From Industrie 4.0
to Pharma 4.0 Operating model and
The Holistic ICH Control Strategy
Christian Wölbeling
ISPE SIG “Pharma 4.0” Founder & Chair
for the ISPE Special Interest Group/SIG “Pharma 4.0”
c/o Werum IT Solutions GmbH
Christian WoelbelingSenior Director Global Accounts
Werum IT Solutions GmbH
+49 4131 89 00 490
My Background…
Market Leader
in MES for Pharma & Biotech
❑ SIG Pharma 4.0 Founder & Chair
❑ GAMP Europe Steering Member at Large
❑ GAMP MES SIG Co-Chair
❑ KNC Council Chair
❑ Global Steering Team Member CoP „PAT & LCS“
❑ Affiliate Germany-Austria-Swiss / DACH Board Member
…25 Years Pharma Industry Experience
Connecting Pharmaceutical Knowledge ispe.org 2
1. Problem Statement
❑ 6 Sigma Quality in Pharma
2. The Pharma 4.0 Operating Model
❑ Elements
❑ Enablers
3. The Holistic Control Strategy
❑ Digitalization of the Pharmaceutical Quality System (PQS) / ICH Q10 - Based on ICH Q8 – 12
4. Benefit of the Holistic Control Strategy
❑ Shorter Time to Market – Reduced Inventory
5. Summary & Conclusions
From Industrie 4.0 to Pharma 4.0 Operating Model and
The Holistic ICH Control Strategy
Connecting Pharmaceutical Knowledge ispe.org 3
PROBLEM STATEMENT
QUALITY ISSUE?!?
What is the Fundamental Problem? – Quality & Performance!
Source: Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation andResearch
Future of Pharmaceutical Quality and the Path to Get There, 3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24,2017
Drug Shortages FDAApp:
Connecting Pharmaceutical Knowledge ispe.org 6
The FDA Loops Back to 2004...Did we Advance?Hurray...PAT & Quality by Design Revival!
The 2nd Wave of Quality byDesign!
Connecting Pharmaceutical Knowledge ispe.org 7
Vision
Vision & Mission StatementISPE SIG “PHARMA 4.0” Strategy
Source: FDA Presentationat ISPE Conference,Washington,June 2015
Mission
“Manufacture pharmaceutical products with
maximum product & process understanding,
data integrity by design, efficiency and optimal
resource allocation on the basis of full
digital data transparency - to the benefit of
the patient.”
ISPE, Special Interest Group “Pharma 4.0”
Connecting Pharmaceutical Knowledge ispe.org 8
THE PHARMA 4.0 OPERATING MODEL
FROM INDUSTRY 4.0 TO PHARMA4.0
Where we are coming from...Industrie 4.0 & ICH Q8 – 12
Q8 Pharmaceutical Development
Q11 Development and Manufacture of
Drug Substances
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
Q12 Product Life Cycle Management / PLCM
+ =
https://www.acatech.de/Publikation/recommendations-for-implementing-the-strategic-initiative-industrie-4-0-final-report-of-the-industrie-4-0-working-group/
Connecting Pharmaceutical Knowledge ispe.org 10
Future ICH Qx Guidelines
From Industrie 4.0 to PHARMA 4.0 Operating ModelDefinition
The PHARMA 4.0 Operating Model
enables and controls the Holistic Control
Strategy Lifecycle Management with
Data Integrity by Design based on the
organizations Digital Maturity within the
Industrie 4.0 architectural framework.
Source: ISPE SIG “PHARMA 4.0”
Connecting Pharmaceutical Knowledge ispe.org 11
PHARMA 4.0 OPERATING MODEL ENABLER
DIGITAL MATURITY
MATURITY MODEL
The Overall Corporate & Value Network Structure
https://www.acatech.de/Publikation/recommendations-for-implementing-the-strategic-initiative-
industrie-4-0-final-report-of-the-industrie-4-0-working-group/
Connecting Pharmaceutical Knowledge ispe.org 13
PHARMA 4.0 – Operating Model
Strategy and Managementof
Producing Companies.
A VDI book.ISBN 978-3-642-14501-8
https://www.acatech.de/wp-content/uploads/2018/03/acatech_STUDIE_Maturity_Index_eng_WEB.pdf
Key Enabler – Digital Maturity
VALUE NETWORK MODELSTRUCTURALAREAS
Six Maturity Levels
Computerization
Connectivity
Visibility
Transparency
Predictability
Adaptability
Connecting Pharmaceutical Knowledge ispe.org 14
Matching the Industry 4.0 Model with the FDA Digital Maturity Model
Source: Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research
Future of Pharmaceutical Quality and the Path to Get There, 3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24, 2017
Adaptability
Predictability
Transparency
Visibility
Connectivity
Computerization
Connecting Pharmaceutical Knowledge ispe.org 15
PHARMA 4.0 OPERATING MODEL ELEMENT
RESOURCES
DIGITALIZATION WORKFORCE 4.0 ROBOTSAVAILABLE AND QUALIFIED
Connecting Pharmaceutical Knowledge ispe.org
Resources are tangible, physical assets.
These include a company’s
❑ workforce (human resources with new skill sets)
❑ machinery / equipment
❑ infrastructure
❑ tools
❑ materials and
❑ the final product.
PHARMA 4.0 – Operating ModelResources
17
❑ Human / Machine Interface
❑ Digital learning
❑ Speech recognition
❑ Augmented & virtual reality
❑ Chat robots
❑ Artificial Intelligence
Source: Acatech Study
PHARMA 4.0 OPERATING MODEL ELEMENT
INFORMATION SYSTEMS
HOLISTIC VALUE NETWORK INTEGRATION AND TRACEABILITY
Information systems are socio-technical systems in which information is provided based on
❑ economic criteria by both people and
❑ information and communication technology.
They
❑ Prepare,
❑ Process
❑ Store and
❑ transfer data and information.
PHARMA 4.0 – Operating ModelInformation Systems
Source: Acatech Study
PHARMA 4.0
ERPSystems
MESSystems
Systems
Logistics Systems
Digital Product Lifecycle System
Historian
Building Management
Equipment
Data
SCADA
PLCSensors
Maintenance Management
Paper
LIMCSommercialMHPaLnCufacturing
PharmaceuticalDDMSevelopment Technology Transfer IFnilevsestigational Products
Connecting Pharmaceutical Knowledge ispe.org 19
PHARMA 4.0 – Operating ModelInformation Systems – Analytics & Predictive Control
Big Data: 3 Dimensional Holistic Integration
Integrated Enterprise Production Data
Across Sites and CMOs
APR / PQR – “...at your fingertips”
Analyze & Correlate Data
For Predictive Control
All Systems like ERP, LIMS, MES, CAPA, SCADA etc.
Production Data Lifecycle Management
Analyze Big Data across the Product Life Cycle
PHARMA
4.0
Connecting Pharmaceutical Knowledge ispe.org 20
PHARMA 4.0 OPERATING MODEL ELEMENT
CULTURE
COMMUNICATIONDECISION MAKING
Connecting Pharmaceutical Knowledge ispe.org
PHARMA 4.0 – Operating ModelCulture – “Quality is not an Organization”
22
❑ Digital mindset
❑ Pharma 4.0 is more than technical
❑ Different leadership skills (software factors, listening)
❑ Risk Management culture
❑ Accept decisions
❑ “Culture eats Strategy for Breakfast”
Culture covers the value system within
the company and thus describes the soft
factors of collaboration. Nevertheless,
both (Organization & Culture) structural
areas are mutually dependent and must
be coherent with each other.
Source: Acatech Study
PHARMA 4.0 OPERATING MODEL ELEMENT
ORGANIZATION & PROCESSES
ICH HOLISTIC CONTROL STRATEGYLIFECYCLE MANAGEMENT
Connecting Pharmaceutical Knowledge ispe.org
Organizational structure refers to both a
❑ company’s internal organization (structure and operational processes) and
❑ its position within the value network.
In contrast to area of “culture”, the “organizational structure” establishes mandatory rules that organize collaboration both within the company and externally.
Source: Acatech Study
24
PHARMA 4.0 Operating ModelOrganization & Processes
❑ Flexible Communities
❑ What training is needed for the digital
culture (new formats of training)
❑ harmonization of technical processes
❑ switch from hierarchical to process thinking
❑ data stored in silos – to be changed to one
data source – “one source of the truth”
❑ introduction of lifecycle approach
PHARMA 4.0 OPERATING MODEL ENABLER
DATA INTEGRITY BY DESIGN
RISK BASEDAPPROACHCRITICAL THINKING
Connecting Pharmaceutical Knowledge ispe.org 26
PHARMA 4.0 Operating Model
❑ Data Flow Diagrams❑ Data that is necessary for correct decisions
❑ e.g. Global Audit Trail Standards
❑ Along the Data Lifecycle❑ According to regulatory retention time
Key Enabler – Data Integrity by Design
Prerequisite:
Business Process Descriptions and
HarmonizationDo you know your Business Processes?
❑ Based on ISPE GAMP:
“Records and Data Integrity GUIDE”, March 2017
❑ Process Flowcharts
Source: ISPE GAMP: “Records and Data Integrity GUIDE”, March 2017
PHARMA 4.0 OPERATING MODEL
HOLISTIC CONTROL STRATEGY
DIGITALIZATION OF THEPHARMACEUTICAL QUALITY SYSTEM (PQS)/ ICH Q10
BASED ON ICH Q8 - 12
FDA & ICHRoadmap & History of the Term Control Strategy
Risk & Science based Approach
of the FDA & EMA:
▪ ICH Q 8 (R2) Pharmaceutical Development (2005/2009)
▪ ICH Q 9 Quality Risk Management (2005)
▪ ICH Q 10 Pharmaceutical Quality System (2008)
▪ ICH Q 11 Development and Manufacture of Drug
Substances (2012)
▪ ICH Q 12 Technical and Regulatory Considerations for
Pharmaceutical Product Lifecycle Management
(Draft November 2017)
▪ ICH Q13 Continuous Manufacturing (Concept)
▪ ICH Q14 AQbD, Analytical Quality by Design(Concept)
Source: Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research
Future of Pharmaceutical Quality and the Path to Get There, 3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24, 2017
Connecting Pharmaceutical Knowledge ispe.org 28
Control Strategy, ICH Q10Quality Target Product Profile (QTPP)
Quality Manufacturing Focus – “QTPP - Required for all products...”
A planned set of controls, derived from current product and
process understanding, that assures process performance and
product quality. The controls can include parameters and
attributes related to drug substance and drug product
materials and components, facility and equipment operating
conditions, in-process controls, finished product
specifications, and the associated methods and frequency of
monitoring and control.
The control strategy plays
a key role in ensuring that
the CQAs are met, and hence
that the QTPP is realized.
PHARMA 4.0
Source: Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research
Future of Pharmaceutical Quality and the Path to Get There, 3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24, 2017
Connecting Pharmaceutical Knowledge ispe.org 29
Material and Product Control
Process Control
Commercial Process
Facility, Equipment, IT, Automation,
GMP
The Changing Focus of the Control Strategy
End to End Integrated Holistic Control Strategy Lifecycle Management
Control Strategy:
New Drug Application / Submission
Manufacturing Control Strategy:
Execution Engine
Connecting Pharmaceutical Knowledge ispe.org 30
Connecting Pharmaceutical Knowledge ispe.org
Control Strategy
❑ Product-related
❑ Based on ICH Q8/Q10
❑ Established during development, part of the NDA
Manufacturing Control Strategy
❑ Process-related
❑ Defines Master Batch Record
❑ Enables ongoing or Continued Process Verification/CPV
Holistic Control Strategy
❑ Systematic and controlled concept for developing and managing information throughout the lifecycle
❑ End-to-End view (Holistic Product Lifecycle ManagementApproach)
Control
Strategy
Manufacturing
Control Strategy
Holistic Control
Strategy
Definitions
Pharmaceutical Quality System – ICH Q10
Product
Discontinuation
Commercial
Manufacturing
GMP
Technology
Transfer
Pharmaceutical
Development
Investigational Products
Management Responsibilities
Process Performance & Product Quality Monitoring System
Corrective Action/ Preventative Action (CAPA)System
Change Management
Management Review
Knowledge Management (KM)
Quality Risk Management (QRM)Enablers
PQS
Elements
Connecting Pharmaceutical Knowledge ispe.org 32
ICH Q10 PQS needs additional elements and enablers with Pharma 4.0 Digitalization of the ICH Q10 PQS
PHARMA 4.0:
Digital Maturity & Data Integrity by Design
ICH Q10: Knowledge Management & Quality Risk Management
ICH Q10: Process Performance & Product Quality Monitoring SystemPQS
Elements
Corrective Action
Preventative Action (CAPA) System
Change Management
Management Review
Enablers
ICH Q10: Management Responsibilities
Holistic Product Control Strategy Lifecycle Management / PLCM
PHARMA 4.0:Resources: Digitalization, Workforce 4.0, Available & Qualified
Information Systems: Holistic Value Network Integration & Traceability
Organization & Processes: Holistic Control Strategy Lifecycle Management
Culture: Communication & Decision Making
New
Enablers
New PQS
Elements
Commercial Manufacturing Product DiscontinuationPharmaceutical Development Technology Transfer
Investigational Products
Control Strategy Manufacturing Control StrategyMethodology
Connecting Pharmaceutical Knowledge ispe.org 33
Pharma 4.0 Digitalization Strategy:
Best Practice Holistic Control Strategy Implementation Methodology
Knowledge Led Best Practice Methodology
Pharma 4.0
Control Strategy:
New Drug Application
Manufacturing Control Strategy:
Execution Engine
Business Process Harmonization
Process Maps
Process Data Maps & Data Flow
Vertical & Horizontal Data Integration
Risk Based Approach / CriticalThinking
Transfer to CMOs
ICH Q10 based Process Performance & Product Quality Monitoring System
Applying Data Integrity by Design
Commercial ManufacturingPharmaceutical Development Technology Transfer Investigational Products
Connecting Pharmaceutical Knowledge ispe.org 34
BENEFIT OF THE HOLISTIC CONTROL STRATEGY
SHORTER TIME TO MARKET
REDUCED INVENTORY
Risk Level & Conventional Control Strategy Approachincl. Process Validation ViewLevel of risk
Product Life
Cycle
GMP
Control
Strategy
Facility
Control
Strategy
Initial
Control
Strategy
Production
Control
Strategy
Acceptable
level of risk
Commercial
Manufacturing
Process Design
Development
FDA
EMA
Process Qualification
Qualification & Process Validation
Continued Process Verification
Ongoing Process Verification
Pharmaceutical product & process development
Process engineering, automation, tech transfer, Validation, ramp-up,qualification,
training
Commercial manufacturing, continual improvement, business optimisation,
lifecycle managementIndustry
Source: Line Lundsberg-Nielsen, NNE, February 2018
Connecting Pharmaceutical Knowledge ispe.org 36
Risk Level & Holistic Control Strategy ApproachHolistic Control Strategy Lifecycle Management / Enterprise Recipe Management
GMP
Control
Strategy
Facility
Control
Strategy
Initial
Control
StrategyProduction
Control
Strategy
Acceptable
level of risk
Manufacturing
Process Design
Development
FDA
EMA
Continued Process Verification
Ongoing Process Verification
Pharmaceutical product &
process development
Process Qualification
Qualification & Process Validation
Process engineering, automation, tech transfer,
Validation, ramp-up, qualification, training
Commercial manufacturing, continual improvement, business optimisation, lifecycle management
Industry
Commercial ManufCaocmtmuerirnciagl
Source: Line Lundsberg-Nielsen, NNE, February 2018
Shorter Time to Market
Reduced Inventory
Level of risk
Product Life
Cycle
Enabled by
Digitalization
Connecting Pharmaceutical Knowledge ispe.org 37
HOLISTIC CONTROL STRATEGY IN CELL & GENE THERAPY
BENEFIT OF MANAGINGCOMPLEXITY & FLEXIBILITY
Pharma 4.0 Early Adopters From Start Up...Use Case Patient to Patient...Digitalized
Source: Bradley Glover, 12/4/2017, ISPE Biotech Conference, San Francisco, CA
Connecting Pharmaceutical Knowledge ispe.org 39
New Digitalized Complex Supply Chains: Example Manufacturing Process: CAR-T
Connecting Pharmaceutical Knowledge ispe.org 40
SUMMARY & CONCLUSIONS
Interdisciplinary Collaboration is Key! Silo Breaking...
Product
Development
Design
Commercial
Manufacturing
Execution
Engineering
Automation & IT
Realization
Holistic
Control
Strategy
Tech
Transfer
Innovation Maintenance
Management Responsibilities: Accurate Decision Making
Quality Culture Excellence
Connecting Pharmaceutical Knowledge ispe.org 42
Impact
& Maturity Model
Plug
& Produce
Management Communication
Strategy
Process Maps
& Critical Thinking
Holistic
Control
Strategy
Validation 4.0
Bridging the ISPE Pharma 4.0 Operating Model with the SIG Working Groups
Connecting Pharmaceutical Knowledge ispe.org 43
Read more about the ISPE “PHARMA 4.0 Operating Model”3 Pharma 4.0 Articles in the PE May / June 2019 Issue
Connecting Pharmaceutical Knowledge ispe.org 44
❑ Holistic Control Strategy Approach
❑ Digitalization of the ICH Q10 PQS
❑ Pharma 4.0 is not an IT Project
❑ Pharma 6Sigma Quality Approach
❑ Regulatory Expectations Management
❑ Apply Emerging Technologies e.g. CPV
❑ Digitalization enables Decision Automation
❑ Turn Data into Knowldege & Wisdom
❑ AI driven / supported GMP decisions
Summary & Conclusion
Connecting Pharmaceutical Knowledge ispe.org 45
Christian Woelbeling
Werum IT Solutions GmbH
+49 4131 89 00 490
Thank you for your attention!
Special AcknowledgementsISPE SIG “Pharma 4.0” Members:
Connecting Pharmaceutical Knowledge ispe.org 46
Lorenz Binggeli
Lothar Hartmann
Hans Heesakkers
Uli Kuchenbrod
Line Lundsberg-Nielsen
Volker Roeder
Thomas Zimmer
ISPE: Let’s shape the future of life sciences together !
