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Enablers to increase predictability and service in a demanding and complex commercial supply chain, presentation made to MERCK SUN Conference, September 2013

Enablers to increase predictability and service in a demanding and complex commercial supply chain, presentation made to MERCK SUN Conference, September 2013

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  • ThanksIndustry turning point.
  • EulogizeGame Changing technology etc
  • However
  • Link so what are my credentials
  • Seen a transition, understood it and spent 20 years helping other industries transform along similar lines and also steel from other industries and
  • Helping to mature All have different challenges Take it back to 1st principles

STANDARDIZATION AND PARTNERSHIP STANDARDIZATION AND PARTNERSHIP Presentation Transcript

  • STANDARDIZATION AND PARTNERSHIP Enablers to increase predictability and service in a demanding and complex commercial supply chain Tony White Merck SUN – 24 September 2013
  • 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 2
  • 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 3
  • 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 Merck SUN Symposium 4
  • My back story - The British Automotive Industry - 1983  Rover  Ford  GM  Peugeot (Chrysler)  Jaguar Poor quality Qualityinspected in Confrontational relationship High inventories Infinite options Merck SUN Symposium 5
  • The British Automotive Industry 2013 • Nissan Toyota Honda Mini Jaguar Land Rover  Highest quality  Quality built in  Partnerships  Lean operations  Platforms and option packs Merck SUN Symposium 6
  • 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 Merck SUN Symposium 7
  • 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 Merck SUN Symposium 8
  • 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 Merck SUN Symposium 9
  • 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 Merck SUN Symposium 10
  • 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 Merck SUN Symposium 11
  • 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 12
  • 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
  • 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
  • Enabler 1 STANDARDIZATION Enabler 2 PARTNERSHIP and a Solution Provider paradigm Merck SUN Symposium 15
  • 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 16
  • 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 17
  • 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. Merck SUN Symposium 18
  • Enabler 1 STANDARDIZATION Enabler 2 PARTNERSHIP and a Solution Provider paradigm Merck SUN Symposium 19
  • 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 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 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 21
  • 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
  • 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
  • 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 24
  • 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 25
  • 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 26
  • 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 27
  • 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 28
  • 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 Merck SUN Symposium 29
  • 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 Merck SUN Symposium 30
  • 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 31
  • 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 32
  • 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 33
  • 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 34
  • 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
  • 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 36
  • 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 37
  • 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 38
  • 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 39
  • 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 40
  • ‘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
  • 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. Merck SUN Symposium 24/Sept/2013 42
  • 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 24/Sept/2013 43
  • 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. Merck SUN Symposium 24/Sept/2013 44
  • 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 24/Sept/2013 45
  • 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
  • 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
  • Acknowledgement BPOG Standard Extractable Protocol Team Thank You Newsletter 16 48