search
Catalog
Number
Download
Dossier
Customer Request for
Information
•Animal Origin Statement
•Manufacturing Location
•Shelf Life Statement
•Sterility Validation
First Level Support
•Returns available
information to contact.
•Reaches out to individual
content owners if not
readily available.
Second Level Support
•If content not readily
available, information is
gathered, reviewed, and
approved.
Minutes!

EMPROVE® Suite
Demo
Anne Knauer

Emprove® Suite
Convenience, Ease and Relevance
Emprove® Suite - Facilitate your
effort to collect information:
 Online access to all dossiers of the
entire Emprove® portfolio in its most
current state
 Access 24/7 for subscription period of
1, 2, 5 years
 10 Emprove® Suite users per
company
 Emprove® Chemicals
 Emprove® for Filter and Single-Use
 Emprove® Chromatography
 Emprove® CCM

Emprove® Suite
Registration process
www.emprove.de
Click on „Subscribe“ or „Emprove® Suite Subscription“ Fill out the form to get registered
1
2 3

Emprove®
Program for
Chemicals
Torsten Schadendorf

Chemicals Expanding content
PharmaGradeTM Integration in progress
Filters & Single use Constant portfolio expansion, supporting launches
Chromatography Launched Q2/2020
Cell Culture Media Launched Q3/2020
Emprove® Material Qualification Dossier
Emprove® Quality Management Dossier
Emprove® Operational Excellence Dossier
Portfolio, Dossiers, Suite
Emprove® Program
Emprove® Suite
13 The Emprove® Program for Chemicals | Nov 10th 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
Emprove® Evolve
 Non-GMP, manufactured utilizing
GMP concepts and elements
 Evolving regulatory needs

Emprove® Essential / Emprove® Expert
Emprove® Program for Chemicals
Operational Excellence Dossier
 Product quality report
 Elemental impurity information
 Analytical procedure
 TUPP (if applicable)
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
 Product Quality Self Assessment
 Audit report summary
 Supply chain Information
 Stability data
Answers questions during risk
assessment

 Manufacture
 Materials
 Stability
qualification
 Stability data
assessment

17
EXCiPACT™ / ANSI - confirms GMP confirmation scheme
 The EXCiPACT™ / ANSI
certificate in conjunction with
audit report provide evidence of
cGMP and cGDP compliance of
pharmaceutical excipients.

18
Manufacture Information and Process Flow Chart
 When Merck KGaA is the original manufacture
- dossier indicates our address
 Others: eOMT

The
Emprove®
Program for
Chemicals
| Nov 10th
2020
OM data for all Emprove® Chemicals
Enter SKU (10 digits) without dots (e.g. 1002019025)
19
Former: New:

Certificates
 Aflatoxin
 Allergen
 BSE/TSE
 GMO
 Melamine
 Halal
 Kosher
Further certificates upon request

Certificates
 Aflatoxin
 Allergen
 BSE/TSE
 GMO
 Melamine
 Halal
 Kosher
 Nitrosamine

Requests Marketing Authorization Holders (MAHs) to evaluate the risk of
the presence of nitrosamine impurities in human medicinal drug products
containing chemically synthesized or biological APIs
 Risk assessment for medicinal products, irrespective of marketing
status
 Report is due by October 1st, 2020, March 31st 2021 for medicinal
products containing chemically synthesized APIs
 Report is due by July 1st 2021 for medicinal products containing
biological APIs, even if no risk is identified
Nitrosamines
Authorities call for Preventive Actions

FDA guideline
Nitrosamine Impurities

 Manufacture (eg Nitrosamines)
 Materials
 Stability
qualification
 Site Quality Self Assessment (starting
Q1/2021)
 Stability data
assessment

Quality Self Assessments
PQSA SQSA (starting Q1/2021)
 Section 1: General Site Information
 Section 2: General Site Operating Information
 Section 3: Objectionable Materials on Site
 Section 4: Cross Contamination Control
 Section 5: Site Operating Policies
 Section 6: Quality Assurance and Production
 Section 7: Laboratory Procedures
 Section 8: Packaging, Storage, and Transport
25

26
Supplier Audit Report Summary

27
Supply Chain Information

 3 batches
 ICH conditions
Stability Data

 Manufacture
 Materials
 Stability
qualification
 Stability data
assessment

Product quality report: Demonstrated consistent product quality

Product quality report: Demonstrated consistent product quality
Transparency in case of changes

Elemental Impurity Information
“Elemental impurity
specifications have been set
considering ICH Q3D (Guideline
for Elemental Impurities).
Class 1-3 elements are not
likely to be present above the
ICH Q3D option 1 limit, unless
specified and indicated (*).”
Specification footer: Operational Excellence Dossier:
Info on intentionally
added elements

33
Analytical procedure
 If possible cross-validated inhouse
method covering pharmacopeias

 Manufacture
 Materials
 Stability
qualification
 Quality Self Assessment
 Stability data
assessment
34
free of charge
charged charged

 are typically considered as threat to final product
quality by customers of pharmaceutical industry
 give rise to different measures of crisis-
management on side of customer such as
rejection of batches, stop of production and
blockage of final products
 result in high efforts on customers and
manufacturers side, for example complaints,
(unnecessary) analysis and for-cause-audits
Customer Reaction – Typical Action Cascade
Findings of foreign matter in products…

 can not be reduced to nothing for technical reasons
 are visibly different from material when viewed with naked eye
 have been present for long time in the history of the product
 are not homogeneously distributed over the batch size
 number of these inherent, technically unavoidable particles is
very small
 do not pose higher risk for patient safety for any application
 should not affect efficacy and quality of related drug product
IPEC Federation TUPP Guide
Technically unavoidable particles…

Types of technically unavoidable particles
Type of particles Origin Example
Charred particles, discolored Exposed to heat Discolored particles in Sucrose
Intrinsic components carried through from raw
material (mined mat. or natural products)
Raw material
Discolored particles in sodium
chloride
Process materials of construction Wear of equipment Metal from piping, reactors etc.
Particles from routinely used gaskets, seals,
filters etc.
Wear of gaskets PTFE-particles, fibers from filters
Packaging component particles
Wear of primary or secondary
packaging materials
Cardboard, fibers from paper
shedding, PP-suture material from
big bags

Picture and Identity

Detailed information for each type of TUP
From Reactive to Proactive
 Intention, quality policy towards foreign particles
 Flow chart of manufacturing process (reference to MQD)
 TUP information
 Particle picture
 Identity and composition
 Mass balance
 Root cause
 Assessment of additional microbial and BSE risks

 Manufacture
 Materials
 Stability
qualification
 Stability data
assessment
free of charge
charged charged

Emprove® Essential
 GMP (IPEC)
Emprove® Expert
 GMP (IPEC)
Emprove® API
GMP (ICH Q7)
Existing Emprove®
Chemicals categories
(> 400 products)
Emprove® Program – Chemicals Categories
Emprove® Evolve

44
Emprove® Evolve - Target Applications

45
Emprove® Evolve – Non-GMP Chemicals With Transparency & Control
GMP/Non-GMP are not simple binary states
-
Sliding scale of quality features:
Tailored to application and regulatory needs.
Emprove® Evolve is high on the scale.
+

Emprove® Evolve - Quality Attributes Summary – Main Differentiators
Product
Quality
Attributes
Quality Categories
Technical/Laboratory Grade Emprove® Evolve Emprove® Essential & Expert
Regulatory
 No GMP
 No regulatory needs; customer
expectations for reliable technical
performance
 Non-compendial, not for direct human use
 Non-GMP: Manufactured utilizing GMP
concepts and elements; ISO9001 or equivalent
 Supply chain transparency and control
 No defined industry standards or regulations
 Non-compendial, not for direct human use
 GMP: IPEC plus elements of ICH
 Defined regulations and GMP standards
 Compendial compliance (if applicable)
 Intended as suitable for human use
Example Uses/
Applications
 Laboratory use
 For synthesis in uncontrolled applications
 Process chemicals & clean-in-place
 Upstream, early downstream, early synthetic steps
 Close to final drug product & patient
 Formulation, late downstream &
purification
Product shelf-
life/stability
 Optional, depending on chemical stability
 Shelf-life based on analysis of 3 batches/
historical data/ retests
 Summary statement in Emprove dossier
 Long-term stability studies
 Detailed stability study data in
Emprove® dossiers
Supplier
Qualification
 Low
 No on-site audit
 Paper assessment optional
 No quality or change agreement
 Medium/High
 Paper assessment mandatory
 On-site audit preferred; exceptions possible
 Change agreement
 High
 On-site audit mandatory
 Quality/change agreement
Change control  None/Low  High  High
46
The
Emprove®
Program for
Chemicals
| Nov 10th
2020

Evolve dossiers have the same structure as Essential & Expert
47
Emprove® Evolve - Dossiers
 Manufacture
 Materials
 Stability
qualification
 Quality Self Assessment
 Stability data
assessment
free of charge
charged charged

Emprove® Evolve
SAFC PharmaGrade™
(~120 Products)
Integration started
2018
Emprove® Essential
 GMP (IPEC)
Emprove® Expert
 GMP (IPEC)
Emprove® API
GMP (ICH Q7)
Emprove® Expansion – Chemicals Categories
48

PharmaGrade™ Integration

Will Change
Product number
Product name (to reflect the Emprove® category Expert,
Essential or Evolve)
Increased product dossier content
New tests added to product specification in some cases
Extended impurity profiling
Improved stability and shelf-life data
Layout and wording of certificates and statements as a
result of harmonization
Label format and branding
PharmaGrade™ Integration – Product Changes
50
Not Changing
Manufacturing site
Manufacturing process
Distribution / supply chain / ordering process
Raw materials / sources*
Packaging volumes or material of construction*
Existing specification parameters*
* Change only to be made when necessary to
meet higher Emprove® standards
The
Emprove®
Program for
Chemicals
| Nov 10th
2020

Status PharmaGradeTM Integration (Oct 2020)
Article Product
Target
Emprove Grade
Site
Emprove
Article
Emprove
Integration
status
12063 Benzalkonium Chloride EMPROVE® EXPERT Ph Eur,NF Expert Buchs 137123 completed
76857 Benzalkonium chloride (50% aqueous solution) EMPROVE®
EXPERT Ph Eur,NF Expert Buchs 137124 completed
ARK2176 Galactose, plant-derived EMPROVE®
EXPERT Ph Eur,NF Expert Arklow 137129 completed
15702 Tropolone EMPROVE®
EVOLVE Evolve Buchs 108637 completed
76078 L-Methionine Sulfoximine EMPROVE®
ESSENTIAL Essential Buchs 104309 completed
ARK2183 Acetic acid EMPROVE®
EXPERT JP,Ph Eur,USP Expert Arklow 137130 completed
ARK2163 Benzyl Alcohol EMPROVE®
EXPERT Ph Eur,ChP,JP,NF Expert Arklow 137120 completed
80443 Sodium Pyruvate Essential Buchs 105477 completed
ARK2174 Triethanolamine (Trolamine) Expert Arklow 137148 completed
2712 Cystamine Dihydrochloride Essential Buchs 108318 completed
56454 1-Thioglycerol Essential Buchs 108704 completed
ARK2161 Sodium Butyrate Expert Arklow 137127 completed
ARK2169 Ethanolamine Expert Arklow 137133 completed
93792 Benzenesulfonic Acid Essential Buchs 103893 in progress
53729 Cysteamine Hydrochloride Expert Buchs 137139 completed
91541 Oleic Acid Evolve Buchs 104415 in progress
11317 Methanesulfonic acid Expert Buchs 137152 in progress
7604 2-Mercaptoethanol Evolve Buchs 137151 in progress

Marketing Manager Digital Solutions
anne.knauer@milliporesigma.com
Senior Marketing Manager Emprove® Program
torsten.schadendorf@emdmillipore.com
Anne KnauerDr. Torsten Schadendorf
For more information please visit www.emprove.de
Thank You

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