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.