The document discusses the benefits and risks of single-use systems (SUS) in the biopharmaceutical supply chain, emphasizing the need for standardization and partnerships to enhance predictability and service. It presents the Biophorum Operations Group (BPOG) as a collaborative effort of biopharmaceutical manufacturers aimed at sharing best practices and improving industrial maturity through non-competitive cooperation. By using the automotive industry as a model, the document calls for addressing challenges and implementing solutions that would streamline processes, reduce costs, and mitigate risks associated with SUS.

1. STANDARDIZATION AND PARTNERSHIP
Enablers to increase predictability and service in a
demanding and complex commercial supply chain
Tony White
Merck SUN – 24 September 2013

2. In Clinical, the benefits of Single Use Systems are clear
BENEFITS
Cross contamination
SIP and CIP load
Facility downtime
Capital expenditure
Facility start-up time





 The benefits
• Are overwhelming given product trends
• Have appreciably reduced entry costs for biotech start-ups
• SUSuse has grown rapidly and will continue to do so
Merck SUN Symposium
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3. For Commercial use, many companies remain to be convinced that SUS are
a better overall solution that Stainless Steel
BENEFITS
Cross contamination
SIP and CIP load
Facility downtime
Capital expenditure
Facility start-up time





RISKS and CONCERNS
Control of change
Predictability of output
 Implementation complexity
 SKU complexity
 Supply, capital and space
 The risks and concerns are
• Retarding uptake of commercial applications, but
• Addressable, when and where suppliers and users work as partners
Merck SUN Symposium
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4. This presentation will
 Reference the concerns
 Call for
• More standardization in „designs‟ and ways of working
• Users to organise themselves along Life Cycle Management and
Partnership principles
• Integrators to adopt a „Solution Provider‟ paradigm and deliver more
service innovation
 Use an automotive industry example as a model for debate
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5. My back story - The British Automotive Industry - 1983
 Rover
 Ford
 GM
 Peugeot (Chrysler)
 Jaguar
Poor quality
Qualityinspected in
Confrontational relationship
High inventories
Infinite options
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6. The British Automotive Industry 2013
• Nissan
Toyota
Honda
Mini
Jaguar Land Rover
 Highest quality
 Quality built in
 Partnerships
 Lean operations
 Platforms and option packs
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7. How did the transformation occur
 Toyota Production System (TPS) and Japanese transplant plants
• JIT (Just-in-time)
• TQM (Total Quality Management)
• Kaizen
 Platform architecture and option packs
 Restructuring and reinvention of the supply base
• Outsourcing strategies
• Supplier Quality Assurance to Supplier Development to Partnership Sourcing
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8. Transferring Lean ‘principles’ into other industries
 Each industry = unique set of challenges
 Best solutions = lean„principles‟ x local needs
 Adoption is expensive, takes time and is needs
driven
 Mature technology
 Increasing customer expectation on quality
 Supply chain complexity
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9. What is the BioPhorum Operations Group (BPOG) ?
 BPOG is a global collaboration of biopharmaceutical
manufacturers. Since 2008 it has grown to
• 20 member companies
• 600 active representatives working in
• 12workstreams, of which only one is Disposables
 BPOG mission
• To accelerate the journey to industrial maturity, by sharing and developing
non competitive best practices, faster, smarter and cheaper
 BPOG is not a standards body or representative of suppliers
• It works with and through other bodies to realise change
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10. BPOG Member Companies
AbbVie
Amgen
Bayer
Baxter
Biogen
BMS
Dynavax
Fujifilm Diosynth
Gallus
Genentech/Roche
GSK
Janssen
Lonza
AstraZeneca
Merck& Co., Inc
Novartis
Onyx
Pfizer
Sanofi/Genzyme
Regeneron
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11. Benefits come at many levels
1. Contacts and networks
2. Comparison of competence
3. Sharing experience & knowledge
4. Cooperative development of best practice &
implementation approaches
5. Consistent position with regulators & 3rd parties
We will constantly encourage movement in this direction
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12. BPOG Programme for 2013
Jan
Mar
L1 and Non BPOG
Members Executive
Jul
Sep
Nov
21 – 23 May
BPOG16 – Manchester
Jaguar Landrover
26 – 28 Feb
Emerging issues and
direction setting
BPOG17 – Westlake Village, CA
Baxter Healthcare
18 - 20 Jun
BPOG18 – Raleigh Durham, NC
Biogen Idec
15 - 17 Oct
Operational Excellence
BPOG L2 F2Fs
For detailed sharing,
collaboration and long
term communities of
interest
May
BioPhorum - Boston
BioPhorum
L3 Work
Streams
as of 05 July 2013
Technology Transfer
Review and Plan 2014
Reliability (Q2 2009 – next charter review Q1 2013)
Quality Control & Lean Labs (Q3 2009 – next charter review Q4 2013)
Room Class (Q1 2010)
Supplier Quality & Continuity Assurance (Q3 2011 – next charter review Q2 2013)
HER (Q1 2012 - next charter review Q1 2013)
BioBurden
(Q4 2012 )
Circle back on Contamination in 2014
Multi-Product Facilities (Q2 2011 – in charter review)
Disposables (Q2 2012, program in development)
Continued Process Verification (Q3 2012, next charter review Q3 2013)
Circle back
CPV Informatics
Inline Buffer
(Q2 2013, Ph1 Best Practice, reconfirm PhII Implementation)
BioPharma Production System (Q3 2013, starting with 5S)
Technology Transfer
Merck SUN Symposium
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13. Single Use Systems bestow many benefits but also introduce a number of concerns
that need mitigation
Benefits
 Risk
• Cross contamination
• Cleaning and change over
 Operational
• Flexibility of facility
• No CIP / SIP
o Reduce cycle times / higher capacity
 New products and process
• Scale up
Issues and concerns
 Risk
• Cell culture performance
• Outsourcing parts of the process
o Supplier change control
o Integrity and particulate
 Operation
• Lead-time of supply
• Increase warehouse capacity
 New products and process
• Implementation speed
o Extractablesand leachables
 Cost
• Capital cost
• Faster construction / validation schedule
• Utility load down
 Cost
• Unit cost
• Inventory holding cost
Merck SUN Symposium
13

14. Users vision to reduce risk…
 SUS designed to be ROBUST and FIT FOR PURPOSE through transparent
technical exchanges between suppliers and end users
 Better correlations between VARIABILITY in the SUS and end user‟s process
and products
 Effective CONTROL STRATEGIES for RMs and manufacturing processes
throughout the entire supply chain
 CHANGE CONTROL processes that identify, track and communicate
parameters that are aligned to specifications
 FASTER and more PREDICTABLE SUPPLY of SUS meaning less inventory
14
Merck SUN Symposium

15. Enabler 1
STANDARDIZATION
Enabler 2
PARTNERSHIP and a Solution Provider paradigm
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16. Users are starting to standardize the SUS they buy and are seeing benefits
 In 2011 one biopharmacuatical across their network
• Consolidated 13 designs down to 2
• Included 7 suppliers in competitive RFP
• Qualified 2 sources for new designs
• Increased value of business to successful suppliers
• Reduced purchase cost
• Reduced inventory levels on sites
• Reduced inventory obsolescence risk
• Improved inventory turns for suppliers
Merck SUN Symposium
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17. How about some audacious standardization goals?
One film specification
One connector type
One set of dimensions for each bag volume
One standard extractable protocol
One change notification and control standard
One standard information pack
Merck SUN Symposium
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18. Merck’s Vendor Expectation
 Those Attributes include:















Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
Attribute
1: Biocompatibility testing
2: Mechanical properties
3: Gas transmission properties
4: Compendial Physiochemical Testing
5: E.P.5.2.8. on TSE-BSE
6: TOC analysis
7: pH/Conductivity
8: Extractable/Leachable (E/L) testing
9: Chemical compatibility testing
10: Protein adsorption studies
11: Endotoxin testing
12: Sterilization validation (e.g., gamma irradiation)
13: Container closure integrity (CCI)
14: Particulates
15: Calibration of embedded instrumentation (sensor)
 Not all attributes are applicable to all SUSs.
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19. Enabler 1
STANDARDIZATION
Enabler 2
PARTNERSHIP and a Solution Provider paradigm
Merck SUN Symposium
19

20. Johnson Controls – A leading Solution Provider and Partner
Building Efficiency
Power Solutions
Automotive Experience
• Overhead systems,
• Door and instrument panels
• Interior electronics
• Automotive seating
Merck SUN Symposium
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21. Johnson Controls – A leading Solution Provider and Partner
Building Efficiency
Power Solutions
Automotive Experience
• Overhead systems,
• Door and instrument panels
• Interior electronics
• Automotive seating
o Largest Complete Seat supplier globally
o > 22million seat sets delivered per year
o > 120 JIT seating plants globally
o > 25 years of experience in JIT delivery
Merck SUN Symposium
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22. Being a Solution Provider means
• Assuring the quality of ALL components
inan assembly
 Guaranteeing on-time delivery at point of
use
 Signing up to a cost down contract with
„line stoppage‟ penalties
 Being the single source of supply and
acting as a Partner
 Being driven by the customer‟s standards
Merck SUN Symposium
22

23. Car seats are have nothing to teach us in terms on technology …..
but lots in terms of how to deliver a product that is
 A complex assembly
 Hand built from many
3rd party fabricated
parts
 Prone to parts
shortages
 Bulky and space
consuming
 Challenging to
transport and easily
damaged
 Safety critical
 Designed to customer
requirements
 High value
 Connected up by the
user‟s staff
Merck SUN Symposium
23

24. The supply chain
 Trim
• Fabric or leather
• Thread
• Backing
 Foam
• Resin
 Plastics
• Resin
 Frame
• Pressings
o Strip steel
o Tube
• Heaters
• Springs
o Wire
• Controls
• Programmer
 Slides
• Ball bearings
• Pressings
o Strip steel
• Welding nuts
 Risers
• Gears
• Motors
• Pressings
o Strip steel
Merck SUN Symposium
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25. How do they Assure Quality?
 Quality means - Zero Defects
 Take accountability for the quality/performance of
the entire seat.
 Own the SQA/Development process down the supply
chain to all 2nd and 3rd tier suppliers.
• Train suppliers (and charge suppliers) in process control,
Kaizen, 5S, and Lean.
• Deploy Process Controls on critical parameters in Quality
Plans with all suppliers
• Track and have complete visibility of Quality Metrics
 Systems Engineer owns the Product Design and
controls all Changes in the supply chain
 When things go wrong
• Take staff to the customer site and rework any issues at
their own expense
Merck SUN Symposium
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26. How do they guarantee product at point of use?
 On-time delivery means – Sequenced vehicle
„sets‟ at 2 hours lead-time, direct to side of
car assembly track
 Invest in satellite factories minutes from the
customer‟s assembly line
 Plan and reserve capacity with the customer
and suppliers
 Create flow
• Balance process lines and manning levels
• Set up „Pull controls‟
• Hold component inventory in kanbans
 Get quality right first time at each stage to
eliminate line disruptions
 When things go wrong
• Helicopter in product to keep lines going and
avoid line stop penalties of £100k‟s per hour
Merck SUN Symposium
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27. Why are they prepared to sign up to a cost down contract?
 Because this is a Partnership, built on a single source supply agreement and a joint,
long term commitment to make the relationship work
 Because they know they will get better at making a seat during it‟s life cycle and
cost will come down
 Because it is the norm in the industry and all customers expect the same
Merck SUN Symposium
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28. Why does Toyota and many automotive manufacturers single source
 They will state
• “The cost and time needed to develop a trusted zero defect supply
partner, for mission critical, custom parts is so great, that they can not
justify the cost and time to create a second source”
 Because
• Over the long term this approach delivers the lowest risk and „Total Cost
of Supply‟
• The challenges of managing quality from two sources far outweigh any
claimed improvement in supply security
Merck SUN Symposium
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29. What can Users do?
 Create a SUS Leadership Team / Owner at company level
• Adopt a Life Cycle Management approach and make sourcing and design
decisions accordingly
• Invest in Supplier Engineers on the road to build understanding and the
suppliers you can trust.
 Consolidate volumes by standardizing the range of parts and
systems sourced
• Base this on your own „standard‟ or platform of components
• Drive up supplier volumes, and smooth the demand they experience
 Move towards single sources and partnership
 Work with Partners more closely on needs, and variability. Deepen
understanding and publish together
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30. What can Integrators do?
 Adopt a “Service Provider‟ paradigm
• Understand customer service needs not just product needs
• Aim to delight customers, and win contracts through outstanding service
 Become outstanding at
• Process Control and SQA services
• Supply Chain Management and Logistics and offer consignment inventory
solutions
 Search out those who are serious about Partnership
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31. What can BPOG do?
 Encourage ambition and debate on these ideas among users
and help identify those elements that bring value
 Facilitate alignment among users on the process of
standardization
 Help users identify their needs and communicate these to
create an open „Pull‟ in the industry
 Collaborate with other bodies to further this agenda.
Merck SUN Symposium
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32. BPOG’s Extractables Protocol Standardization
Efforts – A Step Forward to Facilitate
Implementation of Single-Use Systems
BPOG Standard Extractable Working Group
Ken Meng Wong
Merck
Merck SUN Symposium
24/Sept/2013
Merck SUN Symposium
24/Sept/2013
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33. How is Merck Contributing in SUS Standardization Effort?
Standard
Extractable
Protocol
 Collaborate with other end-users and suppliers:
• to harmonize and balance the expectations and needs from both sides
within the regulatory constraints.
Merck SUN Symposium
24/Sept/2013
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34. Merck Will…
Bioreactor
Centrifugation
•1-3%
WCW
Depth
Filtration
Capture
0.22um
filtration
Viral
Inactivation
(pH hold)
Polish 1
Polish 2
Viral
filtration
Bioburden
Reduction
Filtration
Storage
Sterile
filtration
Filling
Develop a new process
o100% Disposables Components
Ready to qualify the entire process train
150 Process Contact Materials
(PCMs)
Merck SUN Symposium
24/Sept/2013
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35. What it Could Be: Simple and Efficient Qualification Process
 Have easy access to suppliers‟ validation data packages – meet
Merck‟s supplier expectation
• 16 attributes (not all are applicable)
 Each and every packages are identical in format
• e.g., Regulatory filing – CTD format; Production record – batch
recordformat
• Easy to locate the section where the specific information will reside
 Perform Risk Assessment according to our WP-2012-05
 Perform additional risk-based studies
• Risk score dependent
 Document the completed qualification
Merck SUN Symposium
24/Sept/2013
35

36. How is the Process Now?
Simple &Efficient
Qualification Process
Current State:
1. Call each supplier numerous times (e.g., follow ups) to gather all
the Merck’s supplier expectation (16 Attributes)
• Non-existence / information with no clear linkage to the SUS
we procure / unsigned certified letter
2. Numerous formats of supplier data and multiple set of data for
one components
3. Data packages for most assemblies are generally weak
• Lack identity of some subcomponents (e.g., Silicone tubing)
• Missing data for certain subcomponents
Our qualification package is as good as the
weakest linkof the process train.
Merck SUN Symposium
24/Sept/2013
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37. Partner with Others to Effect Change
BPOG is uniquely end-users only memberships based
collaboration platform for 3 basic reasons:
1. Allow end-users to debate openly (other than confidential details) about
issues (e.g., supplier data, common issues);
2. Align and compromise among ourselves
• one set of end-users expectation
3. Cross pollinate our best practices
Merck SUN Symposium
24/Sept/2013
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38. Business Case – Why Do We Need Standardized Extractable Protocol
 Extractables data is key to SUS Implementation and used to assess
•
•
•
•
•
Risk to patient safety
Probable Process Leachables
Product compatibility
Process performance, and
Demonstrate due diligence to regulatory bodies
 No specific FDA Guidance how to handle process related Extractables, only
container closure extractables
• No consistency between individual End User submissions
• BPOG Protocol can help bridge this gap with regulators
 Some suppliers extractables data packs - not technically adequate for most
processes evaluation as is & not consistent between suppliers
• Model solvents and conditions - not representative enough for expected process conditions
• Solvents used are not always the strongest solvent
• Extractable data is not comparable between suppliers and too often not as comprehensive as
users require
– Necessitate End Users to perform additional studies
• For assembler (with different Extractables data) providing consistent supplier data across different
component suppliers – ease of use of extractable data for end users
 Adoption of SUS is being slowed in commercial space
• Increasing regulatory scrutiny with commercial application
• Lead-time for SUS implementation is long driven in part by inconsistency between supplier data
Merck SUN Symposium
24/Sept/2013
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39. Value Add: Win-Win for All
Regulators
•Consensus Standards for Extractablespublished by ASTM/USP
•Clear expectations for suppliers and end users
• Consistent level of baseline data provided for extractables, from different applicants
• Reduced effort to review extractables data
• Risk based approach to extractables applied rather than performing test in every application
• Review efforts can be focused on control strategy for process specific leachables
Suppliers
•Consensus Standards for Extractablespublished by ASTM/USP
• Know what extractable protocol to follow
• Solid starting point – standard extractable protocol
• One Voice of Customer (major biopharma are represented), clear end-user expectation
• The go-to group to solicit feedback for your extractable study planning
• Clear reporting format
End Users
•Consensus Standards for Extractablespublished by ASTM/USP
•Know what extractable protocol to use
• Solid starting point for in-house evaluation – standard extractable protocol
• Know exactly what will be available from suppliers
• Reliable extractable data
• Able to make rapid decision to move SUS forward along the developmental path
• Able to identify additional work early for development programs
• Few regulatory questions with consistent data package from all biopharma/CMO companies
Merck SUN Symposium
24/Sept/2013
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40. Where BPOG are – Consultation Phase
End of our consultation Phase
 Provided Draft BPOG Standard Extractable Protocol for industry
review since mid May 2013
 Have had comments and 1-on-1 review meetings with 9
selected suppliers
• Plus a BPSA collective review
• Expect more feedback from non-BPSA associated suppliers
 Have heard/written comments from 10+ CROs
 Heard generate comments/recommendations from Dennis
Jenke
• USP <661>: Chair of the expert committee
• PQRI: Chair of PODP working group
• ELSIE: Chair of board of directors
Merck SUN Symposium
24/Sept/2013
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41. ‘Standardization of Single Use Components’ Extractable Studies for Industry’




Published in Pharmaceutical Engineering, May 2012
Authored by Ekta Mahajan, Trishna Ray-Chaudhuri and James Dean Vogel
Work originated by the ISPE CoPon Single Use Systems
Article proposed
• A standard protocol for extractable studies which would take away majority of the needs for additional
studies
• Called for the endorsement of a suitable User and or Supplier grouping
 The protocol has three parts which serve as our starting point
Part I
 Model Solvents
•
•
•
•
•
•
•
WFI pH 11-12
5M NaCl
PBS
50% Ethanol
WFI pH 2
20% Polysorbate 20
WFI neutral
Merck SUN Symposium
24/Sept/2013
Part II
 Time points and temps




0 hours
48 hours
30 days
120 days
25oC
40oC
40oC
40oC
Part III
 Analytical techniques





pH measurements
Conductivity
TOC
Screening of metals
Volatile Organic Compounds
(VOC) with direct injection into
gas chromatography/mass spec
(GC/MS)
41

42. Standard Extractable Studies – Subset of Sample Preparation Table
SUT Types
Recommended Sample Extraction
Small bag (2D can represent 3D bags) / fill to 10% of bag volume / meet ≥ 3:1 surface area to
Flexible Storage /
volume ratio (cm2/mL) / at horizontal orientation (Ensure all surfaces contact with extraction
Mixing / Bioreactor Bags solvent).
Specific film thickness of the test sample and express results in µg/cm2.
Rigid vessel / extract 60cm2 (both sides of the samples) / cut pieces (e.g., 1cm X 3cm) / 10mL of
Rigid Bioreactor Vessel
extracting fluid.
Express the extractable values in µg/g.
Use small ID tubing for the recommended internal contact extraction study. Extract 60cm2 of
Tubing
tubing (record - total length & weight) for every 10mL of extracting fluid.
Express the extractable values in µg/g, µg/cm, and µg/cm2
Sterile / Process Filters
Express the extractable values in µg/cm2 or µg/filter (specify filter effective filtration area)
Flush min. volume as recommended. Circulate volume extraction solvent through the UF/DF unit
UF/DF Filters
during the full duration of the extraction study. Express the extractable values in µg/cm2 or
µg/unit.
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43. Standard Extractable Studies – Appendix B
Part I
 Model Solvents
•
•
•
•
•
•
•
WFI pH 11-12
5M NaCl
PBS
50% Ethanol
WFI pH 2
20% Polysorbate 20
WFI neutral
Part I
 Model Solvents
•
•
•
•
•
•
•
•
Part II
 Time points and temps
WFI pH 11-12
5M NaCl
PBS
50% Ethanol
WFI pH 2
10% Polysorbate 20
10% Polysorbate 80
WFI neutral




0 hours
48 hours
30 days
120 days
25oC
40oC
40oC
40oC
Part II
 Time points and temps




0 hours
21 days
56 days
140 days
25oC
40oC
40oC
40oC
Part III
 Analytical techniques





pH measurements
Conductivity
TOC
Screening of metals
Volatile Organic Compounds
(VOC) with direct injection into
gas chromatography/mass spec
(GC/MS)
Part III
 Analytical techniques







pH measurements
Conductivity
TOC
Metal ions: ICP-MS/OES
Volatiles: HS-GC-FID/MS
Semi-Volatiles: GC-FID/MS
Non-Volatiles: LC-PDA/MS
BOLD: New additions/changes in comparison to the ISPE’s article
Merck SUN Symposium
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44. 56 days
140 days
40 C
40 C
Time 0*
Ambient 25 C
21 days
WFI neutral
X
10% Polysorbate 80
X
10% Polysorbate 20
X
WFI pH 2
X
50% Ethanol
x
PBS
X
5M NaCI
X
WFI pH 11-12
40 C
Appendix B – Extraction Solvents, Times and Temperatures
Storage bags
X
X
X
X
X
X
X
X
X
Mixing bags
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bioreactor bags**
Tubing
X
X
X
X
X
X
X
X
X
X
Filters
X
X
X
X
X
X
X
X
X
X
Aseptic Connectors
X
X
X
X
X
X
X
X
X
X
X
Tubing Connectors
X
X
X
X
X
X
X
X
X
X
X
Disposables Sensors
X
X
X
X
X
X
X
X
X
X
X
* Initial sample will be prepared in the same manner as all other samples.
** All associated components such as tubing and connector should be subjected to the same worse case test conditions.
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44

45. Standard Extractable Studies – Appendix C
4 tables to detail the recommended analytical instruments
and detectors conditions (serve as starting points)
Suppliers with existing practice – follow this for new products /
provide scientific rationale of using the existing data
 Table 1: LC-PDA/MS
• Column, mobile phases, gradient, UV range (200-400nm), stds, reporting
limit
• Criteria: sensitivity, spiked recovery, precision
 Table 2: GC-FID/MS
• Column, oven program, scan range (30- 400 amu), stds, internal std,
reporting limit, liq-liq extraction solvent and procedure
• Criteria: sensitivity, spiked recovery, precision
 Table 3: HS-GC-MS
• Similar to GC-FID/MS
• Extra test - neat sample as well as the extract
 Table 4: ICP-MS/OES - DL
Merck SUN Symposium
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46. Where is BPOG Going?
 All the talking are done
• several members of BPOG standard Extractable protocol team (May 2013
till now)
 Revise proposal during F2F meeting in early Oct 2013
 Publish the new revision in late 2013
 Next up  Collaboration
Merck SUN Symposium
24/Sept/2013
46

47. No Too Distance Future, Merck Can …
Centrifugation
•1-3%
WCW
Depth
Filtration
Capture
0.22um
filtration
Viral
Inactivation
(pH hold)
Polish 1
Polish 2
Viral
filtration
Bioburden
Reduction
Filtration
Storage
Sterile
filtration
Filling
 Qualifying 100+ of PCMs
Simple & Efficient Qualification Process
 Reliable and Robust Regulatory Submission Package
Merck SUN Symposium
24/Sept/2013
47

48. Acknowledgement
BPOG Standard Extractable
Protocol Team
Thank You
Newsletter 16
48