1

2

Pharmaceutical development

Chemical development

Target

therapeutic

area

CANDIDATE

DRUG

• Cancer, immunology research

• Cardiovascular diseases

• Central nervous system diseases

• Metabolic diseases

• Microbial diseases

• Respiratory and Inflammatory diseases

• Viral diseases

DISCOVERY/PIPELINE

Initialsynthesis,

primary andsecondary

screens

Drug metabolismandpharmacokinetics

Toxicology

Pre-clinical development

PHASE I PHASE II

IND CTX

EXPLORATORY

PHASE III

Regulatory

submission Product

licence

Product launch

Post - launch (PHASE IV)

Pharmaceutical developmentPost-launch line extension

development

FULL DEVELOPMENT POST-REGISTRATION

DEVELOPMENT

The Drug Development Process

1

5

7

6

PRIMARY MANUFACTURING

3

2

41. Batching

2. Charging

3. Reaction

4. Separation

5. Filtration

6. Drying

7. Off-Loading

RESEARCH AND DEVELOPMENT

Inhaled

Solid Oral

Suspensions

Solution

Tablet

sHard Gelatine Capsules

Oral suspensions

Injectables / Topical

sSprays / Nasal sprays,Soft Gelatine Capsules

Metered Dose Inhalers

Dry Powder

Inhalers

S

E

C

O

N

D

A

R

Y

P

R

O

C

E

S

S

I

N

G

SECONDARY MANUFACTURING

DOSAGE FORMS

3

1

3

25

7

6

4

1. Batching

2. Charging

3. Reaction

4. Separation

5. Filtration

6. Drying

7. Off-Loading

TYPICAL PHARMA PROCESS

4

0

1

2

3

4

5

6

7

8

9

10

Kg of Waste Generated / Kg of Drug Produced

Solid

Water

Solvent

VOC's

Others

TYPICAL WASTE GENERATION

5

TYPICAL WASTE GENERATION

0

200

400

600

800

1000

1200

1985 1990 2000 2005 2010

Value of API

Value of Waste

US$ b

illion

YearWHO estimates from database

of UNIDO, OECD Health

Data, World Development

Indicators

6

PRESENCE OF PHARMA INDUSTRIES

World Investment Report, UNCTAD, Geneva

7

CURRENT SITUATION

Operation• Batch Processing• Age Old Technology• Catching up with

Technology

Chemistry• Unstable intermediates• Hazardous intermediates• Energetic systems• Green – Red / Red - Green

Engineering• Chemistry to Operation• Process not optimized• Scale-up Challenges

Business• Speed to Market• Highly Risk Averse• Regulatory Challenges• Capital Intensive

8

What could be the best

possible approach to

reduce waste?

9

CONTINUOUS PROCESSING

10

Continuous Mfg of Lam Stg 3-4 Mfg Capacity: 3.5 TPD (1100 TPA)

B2

(New

)CSTR

CSTR

CSTR

Batching

Separator

pH <4.5

pH >6.8

Continuous

DistillationWashing

Extraction

B1 (Retrofitted to PB1 NH)

Crystalliser

4

3500 kg of Lam Stg 4/day

2565 kg/h

3885 kg/h

1297 kg/h

1590 kg/h

2640 kg/h

1328 kg/h

1328 kg/h

1328 kg/h

145 kg/h

300 kg/h

CME

F/D or

Spray Drier

11

PERFORMANCE

12

Batch

Semi Continuous

Continuous

Capacity (TPA) 100 380 1100

Unit Cost (GBP) 693 470 366

% Unit Cost Reduction

25 48 60

Gain in Profit (Million GBP)

22 170 610

COST BENEFIT FOR LAMIVUDINE

13

CONTINUOUS CLAISEN SET-UP

14

• Pilot reactor has been run at 650g/hr of crude product (~4mtpy)

Reactor 1 & 2Volume 120mlOutput 3-4 mtpyCost $15k each

Reactor 3Volume ~1mlOutput 3-4 mtpyCost <$50

Phase separator

PILOT RIG FOR PRAGABALIN(Nitroalkene Reaction)

15

FOOT PRINT OF PRODUCTION RIG

Partial Skid Layout for Single

Product Continuous Facility Primary

Dose and

Blend

Granulation

Drying

Secondary

Dose

Secondary

Blender

Tablet Press

Coaters

7.5 metres

16

0 5 10 15 20 25 30 35

Batch CapEx

Cont. CapEx

Batch OpEx

Cont. OpEx

Cost £m's or £m's/yr

Overall Cost Comparison

CAPEX & OPEX COST BENEFITS

17

OPPORTUNITIES

• Significant cost reduction

• Green Chemistry

• Higher efficiencies / conversions

• Dedicated Plants – Better Planning

• Product Consistency

• Higher Quality

• Safe Operations

• …………………..

18

BARRIERS

• Accidental Discovery vs Systematic Development

• Abundance of required raw materials

• Speed to Market – Make it work!

• Commitment of Environmental Protection

• Regulatory Hurdles – Intermediates

• Stringent Quality Requirements

• Analytical Method Development Challenges

• Technology vs Process Requirement

• Lack of Process Analytical Technologies

• Willingness to do something different…

19

Good News…..

…………..Our Future could be More Greener Than Past….

• 7 out of 10 Pharmaceutical Companies have already a semi continuous process in their operation.

• 3 out of 10 Pharmaceutical Companies are working on Continuous Processing

• 1 out of 10 Pharmaceutical Companies are already very close (or have) a first generation continuous manufacturing in place.