Chairs:
Suzanne Farid (UCL)
Andrew Davidson (UCL)
VISION Briefing, London, UK, 4 November 2014
www.ucl.ac.uk/biochemeng/industry/vision
Sponsored by EPSRC CIM hosted by UCL
www.ucl.ac.uk/epsrccim
www.ucl.ac.uk/epsrccim
Academic Centre Team
Academic Network Partners
User Network
“Connectivity is our strength”
Contact mbi-training@ucl.ac.uk to register
BRIEFINGS:
20 November 2014 Bioseparation: The right way to do the wrong thing with protein chromatography
Chair: Professor Ajoy Velayudhan, UCL. Speakers: Dr James Van Alstine, Royal Institute of Technology, Stockholm
20 January 2015 Next Generation QbD
Chair: Dr Dan Bracewell, UCL. Speakers: Keith Chidwick, MHRA and Arne Staby, Novo Nordisk A/S
19 February 2015 Personalised Medicine only for the lucky and the privileged few? Likelihood of change?
Chair: Professor Steve Arlington, PricewaterhouseCoopers LLP
March 2015 Continuous Bioprocessing: Separating the Wheat from the Chaff
Chair: Professor Ajoy Velayudhan, UCL
TECHNOLOGY SHOWCASES:
26 November 2014 The use of Membrane Adsorbers in the Purification of Biopharmaceuticals. Updates and Trends
Sponsored by: Sartorius
CORE COURSE:
20-22 May 2015 Executive Course for Leaders in the Bioprocess Industries (£1,995, discounts for SMEs)
www.ucl.ac.uk/biochemeng/industry/vision
Biopharma/ATMP Supply Chains - Debate
 Will the current supply chain infrastructure serve our future needs?
 Is being good, good enough? Are we at a tipping point?
 Will new supply chain tools be game-changing?
 What are the knock-on effects for process development?
 Can biomanufacturing supply chains be as automated as Amazon?
EPSRC CIM - UCL VISION Event 2 Dec 2013
Biopharma/ATMP Supply Chains – Themes
Patient-specific supply chains
Customer-supplier relations
Visibility and integration across
supply chain
Speakers
Panellists
James Christie
Oxford Biomedica
Kevin Smith
Trakcel
Linda Randall
Actavis Biologics
Scott Lawson
PwC
Proposed Session Format
Chairs:Patient-centric gene therapy
Suzanne Farid–(UCL)
the supply chain
Andrew Davidson (UCL)
James Christie,
VISION Briefing, London, UK, 4 November 2014
www.ucl.ac.uk/biochemeng/industry/vision
Oxford Biomedica
Sponsored by EPSRC CIM hosted by UCL
www.ucl.ac.uk/epsrccim
A PATIENT SPECIFIC SUPPLY CHAIN
AND ITS CHALLENGES
J Christie
Connecting the Value Chain
BUSINESS DRIVERS
BUSINESS STRATEGIES
DESIGN PROCESS
The MARKET
RESEARCH
CONCEPT
EMBODIMENT
DETAIL
DEVELOPMENT
VALIDATION
ENABLERS
Design Management
Design Technologies
Design Tools
CIM
ORGANISATION
BUSINESS STRUCTURE
LOGISTICS
Marketing Product Design Quality FinanceManufacturingSupply
Strategy Strategy Strategy Strategy Strategy Strategy Strategy
MANUFACTURING PROCESSES
Competition
Legislation
Technology
Socio-demographics
Trends
Environment
JIT
MRP
CUSTOMER
Some food for thought

Supply chain comments
 The
worlds most successful businesses are part of an
integrated supply chain.
 A well designed supply chain is a source of innovation,
organisational learning and continuous blend of
improvement.
 Today’s supply chains in the Medicines Manufacturing
sector need to be re-engineered
Why supply chains do not perform
effectively






For robust patient supportive and cost effective supply chains
to be achieved all the parameters that define that supply
chain must be decided prior to the regulatory filing.
Adverse supplier selection
Outsourcing of the drug product manufacture
Fragmentation
End user/Patient need, not fully understood
Lock in
Drawing science and technology into
the supply chain world
End user
Problems
hard to see
BUT easy to
prevent
production
Mfg/validation
Development
Research
Problems
easy to see
BUT costly to
fix
Case study ONE (1)

A bad case of precipitation
 Standard
media used by industry all over the world in
traditional cell growth businesses
 In gene therapy application when used in process the
media did not perform as typical
 Investigation
 no route cause detected
 Repeat issue
 Back round the loop
Case study one (1)

Learning
 Supply
chain relationships need to be collaborative
 Risk share in the future
 Organisationally systems need to be in place that
integrate aspects of supply chain (ERP)
 TRUST in relationship
 Innovation may be shared as opposed to wholly owned
Case study two (2)

“To be disposable or NOT to be” that is the ?
 By
adopting a disposable approach this brings with it a
fragility to the supply chain
 Innovation
may sit with supplier of technology
 Linked in long term ( Lock in )
 Strategic investments need to be in-sync between both
participants in supply chain
 Collaborative partnering within the development groups
 Risk sharing
The technology challenge



Analytical toolkit (rapid delivery)
Fill & Finish (“why always a vial”)
Track and trace
Track and trace or “where is my
patient”? “where is the Therapy”?

ORCHESTRATION OF THE SUPPLY CHAIN
Analytical
Testing
Manufacturer
PATIENT
PATIENT
PATIENT
Technology
supplier
Therapy centre
The key issues





The need for certainty that the origin of a patient’s
treatment is from their own cellular starting material
Scheduling time critical pre-treatment prior to engraftment
for regenerative therapies with variable growth
dynamics/chemo prior to re-donation
Labour intensive documentation unsuitable for scale up/scale
out associated with Phase II and Phase III studies
The high unit cost associated with Advanced therapies make
temperature excursions and shipping delays intolerable
Coordinating multiple treatment sites with one manufacturing
facility.
Track and trace or “where is my
patient”? “where is the Therapy”?

ORCHESTRATION OF THE SUPPLY CHAIN
Analytical
Testing
Manufacturer
PATIENT
PATIENT
PATIENT
Technology
supplier
Therapy centre
Track and trace or “where is my
patient”? “where is the Therapy”?

ORCHESTRATION OF THE SUPPLY CHAIN
Analytical
Testing
Manufacturer
PATIENT
PATIENT
PATIENT
Technology
supplier
Therapy centre
Track and trace or “where is my
patient”? “where is the Therapy”?

ORCHESTRATION OF THE SUPPLY CHAIN
Analytical
Testing
Manufacturer
PATIENT
PATIENT
PATIENT
Technology
supplier
Therapy centre
Track and trace or “where is my
patient”? “where is the Therapy”?

ORCHESTRATION OF THE SUPPLY CHAIN
Analytical
Testing
Manufacturer
PATIENT
PATIENT
PATIENT
Technology
supplier
Therapy centre
What “ENABLERS” make this happen
Linking the Landscape







Medicines Manufacturing Industrial Partnership (MMIP)
ABPI
CPI : National Biologics Manufacturing Centre (NBMC)
& Factory of the future
Catapults: CTC Manufacturing Hotel
BIA
KTN
BIS/Innovate UK
AMSCI Project Vision – A Blueprint for UK
Gene Therapy
AMSCI, its impact

AMSCI funding
 To
achieve a fully integrated supply chain in the area
of gene therapy that was patient specific.
 Provided knowledge management systems
 Bricks and mortar
 Open door into the NHS
 Cross sector learning
 Industrialisation of platform
AMSCI






Highly effective funding vehicle for the medicines
manufacturing sector
Promotes cross-sector knowledge share
Promotes industry engaging with public sector e.g NHS
Allows for risk funding/investment in prep for phase 3
and market supply
Knowledge management systems
Accessing world leading academic institutions
The advanced therapy challenge






Flexibility in supply chain
“Orchestration” of supply chain
Technologies e.g disposables
Integration of suppliers with R&D through to
manufacturing through to end user and back
Innovation : where will it sit?
Fill and finish : “why always a vial”?
Thank you
Supply chain challenges for
biopharmaceuticals
Linda Randall,
Actavis Biologics
Supply Chain Challenges for Biopharmaceuticals
and Impact to Process Development
Linda Randall, Operations Director, Actavis Biologics
31
Presentation Overview
• Actavis Biologics
• The complexities of supply chain
management in the clinical
development phase
• Focus on materials and
manufacturing
• Conclusions
Actavis (NYSE:ACT) markets a broad portfolio of branded and generic pharmaceuticals and
develops innovative medicines for patients suffering from diseases principally in the Central
Nervous System, Gastroenterology, Women’s Health, Urology, Cardiovascular, Respiratory
and Anti-infective therapeutic categories.
The Company is an industry leader in R&D, with one of the broadest brand development
pipelines in the pharmaceutical industry, and a leader in the submission of generic product
applications.
Actavis has commercial operations in 60+ countries and operates 30+ manufacturing and
distribution facilities around the world.
33
Industry-leading Global Supply Chain
Houdan • France
Quebec • Canada
Larne • Northern Ireland
Solid Dosage,
Solids, Semisolids,
Coleraine • Northern Ireland
Manufacturing
Packaging
Liquids
API
Hafnarfjordur • Iceland
Dublin, Clonshaugh &
Solid Dosage
Baldoyle • Ireland
North Brunswick, NJ • USA
Pharmaceutical Technology
Elizabeth, NJ • USA
Solid Dosage
Solid Dosage, Inhalation,
Semisolids
Copiague, NY • USA
Gum
Corona, CA • USA
Solid Dosage
Bucharest • Romania
Injectables
Liege • Belgium
Women’s Health
Gurnee, IL • USA
Distribution
St. Louis, MO • USA
Distribution, Packaging
Weiderstadt • Germany
Manufacturing, Packaging
Podolsk • Russia
Solid Dosage
Groveport, OH • USA
Distribution
Salt Lake City, UT • USA
Transdermal, Gels,
Ointments
Milan • Italy
Solid Dosage
Dupnitsa • Bulgaria
Solid Dosage
Troyan • Bulgaria
Solids, Semisolids,
Liquids
Liverpool • UK
Biologics
Barnstaple • UK
Solid Dosage
Nerviano • Italy
Injectables
Leskovac • Serbia
Solid Dosage,
Liquids
Athens • Greece
Solid Dosage
Actavis
Forest
Olive Branch, MS • USA
Distribution
Birzebbuga • Malta
Solid Dosage
Birmingham, AL• USA
Ambernath • India
Zejtun • Malta
Singapore
Packaging
API
Manati • Puerto Rico
Various
Solid
Dosage
Weston, FL • USA
Distribution
Formulations
Anda
Fajardo • Puerto Rico
Rio de Janeiro • Brazil
Goa
•
India
Davie, FL • USA Manufacturing
Solid Dosage
Solid Dosage
Solid Dosage
Vandalia, OH • USA
Solid Dosage
34
Cincinnati, OH • USA
Solid Dosage, Liquids,
Packaging
Jakarta • Indonesia
Solid Dosage
Impressive Combined Global R&D Organization
Liege • Belgium
Hafnarfjordur • Iceland
Dundalk • Ireland
Larne • Northern Ireland
Bucharest • Romania
London • UK
Elizabeth, NJ • USA
Parsippany, NJ • USA
Actavis
Forest
Troyan • Bulgaria
Long Island, NY • USA
Jersey City, NJ • USA
Liverpool • UK
Bangalore • India
Salt Lake City, UT • USA
Nerviano • Italy
Chennai • India
Oakland, CA • USA
Owings Mills, MD • USA
Jakarta • Indonesia
Weston, FL • USA
Miramar, FL • USA
35
Ambernath • India
Navi, Mumbai • India
Actavis Biologics at a Glance
• Liverpool, UK (formerly Eden Biodesign) designated as the Actavis Global Centre
of Excellence for Biologics
• 160 Employees engaged in the development, manufacture & supply of biosimilars
• Lead product Gonal F® biosimilar
• 2011 Partnership with Amgen (Herceptin® , Avastin® , Rituxan/MabThera ® , Erbitux®)
• Acquisition and contribution of Synthon Herceptin® biosimilar demonstrates flexibility
of Actavis – Amgen collaboration
The Pharmaceutical Supply Chain – Simple?
37
The Biopharmaceutical company has many challenges to
overcome to ensure seamless supply versus demand
38
The Biopharmaceutical company has many challenges to
overcome to ensure seamless supply versus demand
39
The Biopharmaceutical company has many challenges to
overcome to ensure seamless supply versus demand
40
Materials Supply Management
41
Materials Supply Chains are vulnerable and present risks
of interruption in the manufacture of biopharmaceuticals
Reliance on having key components at right time
Vulnerability arises from
•
Global financial markets present uncertain outlooks
•
Natural disasters have potential to impact supply
•
Many materials are single sourced
•
Volcanic Eruption, Iceland 2010
Non-standardisation and regulatory challenges
make dual sourcing challenging
Process Development play critical role in the
selection of materials through successful
•
Vendor selection and business continuity planning
•
Dual sourcing where possible
42
Tsunami, Japan 2011
Out with the OLD and In with the NEW
43
Our approach is based on a hybrid model with significant
focus on Single Use Technologies
Main benefits
• Reduced Cost of Goods for biosimilars
• Increased flexibility for multi-product portfolio
• More rapid product change-overs
Challenges
• Early adopters / first users of some technologies
Media & Buffer
Preparation
Cell Expansion &
Fermentation
Harvest
Viral filtration
Final formulation
44
Single Use Technologies can account for a significant
proportion of material costs in the Cost Of Goods
Chemicals
Resins
Bags and
Tubing Sets
€
45
Filters
Management of the supply chain in the clinical
development phases is critical to commercial success
Product Design
Product
Development
Product Delivery
46
Rigorous selection
• Hardware
• Single Use Technologies
• Suppliers
Understanding
• Performance
• Robustness
• Security of supply
Monitoring & Review
• Performance
• Delivery
• Change Management
• Quality
We achieve technology & supplier selection through a
cross functional supplier management team
Building relationships with our suppliers early on is one of the
most important activities
Technical
Avoids risk that
decisions are solely
technically driven
47
• Check,
challenge and
confirm
commercial
viability of
solution
Quality
• Conduct presupply audits
• Risk based
approach to
select paper
based versus
on site audit
Business
• Review
performance of
supplier
• Business
meetings with
new suppliers
to establish
expectations of
cost, lead
times, delivery
performance &
responsiveness
Effort in managing the supply chain in clinical
development avoids delays & secures ongoing supply
Product Design
Early Development
Product
Development
Product Delivery
48
• Speed
• Security of Supply
Late Stage
Development &
Commercialisation
• Cost
• Security of Supply
• Speed can be
managed
During development our strategic review of the supply
chain for SUT identified a number of risks
Project established to Simplify, Stabilise, Secure & Save Money
•
•
Stabilise – can we identify
suppliers?
•
Secure – how can we improve our
processes and performance around
supplier management and procurement?
•
49
Simplify – can we reduce the number of
suppliers & gain improved control & need
fewer resources to manage?
2nd
source
Save – how can we reduce the CoGs
without detriment to supply chain security
Simplify
Stabilise
Supply
Chain
Supply
Chain
Secure
Save
Money
Supply
Chain
Simplify
Secure
Stabilise
Save
Money
Stabilising the Supply Chain
Quality issues with one supplier of Tubing & Bags
impacted our manufacturing schedule
Increased defects on incoming inspection (particulates)
-
More than 30% of batch rejected on incoming inspection
Problem analysis conducted & root causes identified by
Supplier & Subcontractor but no improvement
Needed to source alternative supply to minimise impact to
our batch production
Procurement Strategy to dual supply to secure
-
Extractables & Leachables risk assessments very important
Strategy defined based on analysis of current SUT
suppliers
50
Simplify
Stabilise
Secure
Save
Money
Simplifying the SUT Supply Chain
Our manufacturing process and the preparation of media
and buffers evolved during development and an
opportunity to standardise prior to commercialisation
Process review conducted
Guiding principles to ensure
- using off-the-shelf market options
- using standardised connector types &
tubing lengths
- minimal number of different SUT items
User Requirement Specification &
Tender process followed
40% reduction in SUT items used by a
single system design to replace multiple
SUT in Bill of Material
51
Simplify
Secure
Stabilise
Save
Money
Securing the Supply Chain
Product Robustness issues with two Unique SUT
posed significant risk to our manufacturing process
2 regular failures on 2 different SUT Unique systems during operation
that compromised our ability to deliver product
Short term - safety stock to replace the unit in manufacture
Long term – agree issue with supplier and ensure preventative
measures implemented
What made a difference?
• Clear communication and transparency
• Face to face meetings
• Supplier on site during set-up to see fail in action
• Solved together – we trialled the fix on our site
• Takes time and effort on both sides
52
Simplify
Secure
Stabilise
Save
Money
Securing the Supply Chain
Using data to drive discussions and
improve the supply chain performance
Regular performance reviews
Weighted assessment tool to assess
• Contractual obligations
• Responsiveness
• Delivery (volume & on-time)
• Response to audit observations
• Quality defects or complaints
Each supplier is graded as Excellent, Good,
Improvement Needed or Unfavourable
53
Product Supply Management
54
Many biopharmaceutical manufacturers now have globally
located facilities and this adds complexity
to the supply chain
Drug Substance
(Active Pharmaceutical
Ingredient)
Drug Product
Packaged Product
Packaged Product
Country 2
Country 3
Clinical Distribution
Country 1
Clinical Trial supply can take many months
Supply Chain design needs to start during
clinical development
• Planning future capacity on
anticipated demand
• Huge uncertainty
• Clinical trial success or
failure
• Competitor landscape
• Pipeline reviews
Operational
Stage
• Low speed manufacturing
processes
• Hold points from Quality
Control & Quality
Assurance interventions
Early
Development
Modelling batch sizes, scale, production capacity required
Revisiting models as more data becomes available
Strategies for rapid response to changing market demands
Approaches that decouple the steps with coordinated inventory
56
Actavis Biologics have modelled anticipated annual
production volumes and suitable batch sizes so that we
can validate a process that has levels of flexibility
Multiple doses
•
•
•
What is the optimum bulk drug substance aliquot volume?
What scales should we operate the bulk drug product formulation processes for
maximum flexibility against anticipated market volumes of different doses?
What additional flexibility can we gain in process design to minimise bulk drug substance
wastage?
Key challenges for global manufacturing supply chains
Logistics
How can we predict
demand 18 months
before the clinical study?
Forecasting
Supply
Chain
Challenges
Integration
58
How do we ensure quality and
delivery in other facilities?
How do we ensure Cold Chain
Distribution proceeds with no
delays to avoid product loss?
Speed
How agile can we be to
ensure material supply
is not critical path?
The Process Scientist contributes to many studies supporting
the supply chain development and mitigating risks within the
supply chain
Logistics
•
•
•
•
•
•
Analysis of routes and vendors
Trial shipments before entrusting valuable cargo!
Stability data generation to support temperature excursions
Plan for security of product
Plan for entry through customs
Re-testing maybe required for regulatory requirements
Forecasting & Integration ofForecasting
multiple sites & vendors
•
•
•
•
Liaison with clinical teams
Meticulous planning and modelling of demand versus shelf life
Update of shelf life as more data gathered
Technical and Quality Leads to oversee operational delivery and
assurance of quality
• Inventory control
59
Supply Chain Management hinges on building
effective relationships
to aid the business process
Invest time & effort
Manage issues
Communicate openly & transparently
Understand & seek to improve
60
Build your supply chain with “the end in mind” by
balancing simplicity, security, stability
and cost effectiveness
•
•
•
•
Manage as few suppliers as possible
Design simple, integrated supply
chains
Track market place
Quality & Supply Agreements
Invest in Relationships & Partnerships
Simplify
Stabilise
Secure
Save
Understand your supplier’s capability
Manage the risks – trial processes
and dual supply where possible
61
•
•
•
•
•
Balance cost versus risk
Plan to optimise costs once supply
route established
Acknowledgements
Actavis Biologics, Liverpool
Global Procurement Group
Consultancy for supplier management
project provided by:
• Andrew Sinclair
• Miriam Monge
• Andrew Brown
• Yuki Abe
62
Any Questions
63
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
Chairs: Suzanne Farid, Andrew Davidson
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
1. What supply chain lessons can biotech learn from other industries?
What challenges are distinctive to biopharma/ATMPs?
2. How are customer-supplier relationships best managed in the
supply chain?
3. What tools can be used to improve visibility and integration across
the supply chain?
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
1. What supply chain lessons can biotech learn from other industries?
What challenges are distinctive to biopharma/ATMPs?
2. How are customer-supplier relationships best managed in the
supply chain?
3. What tools can be used to improve visibility and integration across
the supply chain?
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
1. What supply chain lessons can biotech learn from other industries?
What challenges are distinctive to biopharma/ATMPs?
2. How are customer-supplier relationships best managed in the
supply chain?
3. What tools can be used to improve visibility and integration across
the supply chain?
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
1. What supply chain lessons can biotech learn from other industries?
What challenges are distinctive to biopharma/ATMPs?
2. How are customer-supplier relationships best managed in the
supply chain?
3. What tools can be used to improve visibility and integration across
the supply chain?
PANEL DISCUSSION:
James Christie (Oxford Biomedica), Linda Randall (Actavis Biologics),
Kevin Smith (TrakCel), Scott Lawson (PwC)
1. What supply chain lessons can biotech learn from other industries?
What challenges are distinctive to biopharma/ATMPs?
 How industrialized do biomanufacturing supply chains need to get?
 Is Amazon the exemplar we should be working towards?
 What is the impact of supply chain improvements on process development?
2. How are customer-supplier relationships best managed in the
supply chain?
 How does the current supply chain infrastructure meet our future needs?
 What is the future for small vendors in the future supply chain environment?
 How do you cope with supply chain disruptions?
3. What tools can be used to improve visibility and integration across
the supply chain?




Will new supply chain concepts be game-changing?
How do other sectors share information up and down the supply chain?
Is being good, good enough? Or are we at a tipping point?
How do we assemble teams to de-risk supply chain and meet patient safety?