Luciana Mansolelli

June 2012

The Journey from GMP to Pharmaceutical Quality Systems

Disclaimer

Some of the information contained in this presentation is confidential. Accordingly, Novartis respectfully requests confidential treatment with respect to this presentation and any related materials under the Freedom of Information Act. Further, if any person (including any governmental employee) should request the opportunity to inspect, copy or otherwise obtain Novartis confidential information, Novartis requests that it be immediately notified of any such request, furnished with a copy of all written materials pertaining to such request (including the request itself) and given advance notice of any intended release so that it may, if deemed necessary or appropriate, pursue available remedies.

What is a good quality system?

ANTICIPATE!

A harmonized pharmaceutical

quality system applicable across

the lifecycle of the product

emphasizing an integrated

approach to quality risk

management and science

(Q10)

Quality beyond compliance

Effective Quality Systems ensure:

Rigorous clinical study protocols, execution, oversight and interpretation of all results

• Well understood drug safety/efficacy profile in support of label

• Robust formulations, manufacturing processes and control

strategies

• Complete and transparent NDAs/ANDAs based on good

science

• Consistent high-quality product

Meaningful specifications and measures

GMP compliant Quality Systems

Reliable processes and Batch Execution

Effective Quality Systems ensure:

Storage and distribution systems that maintain product quality and integrity

Predictable, consistent access to

necessary products

• Compliant and ethical sales and marketing practices.

• Sensitive responsive pharmacovigilance program

Why do Quality Systems fail?

A recent Benchmark indicated:

•Benchmark indicated underinvestment for several years in quality training and skill building. As a consequence overstretched quality personnel and insufficient knowledge of quality practices across its network as its growth accelerated.

Lack of quality capabilities

•Accelerated growth and cost pressures increased. Despite at one time being best in class, these companies lost focus on quality: quality issues began when quality and compliance personnel were cut as part of a strong focus on containing costs. Rapid growth of 60 percent between 2000-08 led to a weakening of quality controls with suppliers, due to pressure to expand supply and control costs increase

Loss of quality focus as company

• Responsibility for quality was pushed to the Quality function as operators were increasingly asked to focus on delivery. The supplier network grew, the transparency and ownership of a consistent set of quality practices were lost.

Lack of quality ownership

•As quality issues began to surface at Company A, the focus was placed on immediate issue closure rather than root cause problem solving; even when multiple similar issues emerged, these were downplayed and common causes were not identified. The lack of adherence to quality practices also prevented underlying issues from being uncovered and therefore addressed.

Weak processes and lack of root cause problem solving

•By not investing in manufacturing improvements and quality systems, these companies created environments that were not compliant with regulatory guidelines.

Lack of proactive measures

So why do they fail?

Reactive instead of proactive management systems to prevent problems, mitigate risk and foster continuous improvement.

Drive to low-cost suppliers of ingredients/components and services due to inadequate due diligence, risk assessment, qualification and governance... with potential significant direct and indirect risks

Industry and Consumer Litigation prevalent... with expressive costs

Unprecedented number of compliance issues resulting in regulatory Warnings, “Voluntary” Programs or Legal Action.

1- Fit for Purpose

2- Product Assessment and Metrics

3- Quality System Elements

4- Governance / Risk Management

Are the manufacturing strategies

adequate to support the

business?

Are the products and processes in

state of control?

Does the Quality System result in

sustainable compliance?

Does governance & risk

management show predictable &

consistent decisions ?

Critical leadership role in terms of shifting the paradigm * Source:Quantic methodology

Focus on diagnosing critically products,

systems, people

Effective Quality Systems will drive the required evaluations

Even when the failure is in the Quality System execution itself

Pharma Industry Today The Promise of Q10

Deviations

Rejects

Data gaps

Few surprises

Data-driven

Competitive advantage

Quality beyond compliance

Example 1 Use PQS for the intended purpose

“APR/PQR”

Use PQS for the intended purpose

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102

99

96

In

div

idu

al V

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_X=99,294

UCL=101,384

LCL=97,204

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2

1

0

Mo

vin

g R

an

ge

__MR=0,786

UCL=2,568

LCL=0

6560555045

101

100

99

Observation

Va

lue

s

104,4102,6100,899,097,295,4

LSL USL

LSL 95

USL 105

Specifications

1021009896

Within

O v erall

Specs

StDev 0,696753

C p 2,39

C pk 2,05

Within

StDev 0,882446

Pp 1,89

Ppk 1,62

C pm *

O v erall

1

1

Process Capability Sixpack of TERBINAFINE HCL

I Chart

Moving Range Chart

Last 25 Observations

Capability Histogram

Normal Prob PlotA D: 0,531, P: 0,168

Capability Plot

Use PQS for the intended purpose

61554943373125191371

102

99

96

In

div

idu

al V

alu

e

_X=99,294

UCL=101,384

LCL=97,204

61554943373125191371

2

1

0

Mo

vin

g R

an

ge

__MR=0,786

UCL=2,568

LCL=0

6560555045

101

100

99

Observation

Va

lue

s

104,4102,6100,899,097,295,4

LSL USL

LSL 95

USL 105

Specifications

1021009896

Within

O v erall

Specs

StDev 0,696753

C p 2,39

C pk 2,05

Within

StDev 0,882446

Pp 1,89

Ppk 1,62

C pm *

O v erall

1

1

Process Capability Sixpack of TERBINAFINE HCL

I Chart

Moving Range Chart

Last 25 Observations

Capability Histogram

Normal Prob PlotA D: 0,531, P: 0,168

Capability Plot

Rolling review

Data collection

Control Charts

Capability Six-Pack

Set next release limits

Self-diagnose target problems

A journey of mindset changes

AS COMPETITIVE ADVANTAGE

EXCELLENCE

COMPETENCE

UNDERSTANDING

AWARENESS

INNOCENCE

Competitive advantage through

prevention of quality issues

Quality mindset in all functions

Design quality in and anticipate

issues

Quality systems and metrics

reveal reality, and drive action

Quality Unit will identify the

issues

Quality mainly outsourced to

regulators

Description

“I’m good because I passed

the last inspection”

“It’s good as long as quality

approves it”

“We review quality along with

other aspects of the business”

“Tolerance to problems and

mistakes is minimal”

“Failure to integrate quality is

not even an option”

Mindset

…our job is to shift the paradigm! Once we may have been here…

New mindset in Q and Operations

Science, “not only” compliance

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102

99

96

In

div

idu

al V

alu

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_X=99,294

UCL=101,384

LCL=97,204

61554943373125191371

2

1

0

Mo

vin

g R

an

ge

__MR=0,786

UCL=2,568

LCL=0

6560555045

101

100

99

Observation

Va

lue

s

104,4102,6100,899,097,295,4

LSL USL

LSL 95

USL 105

Specifications

1021009896

Within

O v erall

Specs

StDev 0,696753

C p 2,39

C pk 2,05

Within

StDev 0,882446

Pp 1,89

Ppk 1,62

C pm *

O v erall

1

1

Process Capability Sixpack of TERBINAFINE HCL

I Chart

Moving Range Chart

Last 25 Observations

Capability Histogram

Normal Prob PlotA D: 0,531, P: 0,168

Capability Plot

…on old platforms!

We keep having new products...

Invest in new technologies

Root Causes of Recalls

Intermixing

14%

Packaging 11%

Other

Aim to make the product "impossible" to be wrong:

e.g. “enforce” vision systems

But again, understand where your processes stand...

FMEA for each packaging line, re prevention of product

mix-up, including human intervention (intentional mix-

up). Reliability

Administrative

Quality

Operators

Procurement

Supply Chain

Manufacturing

Research & Development

Quality Lever

1000:1

PRODUCT

DEFINITION 100:1

PRODUCT

DESIGN 10:1

PROCESS

DESIGN 1:1

PRODUCTION

PRODUCT

IMPROVEMENT

LOW VISIBILITY

LOW REWARD

HIGH VISIBILITY

HIGH REWARD

Approach to Quality by Design

Product X

Product

Regulatory approval

Application to new products

A fad

Diluted across many projects

Over-reaching

REAL…

NOT…

•Flow

•Integration (end to end)

•Integrated control strategy

•Leaps, not incremental

•Incorporate new technology

•Promote mindset change

Think the “impossible”

106

105

104

103

102

101

100

99

98

97

1 10 19 28 37 46 55 64 73 82 91

Ind

ivid

ua

l V

alu

e

Observation

Launch Volumetric fill on tabletting process

Sieve size change Recirculation channel change

Understand the product/process

I Chart of Assay Product X % by Changes

106

105

104

103

102

101

100

99

98

97

1 10 19 28 37 46 55 64 73 82 91

Ind

ivid

ua

l V

alu

e

Observation

Launch Volumetric fill on tabletting process

Sieve size change Recirculation channel change

I Chart of Assay Product X % by Changes

Understand the product/process

64 73 82 91

Understand the product/process

ATTACK THE BASE!

1

10

100

10,000

100,000

Recalls

Batch Rejections

Critical deviations/Complaints

Deviations

Non-Q. focused behaviors

Understand the leading and lagging indicators

ATTACK THE BASE!

External Traditional focus

for management

Early Warnings

New focus for management

Internal

Implementing a people development strategy, linked with a

manufacturing strategy and underlying organization and

product plan

Formalize Quality Planning to Diagnose Periodically Continuously Periodically

Metrics & KQIs Monitoring & Evaluation

CAPAs Correction & Prevention

Self Inspections Internal Audits External Audits Regulatory Intelligence

Q Risk Assessment Site/Unit

Product Review APR-PQR

Annual

Quality Plan

Q-Systems Review

All of this requires leadership and

management support

Cross functional committees Q Unit functional committees

Site

Division Division

Compliance

Site

Compliance

& Audit

Systems

& Standards

Executive Q. Team

Development Tech Ops Development Tech Ops

CEO & Executive Team

To Successful

Continual Improvement Q10 5 KEYS

The Promise of

Q10 The Promise of

Quality can lead improvement

Q10 The Promise of

Quality anticipates issues

Q10 The Promise of

Quality anticipates issues

CA PA

The traditional view of quality systems based upon lagging indicators must be shifted to a focus on leading indicator in anticipation of risks.

37

Our job to shift the paradigm

Our responsibility with our patients for

reliable supply of high quality products.

Back up

38

Quality beyond Compliance

1. Achieve product realisation

2. Establish and maintain a

state of control

3. Facilitate continual

improvement

(Q10) HOLISTIC

„

applies…throughout the product

lifecycle(§3.1)

• Pharmaceutical Development

• Technology Transfer

• Commercial Manufacturing

• Product Discontinuation”

Quality beyond Compliance

INSIGHT

(Q10)

“…applies to the systems supporting

the development and manufacture of

pharmaceutical drug substances (i.e.,

API) and drug products, including

biotechnology and biological

Products

…application is appropriate and

proportionate to lifecycle stage

...includes…new and existing

products.”

Quality people can lead improvement

Lay foundations for continuous

improvement

Lead innovations in manufacturing

The patient is the customer

41

Innocence Understanding

Dominant

Focus

Absent Detect/Correct

Dominant

Result

Unpredictable Outcomes Chronic Firefighting/Right

Second Time

Failure Mode Surprises Brute Force

Cost of

Quality

External Failures/Internal Failures Internal Failures/Appraisal

42

Excellence Competence

Correct/

Prevent

Prevent Correct/Prevent

Right First

Time/

Consistent &

Predictable

Never Fails/

Adaptive and Intelligent

Right First Time/Consistent and

Predictable

Risk of

Decay

Pursuit of Perfection Risk of Decay

Appraisal/

Preventive

Preventive Appraisal/Preventive

EXCELLENCE

COMPETENCE

UNDERSTANDING

AWARENESS

INNOCENCE

Quality Culture Maturity Model

Quality mainly outsourced to

regulators

I’m good because I passed

the last inspection

EXCELLENCE

COMPETENCE

UNDERSTANDING

AWARENESS

INNOCENCE Quality mainly outsourced to

regulators

Quality Unit will identify the issues

Quality Systems and metrics reveal

reality, and drive action

Quality mindset in all functions

Design Quality in & anticipate issues

Competitive advantage through

prevention of Quality issues

I’m good because I passed

the last inspection

It’s good as long as Quality

approves it

We review Q. along with other

aspects of the business

Tolerance to problems and

mistakes is minimal

Failure to integrate Quality is

not even an option

Quality Culture Maturity Model

EXCELLENCE

COMPETENCE

UNDERSTANDING

AWARENESS

INNOCENCE

“Diagnose” where you are!

Quality mainly outsourced to

regulators

Quality Unit will identify the issues

Quality Systems and metrics reveal

reality, and drive action

Quality mindset in all functions

Design Quality in & anticipate issues

Competitive advantage through

prevention of all Quality issues

Comprehensive Product Assessment and

Trending (CPAT)

Product X

It is critical that we know where we stand with our

products and processes:

• Assessment of Regulatory Compliance

• Assessment of Quality Systems, e.g.:

•Laboratory Controls

•Equipment Controls

• State of Process Validation

This should happen prior to

any improvement actions.