Interphex 2013 presentation-Highly potent and poorly soluble product manufacturing contract with 100% OTIF

Alkermes Contract Pharma
Services
Highly Potent, Poorly Soluble Product
Manufacturing Contract, with 100% OTIF
#501
April 2013
Fidelma Callanan
Senior Director, Marketing and Commercial Development
© 2013 Alkermes. All rights reserved.

Case Study
− Technology Transfer of a poorly water soluble highly potent, compound
with registration batches completed in six months and validation
batches initiated within 12 months of the transfer
Experience Gained
What outsourcers want in a tech transfer
Contents
2

Certain statements in this presentation may constitute forward looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995. Although Alkermes believes
that these statements are based on the reasonable assumptions within the bounds of its
knowledge of its business and operations, there are a number of factors that may cause
actual results to differ from these statements. For instance, there can be no assurance that:
(i) the company will be able to manufacture and successfully commercialize its products; (ii)
clinical trials of the company’s product candidates will continue as planned or be successful,
or be completed on a timely basis or at all; (iii) the company or its partners will continue
development of any product candidate to the point of receiving marketing approval from
regulatory authorities; (iv) the FDA or, if approved, be commercialized successfully. For
additional factors, which could cause actual results to differ from expectations, reference is
made to the reports filed by the company with the Securities and Exchange Commission
under the Securities Exchange Act of 1934, amended.
3

Dublin
Waltham Athlone
Wilmington
Gainesville
Headquartered in Dublin, IRE
− Merger Elan Drug Technologies and Alkermes Inc
G&A and R&D in Waltham, MA
Manufacturing and R&D
− Athlone, IRE
− Gainesville, GA
− Wilmington, OH
NASDAQ: ALKS
4
Alkermes plc- a little history

5
Alkermes Contract Pharma Services –
Who we are
Alkermes Contract Pharma Services provides solid oral dosage product development, scale-
up and manufacturing services as well as sterile fill finish capabilities to the global
pharmaceutical market.
With over 40 years in the service business, we have proven expertise in drug product
development, process design and process improvements, tech transfer and commercial scale
cGMP manufacturing of solid oral and injectable dosage forms.

3 facilities with clinical and commercial scale cGMP manufacturing of solid oral
and injectable dosage forms
Wide range of analytical capabilities
FDA and EMA licensed sites in both
the U.S. and EU
− Also supply products to many other countries
around the world including Japan and BRIC territories
Extensive experience preparing and filing regulatory applications with
agencies in the U.S., EU, and Japan
6
Extensive Development, Scale-up and Manufacturing
Capabilities in the U.S. and Europe

7
Strong Partnering Capabilities Across Pharma Sector

8
We have solved product challenges of over 40 products
Since 2001 we have successfully developed and/or tech-transferred and manufactured
12 leading pharmaceutical products for the U.S. and International markets including:
We are currently tech-transferring three additional products with global market launches
in 2013

9
Athlone, Ireland
Athlone, Ireland Facility
− Located on 40 acre site, the
facility has approximately
505,000 square feet of space
− Operates under cGMP
standards
− FDA/EMA Licensed
− Formulation through scale-up
and full scale manufacturing
− 10 different products are
manufactured and/or
packaged at this site at
present. Manufactures
product for US, European
and Asian markets
− The facility has an equipped
capacity of 2 billion unit solid
oral doses

10Modern Facilities to Fit Your Precise Product
Requirements
Modern Solid Oral Dose and Facilities including:
− Milling
− Screening
− Blending
− Wet granulation (high shear and fluid bed) for
solvent and aqueous processing
− Bead coating (organic solvent and aqueous
based) using Wurster FBP, CF granulation and
pans
− Tabletting
− Film coating and sugar coating
− Encapsulation (powder, bead, dual fill)
− Finished product packaging (bottle/blister/vial)
including cold chain capability
− Controlled substance manufacture
− Release testing – EU QP Service available for
U.S. clients doing business in Europe

Case Study
Experience Gained
Contents
11

Product and Technology
Project History
Why Alkermes Athlone Site was Chosen
The Challenge
The Process
The Result
12
Case Study:
Highly Potent, Poorly Soluble Product Manufacturing Contract

www.elandrugtechnologies.com
13
NanoCrystal® technology involves reducing drug to particles the nanometer size. By
reducing particle size, we increase the drug’s exposed surface area. We then stabilize
the particles to maintain the formulation’s particle size.
The result - drug is easier to dissolve and absorb.
A nanometre is a billionth of a metre, or a millionth of a millimetre - dimensions less
than 1/100,000 the diameter of a human hair!
• Technology applied to this product is Alkermes’ NanoCrystal® Technology
• The technology is a formulation and manufacturing approach for poorly water soluble drugs – the
compound involved was poorly water soluble (poor oral bioavailability) and also highly potent
Technology
Case Study: Highly Potent, Poorly Soluble Product
Manufacturing Contract
13
Product
• Poorly Water soluble highly potent compound for chronic use

14
The Technology Applied – NanoCrystal® Technology
A proprietary formulation and manufacturing approach for the delivery of
poorly water-soluble drugs
• Most dosage forms possible (e.g. oral, parenteral and nasal)
• Increases oral bioavailability & reduces fed/fasted variability
• Decreases time to onset of action
• High drug loading possible (up to 30-40% active)
• Combine with other technologies (e.g. controlled release)
• Low viscosity liquid preparations
• Potential for improved chemical stability compared to solutions
• Uses standard pharmacopoeial materials
• Manufactured to commercial scale
NanoCrystal® technology involves reducing drug particles to the nanometer size. By reducing particle
size, we increase the drug’s exposed surface area. We then stabilise the particles to maintain the
formulation’s particle size.
Schematic representation of the
NanoCrystal® technology

15NanoCrystal Colloidal Dispersion® Milling Process
NCD
Recirculation
Vessel
Recirculation
Pump
Milling
Chamber
Milling Media
Agitator
Mechanical
Seal
Motor

16
Technology Applied
- Allowed for Improved Patient Adherence And Convenience
• Originally available only as an oral solution
• Had to be stored in a refrigerator
• Had to be reconstituted using a syringe for dose accuracy
• The formulation required a complicated reconstitution procedure
• Had to be mixed with water or orange juice just prior to administration

17
Benefit to Patient:
• By applying our NanoCrystal® solubility enhancing technology, we …..
– Improved dissolution and oral bioavailability
– Enabled preparation of a tablet
– Eliminated complicated reconstitution and storage procedure associated
with original form
– Enhanced patient convenience and acceptability
– Provided Patient Choice
Before
After
Annual In-market sales at peak in excess of $350M, majority in re-formulated tablet form
“Simplifying drug regimes
is known to improve
patient compliance
(adherence)”
Technology Applied
- Allowed for Improved Patient Adherence And Convenience
17

Improved Patient Adherence And Convenience

Project History
Donor site shutting down in U.S. and so partner was seeking an alternative site to
manufacture commercial product
The compound was both poorly water soluble and also highly potent and had an
Occupational Exposure Limit (OEL) of 0.15μg/m3 and Adverse Drug Event (ADE) level
of 7μg/day and exhibited caracogenic/developmental/reproductive effects (not cytotoxic)
Manufacturing required set up of commercial scale high energy nanomilling to produce a
low bioburden aqueous bulk dispersion for further processing into a tablet form
CASE STUDIES
19

Why the Alkermes’ Athlone Site was chosen
History of manufacturing complex dosage forms
U.S. FDA/EMA inspected site
History of optimizing and manufacturing products for partners for multiple territories
Historical knowledge of process involved – innovators of the NanoCrystal® technology
(albeit at a different site)
Established Relationship with Commercial Partner
20

The Challenge
Highly Potent API – complex handling requirements
− Determining OEL and compound categorization
− Industrial Hygiene (IH) exposure assessment, control verification and sensitive IH analytical
methods
− Engineering controls and maintenance
− General and specific handling guidance
− Procedures and Training
− Medical Surveillance
Poorly water-soluble compound requiring NanoCrystal® Technology
− Technology was developed at another site (within the company)
− NanoCrystal® technology was not commercially manufactured at the site
Required very low bioburden processing
− Cleaning requirements
− Sanitization requirements
− Process controls
21

The Process !

23
Process
Design and
Development
Process
Optimization
Process
Scale Up
Product
Launch
Commercial
Supply
Development Services
Manufacturing Services
Quality Assurance
The Process
Systematic Tech Transfer process with defined work flow applied
Collaborative team representing all functions
Thorough review of available data from donor site
− Aimed at identifying gaps at recipient site through a comparison matrix
− Detailed assessment to evaluate and define programme of work required
Technology implemented at Irish site
− Primary areas: process equipment, manufacturing systems and analytical methods

24
Process
Design and
Development
Process
Optimization
Process
Scale Up
Product
Launch
Commercial
Supply
Development Services
Manufacturing Services
Quality Assurance
The Process
Process Characterization and engineering runs executed
Demonstration batch executed against pre-defined acceptance criteria for
confirmation of successful transfer
Stage Gate Review readiness for validation performed prior to validation
campaign
Process Risk Assessment to define validation approach
Validation campaign

Why Successful ?

26
Why So Successful?
Technology used for the product is robust
− NanoCrystal® technology is a well understood process
− Well designed and well understood equipment train and analytical methods
− Impact of process parameters on process are known
− Process models have been developed
− Process is scaleable from gram to hundreds of kilos
Expertise in isolator technology
− On-site engineers experienced in implementing isolator technology for dispensing and powder
transfers
Milling process very suitable to highly potent compounds
− Equipment used (mills etc) are contained, so execution of a containment strategy relatively easy
Expertise on-site in aseptic processing including microbiology laboratories
− Ensured the development of robust cleaning, sanitization and sterilization methods to achieve low
bioburden product
Transfer followed a structured approach
− With well defined in-site procedures and embedded across all departments

27
The Result
Registration batch manufactured within six months of transfer
initiation
Successful inspections
− U.S. FDA PAI executed
− Irish Medicines Board inspection
Validation batches initiated within 12 months of transfer initiation
Reliable, high yield process that consistently delivery 100% OTIF
No interruption of supply to patients over transfer period
Now available in over 100 countries worldwide

Case Study
Experience Gained
Contents
28

29
Experience Gained
Following successful tech transfer of the high potent
compound we have won other business in high potency
manufacture
− With our experience in tech-transferring the compound in Case Study here,
gained relevant and required experience to tech-transfer a product
incorporating
− A granulation tablet
− Tablet coating
− For high volume production

30
Experience Gained
Robust Containment Strategy
− Primary – high containment processing, transfer and sampling areas
− Secondary – segregated processing rooms
− Tertiary – segregated suite, security access controlled, CCTV, HVAC single
pass air, double HEPA exhaust, pressure cascade, fogging shower area
− Contained dedicated waste water facilities
− On-site PPE, RPE for HPAPI handling
− Segregated high containment dust extraction systems
− Training for staff, medical surveillance, proactive IH monitoring
− Development of safety Risk Management approach for a new product
introduction
− Establishment of an integrated life-cycle risk management approach using a
New Product Introduction (NPI) model

New Product Introduction Model Safety Risk Management
– developed and executed
31

32
Experience Gained
NPI Model allowed for
− A robust approach to be followed
− Integrated approach
− Effective and systematic way in implementing technical transfers and
commercial manufacture of all products including HPAPIs for partners
The Irish facility now has capability to handle APIs to OEL of
0.1μg/m3 at development through to commercial high scale
manufacture

Case Study
Experience Gained
Contents
33

What outsourcers want in a tech-transfer?

Selection
Criteria
Capacity
Business
Model
Regulatory
Facility &
Equipment
EH&S
Costs
Schedule
Technical
Experience
Project
Management
Quality
David Krist Janson, Sweetwater Construction Corp
Site Selection Criteria for Contract Service Providers
35

Paul Duffy, Pfizer Global Supply (PGS), on site selection
criteria
36

The Manufacturing Authorization Holder (MAH) and all participants in the
supply chain must ensure that their own standards and focus on quality are
robust
The MAH is ultimately responsible for the quality of their products and therefore
must ensure a focus on quality exists in their supply chain partners
21 CFR 200.10 says that FDA regards independent contract facilities “as an
extension of the manufacturer's own facility. “
ICH Q10 says “The pharmaceutical company is ultimately responsible to
ensure processes are in place to assure the control of outsourced activities and
quality of purchased materials.”
The cost of getting it wrong….
Quality – the big issue
37

It is expected that Contract Manufacturers will take the
lead to
− Create and sustain an effective quality system
− Focus the organization on continuous improvement
− Know about issues and trends that may affect product quality via
a strong notification process
− Ensure that patient safety drives product quality decisions
− Ensure sufficient resources are available to maintain quality
Ensuring the right quality culture
38

Collaborative Approach – The Fundamentals
39
Our Approach to Successful Partnerships
Collaboration
Provide
Quality
Services
client wants
Transparency
On time, at
the right
price
Performance
(Value
creation)
In quantity
they require
Shared Values
Partner and Collaboration

Our Offering
Quality and Compliance
Very successful audit season – no
483s from audit in Sept 2012 with
U.S. FDA
Experience – technical fit
44 years in service business
Expertise – Timeline, track
record
40+ products developed and/or
manufactured for partners
Price – cost competitive
Customer Relationships –
7 top 10 pharma partners of ours,
multiple partners
C(D)MO Selection Criteria
40
15 16
5 4 1
9
13
11
8
3
4
14
5 11
12Experience/technicalfit
Qualityandregulatory
compliance
Timeline,trackrecord
Price
Customerrelationship
C(D)MO Selection Criteria
Rank 1 Rank 2 Rank 3
Source: High Tech Business Decisions

41
Our Legacy of Quality
2012 audits in Irish plant
Korean FDA May, Successful PAI
IMB (Irish authorities) July, successful GMP
AMVISA (Brazil), July, successful PAI
US FDA September, successful GMP

Over 40 years experience and
expertise manufacturing and
developing products for our
partners
42
Our Collaborative Approach
– Our Promise to our Partners
Speed to market
Compliant, reliable and cost efficient supplier
Effective, robust and efficient technical
transfers
Product and process optimization
Life cycle management strategies
Dedicated customer service
Exceptional compliance track record

43

44
Our Promise to our Partners
- Our Collaborative Approach
Speed to Market
Compliant, reliant and cost efficient supplier
Effective, robust and efficient supplier
Effective, robust and efficient tech transfers
Product and process optimisation
Life Cycle Management strategies
Dedicated customer service
Exceptional track record
Thank you and visit our booth at 4037
Alkermes Contract Pharma Services
Monksland, Athlone. Co Westmeath
Ireland
Phone: +353 90 649 5126
Fidelma.Callanan@alkermes.com
contract@alkermes.com
www.alkermes.com/contract

Interphex 2013 presentation-Highly potent and poorly soluble product manufacturing contract with 100% OTIF

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