Ray Scherzer

FDA ACPSOctober 26, 2005

Breaking with Tradition:

The Manufacturing Challenges Ahead!

2

Setting the stage

• The Traditional Pharma Business Model … changes underway

• Our current technology

• The challenge ahead!

• A vision of the future

• What can you do??

3

The 70s, 80s and 90s … the traditional model

Double Digit G

rowth

+

+

Profits, $$$$$

Challenging Regulators

4

Industry pressures today

Pharma Industry

Regulatory Scrutiny

Attrition

Payer resistance

PoliticsPricing

Generics&Re-importation

5

Fundamental change in regulatory framework

Past

• Avoid change

• Quality “tested in”

• Regulatory fear

• Silo organisations

• Empirical science

Future Opportunities

• Innovation

• Good science

• Collaboration

• Efficiency

• Quality by design

• Real time release

Regula

tory

hurdle

sR

egulatory

hurdles

PATCGMPsCritical

path

6

Regulatory changes

• Major shift by FDA

• Dedicated Pharma inspectorate

• Approvals and inspections focused on scientific and engineering principles

• Hiring physicists, chem engineers, C&I engineers, statisticians ... Plus!

• Empirical methods are last resort

7

Significant impacts

• Higher scrutiny of existing products

• Higher expectations for new products

“If you can’t explain how your manufacturing processes work in the first 25 pages of your submission … the approval process will become much more difficult!”

Moheb Nasr, FDA, Director Office of New Drug Chemistry …

8

The changing pharma business model

DiscoverDevelop

TestLaunch

Market

80s: 7 -8 yrs

90s: 8 -10 yrs

00s: 10+? yrs

$500m

$800m

$1,700m

Launch costsLaunch time Avg. ROI, %

9 -10

5

> 10

9

Today’s business is much different than yesterdays!

The Industry will and is changing!!

10

CurrentTechnology

11

DESCRIPTIVE KNOWLEDGE

CORRELATIVE KNOWLEDGE

CAUSAL KNOWLEDGE

MECHANISTICKNOWLEDGE

1st Principles

Control and release against process signature

Establish processEstablish processoutlineoutline

Prediction of performance (in-vivo)

Correlate process inputs and outputs

Relate critical process variables to quality attributes of finished product

2

1

3

5

4

Extent of knowledge

Manufacturing process knowledge

Industry

12

V Blenders: lab and pilot plant scale

13

Commercial scale

14

“We’ve got a few problems going from lab scale to full scale commercial”

15

The Challenge Ahead!!

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DESCRIPTIVE KNOWLEDGE

CORRELATIVE KNOWLEDGE

CAUSAL KNOWLEDGE

MECHANISTICKNOWLEDGE

1st Principles

Control and release against process signature

Establish processEstablish processoutlineoutline

Prediction of performance (in-vivo)

Correlate process inputs and outputs

Relate critical process variables to quality attributes of finished product

2

1

3

5

4

Extent of knowledge

Manufacturing process knowledge

Industry target

17

Significant gaps exist:

• Manufacturing and scale up sciences

• Unit operation technology and control

• Academic training & skilled resources

• Industrial organization and structure

• Correlation to in vivo performance

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First steps: Unit operation science

• Reaction• Crystallization• Drying• Separation• Particle engineering

• Formulation• Dispensing• Blending• Granulation• Compression• Coating• Filling• Aseptic operations• Packaging

Material Handling, Analytical

Industry basic unit operations

19

Unit operations goals

• Well understood platform technologies• Develop the science of all unit operations• Fully instrumented• Closed loop control … fully automated• Material interactions (formulation & devices)• Predictable scale effects• Design/use the right equipment

• Predict performance without extensive experimentation

• Math modeling to speed design• GOAL: Final testing to confirm operations

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Once UOs understood and platform technologies developed, then

Integrated Process Designs

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Integrated process design: Objectives

• Aligns with FDA’s Quality by Design Concept• Link “Platform Technologies” in an integrated process

design• 1ST step of API to primary pack and device performance• Identify CCPs that affect up and down stream ops • Control systems will manage variability within the process• Link CCPs to traditional release testing; i.e. dissolution,

assay, CU, ACI• Produce in spec product by monitoring and controlling

critical parameters … rather than end point testing• Obtain real time release

PROCESS FLOW DIAGRAM…….PANADOL CONTINUOUS PROCESS

BAG UNLOADING STATION

DISPENSING ROOM

IBC-01

IBC-01

HO-01A HO-01BHO-02

HO-05 HO-04 HO-03

IBC-02

F-01

F-02

F-04 F-03F-05

F-06

F-07

BL-03

BL-03

GR-01 GR-02

DR-01

M-01

BL-02

BL-01

SIFTED & PREWEIGHEDSTARCH MAIZEPOVIDONE

POT. SORBATE

PREGELATINIZED STARCH

CAFFEINE

PANADOL

GRANULATE

BASE

TABLET PRESS

SIFTED & PREWEIGHEDSTARCH MAIZESTEARIC ACIDMAG. STEARATETALCAVICILAC-DI-SOL

MOISTURE

PURIFIED WATER

METERING PUMP

1

2

6

7

7

89

33

5 5

4 4

2 2

TABLETS TO COATING

AHUAHU AHU

10

HO-03

SODIUM BICARB

PARACETAMOL

DELUMPER

FRESH AIR

PARACETAMOLPREGELATIZENED STARCHSODIUM BICARBONATECAFFEINE

IBC-01

IBC-02

SIFTER

SIFTER

SIFTER

SIFTER

SIFTER

DISPENSING ROOM

BL-03

11

DEDUSTER

METALDETECTOR

Integrated process design

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Engineering models would:

• Process design tool of preference• Rapid evaluation of excipients, DS, formulations,

equipment, environmental, devices, etc.• Narrow alternatives in silica• Reduce scale up trial and error … focus testing on high

probability results … time & money!! • After confirmation, use model to demonstrate full

process understanding … regulatory expectation• Would be the basis for continuous improvement studies

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The future manufacturing vision!

• Fundamental understanding of the science• Develop mfg scale processes … before registration• Small scale, contained, dedicated, automated, continuous

processes • Late stage customization• On line measurement and control• Real time release • Product plants … not component plants• Leverage relationships … internal, academia, industry,

regulatory agencies to develop the science

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Gaps in skills and facilities exist

• Manufacturing sciences

• Powder technology

• Chemical / Process engineers

• Rheologists (non Newtonian fluids)

• Physicists

• Spectromisists

• Chemometricians

• Process development pilot plants (not CT PPs)

• “Soft skills” & Business skills

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Some current activities

• Industry/Company Culture changes underway• Empirical to fundamental sciences• Industry pressures key driver• External work lays foundation (FDA, ASTM, CAMP,

ISPE, IFPATma)

• Develop the next level of manufacturing science• PAT and cGMPs for 21st century• Pharma professional of the future … engineering +• Universities need to develop and teach the science

• Capitalize on today’s situation to forge an even stronger future

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Your role in this:

• Support/create means for fundamental research in the Pharma manufacturing sciences

• Encourage students into science & engineering careers

• Encourage universities to create the programs• Be consistent and science based in your activities• Give this priority and attention

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Questions