1. “On-Demand Manufacturing of Pharmaceuticals”
Perspectives and Learnings in Life Sciences Innovation: Opportunities for Growth
Bayan Takizawa
Chief Business Officer, CONTINUUS Pharmaceuticals, Inc.
March, 2018
Good morning everyone, and thank you for coming to my talk.
My name is Bayan Takizawa, and I am the Chief Business Officer at CONTINUUS Pharmaceuticals.
Today I would like to talk to you about End-to-end continuous manufacturing of pharmaceuticals – from concept to commercialization.
Finalist 2013
Technology Innovation Award

2. Efforts at CONTINUUS Pharmaceuticals Perspectives and Learnings
Agenda
Background
Current Pharmaceutical Manufacturing
Integrated Continuous Manufacturing (ICM)
Efforts at CONTINUUS Pharmaceuticals
Perspectives and Learnings
Summary
The way I structured this presentation as follows:
I will start by talking about the current standard of manufacturing in the pharmaceutical industry, batch manufacturing, and its limitations and problems.
Then I will talk about continuous manufacturing efforts in the pharmaceutical industry, focusing on Integrated Continuous Manufacturing, or ICM.
Then I will discuss some commercialization effort underway at CONTINUUS Pharmaceuticals.
And finally, I will provide a brief summary.
12/24/2018
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3. The Problem: Batch Manufacturing
Inefficient processes cost pharmaceutical manufacturers $ Billions/year
Lead times > 200 days, issues with quality
Active Pharmaceutical Ingredient (API)
Drug Product (DP), tableting
So, what is the problem with the current manufacturing paradigm?
With batch manufacturing, the current standard, large batches of intermediates or products are made at a single time, requiring large volume equipment.
These intermediates then are stored, tested, and shipped to the next unit operation; the whole process is fragmented, and occurs across different business units.
In fact the process is divided into two distinct sections – upstream synthetic steps and downstream drug formulation steps.
The two processes are often not coordinated, so often, there are downstream steps taken specifically to correct for undesirable physical-chemical properties introduced upstream.
The result is a very long process, often requiring hundreds of days. Is this necessary?
A recent study estimated that the pharma manufacturing industry leaves approximately $50 B on the table every year.
Most importantly, this process is not very robust, which often leads to quality infractions.
WALL
Raw materials
Tablets
API
API
Multiple, disconnected batch steps
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4. Consequences of Outdated Manufacturing: Compromised Patient Care
And these quality infractions have consequences.
One of them drug shortages.
Every year, there are approximately 200 drugs on the FDA drug shortage list, most of them due to manufacturing and supply chain problems.
And this impacts human health care.
This is a study published in the NEJM oncologists…
138 (78%) switched chemotherapy regimens
135 (77%) substituted a different drug partway through treatment regimen
76 (43%) delayed treatment
65 (37%) excluded some patients
51 (29%) omitted doses
35 (20%) reduced doses
29 (17%) referred patients to another practice
Of 214 oncologists who regularly prescribe chemotherapy, >80% were unable to prescribe the preferred chemotherapy agent because of shortages at least once during the previous 6 months.
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5. Motivations for Change in Pharmaceutical Manufacturing
Pharmaceutical manufacturing technologies have not changed for decades and are not sustainable
Majority of blockbuster drugs going off patent
Increasing R&D expenditures, but same # of drugs
Pricing pressure (e.g. ACA)
Personalized medicines
Stringent regulations, demand for improved quality
Fortunately, there is motivation for change from within the pharmaceutical industry; here are some important contributing trends:
Many of the billion dollar blockbuster drugs are going off patent. Not only that, but the pathway for biosimilars is taking shape, so companies will start to lose margin on their biologic products as well.
A recent study from Deloitte showed that to develop new drugs, it is taking longer and costing more – whereas it used to take several hundred million dollars, there are drugs on the market now that took over a billion drugs to develop.
As our own health system tries to become cost effective, and there’s more vertical integration, there will be more pressure to reduce costs on items like pharmaceuticals, as an example, more and more patients are switched to generics.
There has been more of a focus on personalized medicine, as opposed to the blockbuster that everyone can take.
And finally, the FDA and other regulatory agencies are demanding increased adherence to quality standards; this has been evidenced by the multiple plant shut downs and warning letters in recent years.
So, clearly there is a need for novel and more efficient manufacturing techniques.
There is a need for novel and more efficient manufacturing techniques.
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6. Over a billion dollars has been spent on continuous manufacturing efforts over the past ten years by big pharma
In fact, over the past ten years, large pharma has spent over $1B in continuous manufacturing initiatives.
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7. Continuous Manufacturing Solutions: Matching Risk Tolerance with Reward
end-to-end Integrated Continuous Manufacturing
Reward ($, efficiency, quality)
integrated continuous upstream and/or integrated continuous downstream (API is isolated)
But companies are taking different approaches.
This graph demonstrates the range of approaches that companies are taking.
On the lower left, we see that some companies are taking a limited and targeted approach – for example, employing a single continuous unit operation in an otherwise batch strategy. This approach is less risky, but also limited in terms of reward.
Moving up and toward the right, some companies are employing integrated upstream and/or downstream continuous systems. An example is Vertex, where their downstream drug formulation steps are integrated into a continuous process. However, with these and other cases, there is still the disconnect between upstream and downstream.
And up here and to the right, this is where we are. With Integrated Continuous Manufacturing, or ICM, there is a single, seamless, fully-automated process from start to finish. And this is where we see the industry evolving to – to truly realize the benefits of continuous manufacturing.
continuous unit operations
Risk (time, $, regulatory hurdles)
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8. ICM Demonstrated 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
The proof-of-concept of CM at MIT
2011: Novartis to launch the ‘Technikum’
Translate MIT research into commercial manufacturing
2012: Launch of CONTINUUS Pharmaceuticals
Broader commercialization of Integrated Continuous Manufacturing
Exclusive license for technologies developed at MIT (co-exclusive with Novartis)
So, this technology was actually tested and proven already – at MIT.
In 2007, Novartis invested $65 M to change the way small molecule drugs are manufactured.
It is important to note that this was a white-paper innovative project, and not just technology improvement, based on existing pharmaceutical manufacturing technologies.
In 2011, a pilot plant was revealed, which was extremely successful. We were able to produce tablets that were similar to the marketed drug.
Based on this successful plant, Novartis launched a commercial plant in Basel Switzerland, just as we launched CONTINUUS in 2012.
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9. ICM: How it works 1 2 3 Integration Know-how Plug-and-Play Unit Ops
Separate Unit Operations
Reactor
Filter/dryer
Tableting machine 1 1 2 3 4 5
Integration Know-how
Raw
Materials 1 2 3 4 5
Module 1A
Module 2A
Module 3A
Module 4A
Module 5A 2
Plug-and-Play Unit Ops
Module 1B
Module 2B
Module 3B
Module 4B
Module 5B
So, there are three main components to Integrated Continuous Manufacturing:
First, there’s the integration know-how – this isn’t merely physically connecting the unit operations. Rather, you need to intelligently integrate them, so you understand how the performance of each unit operation affects the performance of downstream unit, and, more importantly, the quality of your final product.
Second, there’ the modularity of the system that allows scale-up. So, you need to be able to use these novel unit operations across different drug classes, and have multiple unit operations at different stages. For example, a plug-flow reactor may be useful for certain reactions, but not all.
And third, there’s the utilization of novel unit operations – again, these are truly continuous and are able to be integrated into these ICM processes.
‘Modular and Portable’ 3
Novel MIT Unit Operations
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10. Key Process Indicators
ICM: Advantages
Courtesy of NVS-MIT Center
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
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11. ICM: Supply Chain Advantages
Development
Manufacturing
Patient Care
Sales/Distribution
Shorter development times
Reduced scale-up 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 globally
But the advantages go just beyond manufacturing and operations when you adopt a truly integrated continuous manufacturing paradigm.
The unit operations are small, and they allow us to hit process space not available in large batch manufacturing.
For example, we can run reactions at high pressure and temperatures, which could be very dangerous at high batch volumes.
In addition, you do not need to scale-up your manufacturing processes as you go across clinical trial phases – you just need to manufacture with the same system for a longer period of time – this could significantly reduce drug development time.
And finally, and most importantly, all of this has positive impacts on the patient, as our products have higher quality assurance, as well as a significantly decreased risk of a drug shortage.
Throughout the supply chain, ICM adds significant value
12/24/2018
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12. Efforts at CONTINUUS Pharmaceuticals Perspectives and Learnings
Agenda
Background
Current Pharmaceutical Manufacturing
Integrated Continuous Manufacturing (ICM)
Efforts at CONTINUUS Pharmaceuticals
Perspectives and Learnings
Summary
The way I structured this presentation as follows:
I will start by talking about the current standard of manufacturing in the pharmaceutical industry, batch manufacturing, and its limitations and problems.
Then I will talk about continuous manufacturing efforts in the pharmaceutical industry, focusing on Integrated Continuous Manufacturing, or ICM.
Then I will discuss some commercialization effort underway at CONTINUUS Pharmaceuticals.
And finally, I will provide a brief summary.
12/24/2018
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13. CONTINUUS Efforts At a Glance
Projects
Commercial Clients (end-to-end, targeted solutions)
Phase I/II/IIB NSF SBIR Grants
FDA Contract ($4.4 M/3 years)
Local incentives
Team
From 2 in 2012 to 23 in 2018
Facility
Shared space in 2012, >5,500 sqft in 2018
>$16 M
raised
And here is a case study for a DESIGN project we performed at CONTINUUS Pharmaceuticals.
We were tasked to develop an ICM process for a large-market generic compound, and here are the results:
We were able to achieve all of the target product profiles for the client’s product. For example, the required purity.
We reduced the projected costs by 35-40% - it is important to note that this was a highly efficient batch process that had been optimized over many years of production.
We were able to increase the yield, and reduce the number of unit operations, the solvent used, the process time, and the required footprint.
The client was very happy with these results, and so we have moved to the DEVELOPMENT phase.
12/24/2018
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14. End-to-End DESIGN Project: High volume generic (>5,000 MT/year)
And here is a case study for a DESIGN project we performed at CONTINUUS Pharmaceuticals.
We were tasked to develop an ICM process for a large-market generic compound, and here are the results:
We were able to achieve all of the target product profiles for the client’s product. For example, the required purity.
We reduced the projected costs by 35-40% - it is important to note that this was a highly efficient batch process that had been optimized over many years of production.
We were able to increase the yield, and reduce the number of unit operations, the solvent used, the process time, and the required footprint.
The client was very happy with these results, and so we have moved to the DEVELOPMENT phase.
12/24/2018
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15. Targeted Solutions: Batch Filters
Characteristics of commercially available Nutsche filter units e.g., MAVAZAG filter:
Large units
Thick wet cake
Operate in batch/semi- continuous
Longer processing time required
Nutsche filter
Moving on to filtration and drying.
Here are some commercial filters and dryers that are currently employed by the industry.
Some of their characteristics include:
They are large
They process thick wet cake, often many inches thick
They operate in batch/semi-continuous
They require long residence times, often many hours
(Agglomeration and degradation mainly for dryer)
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16. Filter Top View (camera)
Targeted Solutions: CONTINUUS Filter
And here is a couple of pictures of our continuous filter.
Mind you, this particular unit is small enough to fit on your back, and it has the throughput capacity of close to 17 tons/year, if operated on a 24/7 basis.
Filter Side View
Throughput: 10 g/hr to > 2 kg/hr
Residence time: ~ 1 min
Footprint: 60 cm x 40 cm
Filter Top View (camera)
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17. FDA Contract: Objective
How drug quality can be monitored and improved via fully automated and Integrated Continuous Manufacturing (ICM)
As I mentioned, we believe that the regulatory agencies are interested advancing the state of pharmaceutical manufacturing.
In fact we recently started a project with the FDA – a 3 year, $4.4 M project.
This is really evidence that the agency is interested in learning more about continuous manufacturing.
The objective of this project is to better understand how drug quality can be monitored and improved through fully automated and integrated continuous manufacturing.
We will do this by developing a fully integrated pilot line through which we will study critical phenomena, such as traceability.
This work will hopefully inform future regulatory guidelines on continuous manufacturing.
12/24/2018
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18. Efforts at CONTINUUS Pharmaceuticals Perspectives and Learnings
Agenda
Background
Current Pharmaceutical Manufacturing
Integrated Continuous Manufacturing (ICM)
Efforts at CONTINUUS Pharmaceuticals
Perspectives and Learnings
Summary
The way I structured this presentation as follows:
I will start by talking about the current standard of manufacturing in the pharmaceutical industry, batch manufacturing, and its limitations and problems.
Then I will talk about continuous manufacturing efforts in the pharmaceutical industry, focusing on Integrated Continuous Manufacturing, or ICM.
Then I will discuss some commercialization effort underway at CONTINUUS Pharmaceuticals.
And finally, I will provide a brief summary.
12/24/2018
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19. Building the Right Team
Board of Directors
Salvatore Mascia, CONTINUUS
Founder & CEO
Bayan Takizawa, CONTINUUS
Co-Founder, Chief Business Officer
Jonathan Fleming, Oxford Bioscience Partners
Former Managing Partner of Oxford Bioscience Partners
Andrea Semprini Cesari, IMA
VP, IMA Active
Prof. Bernhardt L. Trout, MIT
Director, Novartis-MIT Center for Continuous Manufacturing
Board of Advisors
MIT Profs. Charles L. Cooney, Allan Myerson, and Timothy Jamison
World renewed experts in continuous processes, pharmaceutical manufacturing, and flow chemistry
Thomas van Laar and Ajaz Hussain
Former Head of Global TechOps at Novartis; Former FDA Deputy Director, Office of Pharmaceutical Science
With that, I’d like to acknowledge the great team we have assembled at our company.
Many are or were key leaders at the Novartis-MIT Center.
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20. vs. vs. Choosing the Right Location 12/24/2018 CONFIDENTIAL

21. EQUIPMENT MANUFACTURER ICM PROCESS FOR PHARMA CLIENTS
Forming Strategic Partnerships
EQUIPMENT MANUFACTURER
CONTROL/AUTOMATION
ICM PROCESS FOR PHARMA CLIENTS
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22. Funding Considerations
Amount of funding
Type of funding:
Family/Friends
Angels
VCs
Strategic
Incentives
In-state/out-of-state
Government opportunities
SBIRs (e.g., NSF, NIH)
Other agencies (e.g., BARDA)
Fedbizopps.gov
Other
Competitions
With that, I’d like to acknowledge the great team we have assembled at our company.
Many are or were key leaders at the Novartis-MIT Center.
12/24/2018
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23. Funding Considerations
Amount of funding
Type of funding:
Family/Friends
Angels
VCs
Strategic
Incentives
In-state/out-of-state
Government opportunities
SBIRs (e.g., NSF, NIH)
Other agencies (e.g., BARDA)
Fedbizopps.gov
Other
Competitions
With that, I’d like to acknowledge the great team we have assembled at our company.
Many are or were key leaders at the Novartis-MIT Center.
12/24/2018
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24. Lessons Learned Assemble the right team
Listen to your prospective clients
Be ready to pivot
Be passionate
Be resilient
Be frugal
Be patient
Look for non-traditional opportunities
Understand challenges/barriers, and address them
With that, I’d like to acknowledge the great team we have assembled at our company.
Many are or were key leaders at the Novartis-MIT Center.
12/24/2018
CONFIDENTIAL

25. Efforts at CONTINUUS Pharmaceuticals Perspectives and Learnings
Agenda
Background
Current Pharmaceutical Manufacturing
Integrated Continuous Manufacturing (ICM)
Efforts at CONTINUUS Pharmaceuticals
Perspectives and Learnings
Summary
The way I structured this presentation as follows:
I will start by talking about the current standard of manufacturing in the pharmaceutical industry, batch manufacturing, and its limitations and problems.
Then I will talk about continuous manufacturing efforts in the pharmaceutical industry, focusing on Integrated Continuous Manufacturing, or ICM.
Then I will discuss some commercialization effort underway at CONTINUUS Pharmaceuticals.
And finally, I will provide a brief summary.
12/24/2018
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26. Conclusion
ICM and its novel technologies can radically transform pharmaceutical manufacturing
Significant advantages in production lead time (>90%), cost (~30-50%), footprint (>90%), and quality
Modular platform to enhance flexibility in the manufacturing of any dosage form:
Fast dissolving or controlled-release formulations
Novel unit operations to enable integration and improve overall process performance
Real-time, end-to-end model-based process control to consistently achieve high product quality
I hope I have been able to describe how different companies have engaged in continuous manufacturing, and the many benefits of integrated end-to-end solutions.
As I mentioned, it offers significant advantages over current manufacturing methods, including operational advantages.
The platform is modular, and able to process any dosage form.
We utilize novel unit operations that enable integration and enhance system performance.
And the entire process is fully automated, with model-based process control that maintains the process in a tight state of control.
CONTINUUS is advancing the state of ICM through critical projects with pharmaceutical companies and government agencies like the FDA and the NSF.
Finally, with our partnerships, we are making this vision come true.
It would be great if we can develop an ICM plant here in Japan with a Japanese company.
Key projects with pharmaceutical clients and government agencies
Strategic alliances with I.M.A. and Emerson (New England Controls), MOU with JGC
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27. Thank you! The CONTINUUS Pharmaceuticals Team
Thank you very much for your attention.
I would also like to thank JGC for allowing me to speak here today, and specifically Harada-san.
I would be happy to answer any questions you may have.
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