QbD - The Route to Supply Chain Transformation

QbD - The Route to Supply Chain Transformation

Conference on QbD/PAT:

7-10 October, 2012, Cortona (Tuscany), Italy

Presented by: Hedley Rees

Advisory Board Member, IIAPS

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AGENDA

Brief background on the International Institute for Advanced Purchasing & Supply (IIAPS)

Why am I so passionate about the Pharma supply chain?

How did it get into all this trouble?

Where are we now?

Modernization the route to salvation?

What COULD the future hold?

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IIAPS Profile Mission and services

IIAPS Mission

The mission of IIAPS is to raise standards in the procurement profession

This is achieved by providing benchmarking and competence assessment & development for organizations and individuals

Certificates & Belts in Basic &

Advanced Purchasing & Supply

Qualifications

PSCM Index

Organizational Benchmarking

ICA Index

Training & Purchasing Academy Support

Competence Assessment

Competence Development

Shared Learning Roundtables & Advisory Board Meetings

Consulting (Implementation) Support

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For a full list of current Advisory Board members please see www.iiaps.org/advisory.html

IIAPS ProfileCompany & Client References

IIAPS programs are developed in conjunction with 90+ multinational companies serving on our Advisory Board, for example:

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IIAPS Profile Global assessment, training, certification, people development

IIAPS offers globally (and locally)

Competence Assessment:(PSCM Index & ICA Index)

E-Learning: 60 + e-learning modules available 24/7

E-Simulation: online simulation training & category management improvement environment

Classroom Training: in English and in local languages (including English, French, German, Chinese etc) & development of comprehensive Procurement / Supply Chain Academies)

Certification: NVQ to Level 4/5 MCIPS; or IIAPS International Blue Belt in Purchasing & Supply; or, International Green, Red & Black Belts in Advanced Purchasing & Supply

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Why am I so passionate about this subject?

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My three phases of enlightenment

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Life in big Pharma

Life in biotech

Life as an independent

Early career in automotives and consumer durables

Joined miles/bayer late 70s

Spent 16 years in bigpharma, 8 years in sme drug developers and 7 years as independent they have given me deeply enlightening experiences to share

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Life in big Pharma

Why did we do it that way?

Why is it so difficult to change anything?

Why the scepticism of modern improvement methods?

What is underneath it all?

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Life in biotech

Why are they starting at the wrong end?

.and whos doing the sourcing strategy?

Does anyone knows where all the inventory is?

....and what condition it is in?

Who is looking after transportation and storage?

.what to you mean I am!?

They think Im in charge of shopping too!

.but carry on regardless

Supply chain management was something they did in warehouses not something to think about when you were developing drugs

Looking after the status and condition of inventory was for the contract manufacturer wherever I n the world they may be

T & s is why I was taken on you know how to ship it dont you?

Vanguard incident the ultimate insult

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Life in big Pharma

Why did we do it that way?

Why is it so difficult to change anything?

Why the scepticism of modern improvement methods?

What is underneath it all?

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Supply-chain complexity abounds

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3 suppliers of each starting material just in case

1 supplier of API with 1 coming on board

No supplier of DP coming on board.

No packaging supplier(s) and launch approaching.

Information, information, information.

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Different groups at each contactor

Number of documents duplication, opportunities for error

Technical agreements, supply agreements

Life as an independent

All dressed up and nowhere to go

The Milton Park experience

My glucose buddy

My needle free injection buddy

Accepting the inevitable

Enlightenment reigns

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How did it get into all this trouble?

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What my Friends think

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if Airlines had similar process capability to pharma would have 2 crash landings per day at most major airports

Experts say as much as one-quarter of ingredients purchased in China by Western companies come from unknown sources.

"Why don't we place the actual ranges on drug bottles?"on 81 mg aspirin, the label would state: "dose between 72.9 and 89.1 mg.

These are taken form FOMDI say who they are

Basic principle is that generally accepted oharma works between 2 or 3 sigma 70,000 defect per million

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What my Friends think (contd)

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If salt in food had the same API content variation as a drug tablet ....it would range from flavorless to inedible

Coke and Pepsi, made with pharma process capability may taste the same more often than not! Or they would have merged by now and be called Pepsi-Coke!

imagine the chaos in our supermarkets if food and beverage companies generated the same percentage of recalls that pharma does ?

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The patent starting pistol

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The starting pistol initiates behaviours aimed at reducing financial impact of failures and preparing for a race to approval

Bang!!!

Picture of the frighteningly high attrition rates and timescales involved

Somewhere in early stage research molecule is patents gun goes off and raced for the clinic

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The find it, file it, flog it approach.

Eureka!

Is it safe?

seems to be

Is it active?

seems to be

Lets get into the clinic FAST!

better make some for tox studies then.

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Enter the patent fairy

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Bye bye my baby

Better make a batch for pre-clinical then

Hope she realises Ill be watching her

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Making enough for pre-clinical

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Supply chain thinking?

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Typical issues emerging

Scarce/bespoke materials specified.

Limited sourcing options (starting materials and API)

Inappropriate dosage forms.

Contractors with insufficient capacity or capability.

Poor process yields.

Weak compliance with technical agreements.

Analytical Methods not adequate.

Shipping/storage conditions not adequately defined.

Incorrect value declarations to customs.

Poor contractor relationships.

Channel management not considered.

the list goes on, and on, and..

Severe disconnection between sponsor company and its supply chain partners due to supply chain neglect.

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Pharma as it was, and now is

1970s

Vertical integration

Local presence in the company market

Mainly small molecule

2010s

innovator, virtual, biotech, generic/bio-similars, speciality Pharma

Biologics

Markets and supply locations globalize

The vicious circle of outsourcing

Disconnection

Innovations cost real money

Opportunities for error

Price escalation from lock-in

Control over lead times

Tactical, arms length

Mass outsourcing

Rapid expansion of contractor base

Rise of Virtual pharma

Drives growth in contractors

Drive s growth in

Virtual Pharma

Dis-integration of the supply chain

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Outsourcing begins in earnest..

Where are we now?

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Integrity issues

Economically motivated adulteration Heparin, supplied by Baxter, found to be adulterated, with reports of 574 adverse events and nine patient deaths estimated

J&J/McNeil placed under a Consent Decree after numerous recalls associated with supply chain issues.

Novartis shells out hundreds of millions $ in manufacturing issues

Shortages in US/EU supply chains result in governments, patient advocacy and general public searching questions.

Security issues..

Cargo theft and diversion

Abbott hit by $4m diagnostics theft in USA (June 2011)

Eli Lilly warehouse thieves make off with $76m haul (March 2011)

Counterfeiting Operation Singapore, largest counterfeit operation in EU, where 2 million doses of counterfeit medicine enter UK supply chain in 2006/7.

FDA is still concerned that the drug supply is increasingly vulnerable to diversion of legitimate drugs (drugs illegally circulated outside the legal distribution system ie stolen or sold illegally) and concerned about the influx of counterfeit drugs- as both present significant risks to public health. Rx-360 Newsletter September 28 2011

The fall-out.

Crippling impacts in the areas of patient safety, brand image and reputation, costs of remediation, customer service and investor confidence.

A UNIVERSAL CRY FOR CHANGE!

From regulators, governments, other competent authorities and patient advocacy groups.

What has been the response?

EU implements Falsified Medicines Directive.

EMA consults on dramatic tightening of GDP/GMP

FDA pens Pathway to Global Safety and Quality.

US Congressional Committees investigate.

President Obama wades in on drug shortages.

US Pharmacopeia consults on new Chapter < 1083 >.

PEW Charitable Trust writes report After Heparin.

GS1 Global Traceability Standard for Healthcare (GTSH).

Modernization the route to salvation?

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The 21st Century Initiative

Pharmaceutical cGMPs for the 21st Century A Risk-Based Approach:

Desired state:

A maximally efficient, agile, flexible pharmaceutical manufacturing sector without extensive regulatory oversight.

Dr. Janet Woodcock, the U.S. Food and Drug Administration's Deputy Commissioner for Operations

Where have we been since then???

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Laymans QbD (ICH Q8) and PAT

QbD Concepts

Quality should be built in by design

Focus on product knowledge and process understanding

Establishment of design space

Provide opportunities for flexible regulatory approaches

Risk-based regulatory decisions

Real-time quality control and less release testing

Process improvement within design space without further review

Reduction in post-approval submissions

PAT tools facilitates introduction of QbD

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History of industrial improvement

Industrial Engineering

Total Quality Management (TQM)

World Class Manufacturing (WCM)

Theory of Constraints (ToC)

Lean and 6 sigma

Toyota Production System (TPS)

Systems Thinking

Deming wrote the book!

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What did the Toyota Production System teach us?

NUMMI study, Womack & Jones The Machine That Changed the World

Based on Toyota Production System (TPS)

Reduce time between getting order and money in

Respect for people

Continuous improvement

Five principles

Many parallels with TQM, WCM, TOC, etc.

Relate to modernization

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Five Principles of Lean Thinking

1. Specify value from the standpoint of the end customer by product family.

2. Identify all the steps in the value stream for each product family, eliminating whenever possible those steps that do not create value.

3. Make the value-creating steps occur in tight sequence so that the product will flow smoothly toward the customer.

4. As flow is introduced, let customers pull value from the next upstream activity.

5. As value is specified, value streams are identified, wasted steps are removed, and flow and pull are introduced, continue until a state of perfection is reached in which value is created with no waste.

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Process Village v Value Stream

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Traditional functional layout solid dose

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Key points:

Large batches

Produce to forecast

High in-process inventory

Defects are hidden

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Value stream alignment solid dose

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Key points:

Schedule pacemaker only.

Set rate at TAKT (Production rate required to match rate of consumption in the market place.

Pull from the pacemaker (Kanbans and supermarkets)

Solve production problems (A3 Management)

Take out variation (SPC).

Reduce defect rates on incoming materials.

Use Single Minute Exchange of Dies (SMED) to reduce cycle time

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What COULD the future hold?

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Overview of a development process

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Safety

Efficacy

Quality

Principles of Prototyping

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Design prototype based on full stakeholder involvement, including marketing, manufacturing, procurement, key suppliers

Allocate overall management responsibility for the programme

Discovery research stays with prototype testing - iterative

Focus on manufacturability of compounds using predictive methods

Build a deep understanding of material and process capability

Institutionalise risk management into development programmes

Build an outline of the end-to-end supply chain

Principles of Commercial Supply

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Safety

Efficacy

Quality

GMP/GDP mind-set from the start: Good Supply-chain Practice - GSP

Change emphasis from validation to process understanding/capability

Place responsibility for defective work on the producers not the quality function

Re-define the role of quality into improvement activities

Deploy PAT

Become business process oriented and quality systems aware

Institutionalise risk management into supply chain

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Some radical concluding thoughts

Turn the development process on its head put patient-use first

Dont award patents for molecules until they are working prototypes

Supply chain for clinic and the market should be under one responsibility - with strong SCM competencies

Teach SCM principles at University to our chemists, pharmacists etc.

The IND/CTA CMC review process should require a higher level of understanding of the compound and its manufacturability

More radical concluding thoughts

Companies intent on making a financial exit before commercialization should prove the supply chain foundation is sound

Big Pharma should demand supply chain integrity from the companies they do licensing deals with

Regulations wont solve the issues, and in EU they are likely to make matters worse.

Big Pharma CEOs must step up to the plate and make change happen learn from Toyotas handling of the fo0t pedal incident (scientists eventually found no defects in Toyota vehicles and put it down to driver error)

Generic Supply-Chain

-Material Flow-

API

Supplier 4

Tablets

Supplier 7

Finished

Packs

Supplier 9

CTS &

Storage

Supplier 11

Investigator

Sites

API

Supplier 5

CTS &

Storage

Supplier 10

Marketing

Partners

Tablets

Supplier 8

Regional

Depots

Starting

Material A

Supplier 2

Starting

Material A

Supplier 3

Starting

Material B

Supplier 4

Starting

Material B

Supplier 5

Starting

Material B

Supplier 6

Starting

Material A

Supplier 1

CTS Labels

Supplier 12

Packaging

Supplier 13

Bottles

Supplier 14

In-Place

Planned

Generic Supply-Chain- Material Flow -

APISupplier 4

TabletsSupplier 7

Finished PacksSupplier 9

CTS &StorageSupplier 11

Investigator Sites

APISupplier 5

CTS &StorageSupplier 10

Marketing Partners

TabletsSupplier 8

Regional Depots

Starting Material ASupplier 2

Starting Material ASupplier 3

Starting Material BSupplier 4

Starting Material BSupplier 5

Starting Material BSupplier 6

Starting Material ASupplier 1

CTS LabelsSupplier 12

PackagingSupplier 13

BottlesSupplier 14

In-Place

Planned

II

Oversee process

development.

Contract Ops Manuals

(COM)

Master Batch Record

review.

Pharm Ops

MPS model.

Boundary scenarios

Supply agreements

Risk Assessments.

Supply Chain

Territory.

Market responsibility (Co-

Prom?).

Annual rolling fcorecast.

POs

Anti-counterfeiting.

Trade dress definition.

PartnerChem Ops

Methods development

Methods Transfer

Review of test results

Analytical

Master Validation

Protocols

Batch record review

Material disposition

Shelf life determination

QA

Oversee process

development.

Contract Ops Manuals

(COM)

Master Batch Record

review.

Buy to spec.

commercially available

Identity check

Release testing

CofAs

Starting

Materials

Shelf life starting point.

Hold time(s)

Stability data

Drug Product

Shelf life/re-test

API

Registered shelf life

Need to store buffer

inventory for partner

(x months)?

Packaged

Product

Store product to GMP

Distribution

Centre

Make print-ready artwork

GNE/OSI approval

Compatible with

packaging contractor

needs

Artwork Origination -

Contact UK

Concept

artwork

Print ready

artwork

Updated monthly

schedule (per

supply agreement)

IIIIIIII

Hold starting materials &

API

Real time inventory

Transfer order from

Supply Chain

Secure GMP

Store

Need material specs

Samples required

Flexibility to deal with

changes

Packaging

Printers -US

Inventory report

Monthly

rolling

forecasts

Purchase

order

Schedules

for review

Artwork

Samples

Schedules

CofA

CofA

CofA

MBR

creation

& approval

MBR

creation

& approval

Batch recordBatch record

Manufacturing schedule

Batch

record

Request

to ship

Material disposition status

Request to ship

CofACofA

MBR creation

& approval

MBR

creation

& approval

Batch

record

Invoices

Inventory

report

Analytical Methods

Patients