STANDARDIZATION AND PARTNERSHIP

Enablers to increase predictability and service in a demanding and complex commercial supply chain

Tony WhiteMerck SUN – 24 September 2013

STANDARDIZATION AND PARTNERSHIP

In Clinical, the benefits of Single Use Systems are clear

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BENEFITSCross 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

For Commercial use, many companies remain to be convinced that SUS are a better overall solution that Stainless Steel

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BENEFITSCross contamination

SIP and CIP load Facility downtime

Capital expenditure Facility start-up time

RISKS and CONCERNSControl 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

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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

This presentation will

My back story - The British Automotive Industry - 1983

Rover

Ford

GM

Peugeot (Chrysler)

Jaguar

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Poor quality

Qualityinspected in

Confrontational relationship

High inventories

Infinite options

The British Automotive Industry 2013

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• Nissan

Toyota

Honda

Mini

Jaguar Land Rover

Highest quality

Quality built in

Partnerships

Lean operations

Platforms and option packs

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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Transferring Lean ‘principles’ into other industries

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Each industry = unique set of challenges

Best solutions = lean„principles‟ x local needs

Adoption is expensive, takes time and is needs drivenMature technology Increasing customer expectation on quality Supply chain complexity

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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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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Benefits come at many levels

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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

BPOG Programme for 2013 as of 05 July 2013

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Jan Mar May Jul Sep Nov

BPOG16 – ManchesterJaguar Landrover

26 – 28 Feb

Operational Excellence

BPOG17 – Westlake Village, CABaxter Healthcare

18 - 20 Jun

Technology Transfer

BPOG18 – Raleigh Durham, NCBiogen Idec15 - 17 Oct

Review and Plan 2014

BPOG L2 F2FsEmerging issues and direction setting

L3 Work Streams For detailed sharing, collaboration and long term communities of interest

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)

Multi-Product Facilities (Q2 2011 – in charter review)

Disposables (Q2 2012, program in development)

Continued Process Verification (Q3 2012, next charter review Q3 2013)

Technology Transfer

Circle back Inline Buffer

BioPhorumL1 and Non BPOG Members Executive

BioPhorum - Boston

21 – 23 May

BioBurden (Q4 2012 )

CPV Informatics (Q2 2013, Ph1 Best Practice, reconfirm PhII Implementation)

BioPharma Production System (Q3 2013, starting with 5S)

Circle back on Contamination in 2014

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

Cost

• Capital cost

• Faster construction / validation schedule

• Utility load down

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

• Unit cost

• Inventory holding cost

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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

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Enabler 1

STANDARDIZATION

Enabler 2

PARTNERSHIP and a Solution Provider paradigm

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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

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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

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Merck’s Vendor Expectation

Those Attributes include: Attribute 1: Biocompatibility testing Attribute 2: Mechanical properties Attribute 3: Gas transmission properties Attribute 4: Compendial Physiochemical Testing Attribute 5: E.P.5.2.8. on TSE-BSE Attribute 6: TOC analysis Attribute 7: pH/Conductivity Attribute 8: Extractable/Leachable (E/L) testing Attribute 9: Chemical compatibility testing Attribute 10: Protein adsorption studies Attribute 11: Endotoxin testing Attribute 12: Sterilization validation (e.g., gamma irradiation) Attribute 13: Container closure integrity (CCI) Attribute 14: Particulates Attribute 15: Calibration of embedded instrumentation (sensor)

Not all attributes are applicable to all SUSs.

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Enabler 1

STANDARDIZATION

Enabler 2

PARTNERSHIP and a Solution Provider paradigm

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Johnson Controls – A leading Solution Provider and Partner

Building Efficiency

Power Solutions

Automotive Experience

• Overhead systems,

• Door and instrument panels

• Interior electronics

• Automotive seating

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Johnson Controls – A leading Solution Provider and Partner

Building Efficiency

Power Solutions

Automotive Experience

• Overhead systems,

• Door and instrument panels

• Interior electronics

• Automotive seating

oLargest Complete Seat supplier globally

o> 22million seat sets delivered per year

o> 120 JIT seating plants globally

o> 25 years of experience in JIT deliveryMerck SUN Symposium

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Being a Solution Provider means

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• 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

Car seats are have nothing to teach us in terms on technology …..but lots in terms of how to deliver a product that is

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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

The supply chain

Trim• Fabric or leather • Thread• Backing

Foam• Resin

Plastics• Resin

Frame• Pressings

o Strip steelo Tube

• Heaters• Springs

o Wire

• Controls• Programmer

Slides• Ball bearings• Pressings

o Strip steel

• Welding nuts

Risers• Gears• Motors• Pressings

o Strip steel

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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

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How do they guarantee product at point of use?

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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

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

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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

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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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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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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.

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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

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Merck SUN Symposium24/Sept/2013

How is Merck Contributing in SUS Standardization Effort?

Collaborate with other end-users and suppliers:

• to harmonize and balance the expectations and needs from both sides within the regulatory constraints.

Merck SUN Symposium24/Sept/2013 33

Standard Extractable Protocol

http://www.bing.com/images/search?q=logo+PDA&id=E28B1AA15E2150D34C776CA02BEF0409E2E17470&FORM=IQFRBA

http://www.bing.com/images/search?q=logo+ISPe&id=272AE5A5CDBA96EC15EDDA74A43EFFD32A9B45B0&FORM=IQFRBA

Merck Will…

150 Process Contact Materials (PCMs)

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Develop a new processo100% Disposables Components

Ready to qualify the entire process train

BioreactorDepth

FiltrationCapture Polish 1 Bioburden

ReductionFiltrationStorage

CentrifugationPolish 2

0.22umfiltration

Viralfiltration

•1-3%WCW

Viral Inactivation

(pH hold)

Sterilefiltration

Filling

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

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How is the Process Now?

Simple &Efficient Qualification Process

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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 letter2. Numerous formats of supplier data and multiple set of data for

one components3. 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.

Partner with Others to Effect Change

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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




Business Case – Why Do We Need Standardized Extractable Protocol

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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


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

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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

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‘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

Part II

Time points and temps

0 hours 25oC

48 hours 40oC

30 days 40oC

120 days 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)

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Standard Extractable Studies – Subset of Sample Preparation Table

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SUT Types Recommended Sample Extraction

Flexible Storage /

Mixing / Bioreactor Bags

Small bag (2D can represent 3D bags) / fill to 10% of bag volume / meet ≥ 3:1 surface area to

volume ratio (cm2/mL) / at horizontal orientation (Ensure all surfaces contact with extraction

solvent).

Specific film thickness of the test sample and express results in µg/cm2.

Rigid Bioreactor Vessel

Rigid vessel / extract 60cm2 (both sides of the samples) / cut pieces (e.g., 1cm X 3cm) / 10mL of

extracting fluid.

Express the extractable values in µg/g.

Tubing

Use small ID tubing for the recommended internal contact extraction study. Extract 60cm2 of

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)

UF/DF Filters

Flush min. volume as recommended. Circulate volume extraction solvent through the UF/DF unit

during the full duration of the extraction study. Express the extractable values in µg/cm2 or

µg/unit.


Standard Extractable Studies – Appendix B

Part I

Model Solvents

• WFI pH 11-12

• 5M NaCl

• PBS

• 50% Ethanol

• WFI pH 2



• WFI neutral

Part II


0 hours 25oC

21 days 40oC

56 days 40oC

140 days 40oC

Part III


pH measurements

Conductivity

TOC

Metal ions: ICP-MS/OES

Volatiles: HS-GC-FID/MS

Semi-Volatiles: GC-FID/MS

Non-Volatiles: LC-PDA/MS

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Part I

Model Solvents

• WFI pH 11-12

• 5M NaCl

• PBS

• 50% Ethanol

• WFI pH 2


• WFI neutral

Part II


0 hours 25oC

48 hours 40oC

30 days 40oC

120 days 40oC

Part III


pH measurements

Conductivity

TOC

Screening of metals

Volatile Organic Compounds (VOC) with direct injection into gas chromatography/mass spec (GC/MS)

BOLD: New additions/changes in comparison to the ISPE’s article


Appendix B – Extraction Solvents, Times and Temperatures

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WFI

pH

11

-12

5M

NaC

I

PB

S

50

% E

than

ol

WFI

pH

2

10

% P

oly

sorb

ate

20

10

% P

oly

sorb

ate

80

WFI

ne

utr

al Tim

e 0

*

21

day

s

56

day

s

14

0 d

ays

Am

bie

nt

25

C

40

C

40

C

40

C

Storage bags X X X X X X X X X X X x

Mixing bags X X X X X X X X X X

Bioreactor bags** X X X X X X X X

Tubing X 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.


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

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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

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No Too Distance Future, Merck Can …

Qualifying 100+ of PCMs

Simple & Efficient Qualification Process

Reliable and Robust Regulatory Submission Package

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Depth Filtration

Capture Polish 1 Bioburden ReductionFiltrationStorage

CentrifugationPolish 2

0.22umfiltration

Viralfiltration

•1-3%WCW

Viral Inactivation

(pH hold)

Sterilefiltration

Filling


Acknowledgement

BPOG Standard Extractable Protocol Team

Thank YouNewsletter 16

48

Health & Medicine

STANDARDIZATION AND PARTNERSHIP