Presentazione del Dott. Mascia

1. Finalist 2013
“On-Demand Manufacturing of Pharmaceuticals”
Innovation in Pharmaceutical Manufacturing:
Integrated Continuous Manufacturing
Technology Innovation Award
Forum “Future by Quality”
Salvatore Mascia, PhD
June 8th, 2015

2. Motivations for Change in
Pharmaceutical Manufacturing
• Pharmaceutical manufacturing plants and technologies have not
changed since many decades
• Current “batch” pharma manufacturing method is not sustainable any
longer, due to a number of factors:
– Majority of blockbuster drugs going off patent
– Increasing R&D expenditures, but same # of drugs
– Pricing pressure
– Personalized medicines
– Stringent regulations, demanding for improved quality
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There is a need for novel and more efficient manufacturing techniques

3. • Inefficient processes cost pharmaceutical manufacturers
$50 B/year
• Lead times > 200 days, issues with quality
Raw materials Tablets
Multiple, disconnected batch steps
Active Pharmaceutical Ingredient (API) Drug Product (DP), tableting
API API
Nickerson, J.; Macher, J., 2006, http://apps.olin.wustl.edu/faculty/nickerson/results/
Batch Manufacturing of Pharmaceuticals
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4. Tablets out
• Integration of multiple flow steps into one seamless process
• Costs reduced by > 50%, lead times < 2 days, better quality
Raw
materials
(prior to API)
MIT TechReview: http://www.technologyreview.com/news/506511/breakthrough-offers-a-better-way-to-make-drugs/
Integrated Continuous Manufacturing (ICM)
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5. • Use of Novel Process Technologies to
Eliminate “Correction Steps” and Enable Integration
• End to End Integration
• Full Automation with 24/7 Operation
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Vision of “Integrated Continuous Manufacturing”
………more than $1 B invested in the last 10 years among major pharma companies,
in related but “different” Continuous Manufacturing Initiatives

6. ICM Background and Current Status
The proof-of-concept of CM at MIT
Courtesy of NVS-MIT Center
2007: Novartis invests $65 M to launch the
Novartis-MIT Center for Continuous Manufacturing
2011: Pilot plant process of Integrated Continuous
Manufacturing in place at MIT
 Actual Novartis pharmaceutical produced
2011: Novartis to launch the ‘Technikum’
 Translate MIT research into commercial manufacturing
 2015 - currently implementing ICM in their TR&D; Technical Operations will be next
2012: Launch of CONTINUUS Pharmaceuticals
 Broader commercialization of Integrated Continuous Manufacturing
 2015 - currently implementing ICM in its development laboratory
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7. MIT Pilot Plant
Courtesy of NVS-MIT Center
1. Continuous flow
2. End to end integration
3. System approach
4. Integrated control strategy
ICM principles:
Features:
• 100g/hr of API
• 2 synthetic steps
• API salt formation & crystallization
• Drug product and coating
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8. Integrated Control System Interface
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9. MIT Pilot Plant: Continuous Advantages
Aliskiren Hemifumarate
Key Process Indicators Batch Continuous
Processing Time (hrs)
300
(200 days lead time)+ 48
Unit Operations 21 13
Number of Excipients 5 2
Environmental Factor
(kg input / kg output)
[25-100]
15
(green manufacturing)
COGS (CapEx + OpEx) x > 30% reduction
Footprint y y/10
+ Includes off line holding, testing and shipping
Courtesy of NVS-MIT Center
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10. 0
200
400
600
800
1000
1200
1400
1600
1800
6 60 160
PlantFootprint(m2)
Million Tablets/Year
Δ = 835 m2
Δ = 1,607 m2
Δ = 180 m2
Footprint vs. Throughput
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11. Item Continuous Process,
% reduction
CapEx 60
Material Handling 60-70
QA/QC 25-50
Waste 50
Utilities 50
Labor 25-50
Raw Materials 0-46
COGS 30-50
~ 70% of cost saving are fixed costs
Integrated Continuous
Manufacturing offers high cost
savings, while delivering high
quality pharmaceuticals.
Courtesy of NVS-MIT Center
Batch vs. Continuous
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12. Joseph Jimenez, CEO Novartis Bill Gates, founder Gates Foundation
Courtesy of NVS-MIT Center Courtesy of NVS-MIT Center
“In the next 25 years, pharma will shift from batch to continuous
manufacturing and make current production methods obsolete”
FDA CDER Director Janet Woodcock at AAPS 2011 (after MIT PoC)
“Continuous Manufacturing will be a
game changer for the industry”
LGO Conference 2012: The Future of Manufacturing in the US
“Great potential for inexpensive
antimalarial medications”
Bill Gates visiting NVS-MIT Center in April 2012
Positive Outlook on Continuous Manufacturing
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13. Financial Impact: COGS
$3.1B
$2.4B
$1.7B
$-
$10
$20
$30
$40
$50
$60
$70
Pfizer Merck Lilly
Gross Margin
COGS saved
by ICM
COGS
$3.3 B
$1.5B
$-
$5
$10
$15
$20
$25
Teva Mylan
(+21.1% net income)
(+40.6%)
(+39.6%)
(+169% net income)
(+241%)
Source: www.google.com/finance
2012Revenue($BUS/year)
Brand-name Pharmaceuticals Generic Pharmaceuticals
Billions of dollars saved every year in cost of goods sold (COGS)
2012Revenue($BUS/year)
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14. Financial Impact: Small-Molecule Inventories
$0.4 $0,3 $0.2
$3,6
$3,1
$1,8
$-
$1
$2
$3
$4
Pfizer Merck Lilly
Inventory
reduction
ICM
Inventory
$0.4 $0.1
$4,0
$1,2
$-
$1
$2
$3
$4
Teva Mylan
2012Inventory($BUS/year)
2012Inventory($BUS/year)
Brand-name Pharmaceuticals Generic Pharmaceuticals
ICM can decrease billions of dollars tied in inventory
Source: SEC filings
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15. Throughout the supply chain, ICM adds significant value
Development Manufacturing Sales/Distribution Patient Care
• Shorter
development times
• Direct transfer from
development to
manufacturing
• Fast to market
• Reduced lead time
• Decreased COGS
• Greater flexibility
during launch
• Small footprint
• Decreased inventory
• Regional
manufacturing and
distribution network
• Increased
responsiveness to
change in demand
• Reduced chance of
drug shortages
• Improved product
quality
Supply Chain Advantages
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16. Barriers Associated with Implementation
Organization/Mindset
Regulatory
Technology
• Industry inertia
• Excess batch capacity
• API and DP plants are
separated
• No current end-to-end
GMP continuous plant
• Need to define a “batch”
• Perceived risk for public
health among reviewers
• Pilot plant level
• Demonstration runs
~ 10 days
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17. From the FDA….
“The greatest regulatory hurdle is the concern by
manufacturers that regulators will balk at implementing
these processes”………
“I don’t know why it’s not more widely used, as this is
the future”
Janet Woodcock – CDER, FDA, at ISCMP 2014, MIT
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18. Our “Vision” of the Future….
• 1st Commercial ICM plant in 2017-18
• ICM will make current batch manufacturing methods obsolete
in 10-15 years
• ICM can be applied to branded or generic drugs without
limitations
• Transition to ICM will be gradual, and ICM lines will be initially
placed in current manufacturing facilities
• Future will see regional distribution of the ICM plants –
ICM lines are modular and portable
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19. Opportunity for Italy with ICM
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Italian Center of Excellence in
Pharmaceutical Manufacturing
Manufacture “off-patent” pharmaceuticals in Italy, and
sell them at a significantly reduced price
MIT Pilot Plant
Benefits to Italy
• Establish a National Center of Excellence
in Pharmaceutical Manufacturing and
create technical jobs
• Lower lead-time for drug production
(90% reduction) with reduced risk of
shortages
• Reduce healthcare costs by decreasing
spend on common “off-patent”
medications *(~$400 M annual savings)

20. Thank you!
The CONTINUUS Pharmaceuticals Team
www.continuuspharma.com
info@continuuspharma.com
Tel: +1.781.281.0226
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