Alkermes high potency capabilities

© 2014 Alkermes. All rights reserved. © 2014 Alkermes. All rights reserved.

High Potency Manufacturing Capabilities - Four Decades Providing Outsourcing Solutions to our Partners

March 2014

© 2014 Alkermes. All rights reserved.

2 Alkermes Contract Pharma Services –

Who we are

As part of Alkermes plc, Alkermes Contract Pharma Services provides solid oral dosage process development 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 clinical and commercial scale cGMP manufacturing of solid oral and injectable dosage forms including high potency manufacture. We have a blue chip client list including 7 of the world’s top 10 Pharmaceutical Companies.

© 2014 Alkermes. All rights reserved. © 2014 Alkermes. All rights reserved.

High Potency Manufacturing

- Facilities

- Processes

- Equipment

- Services


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Athlone, Ireland – solid oral dosage facility equipped to manufacture highly potent compounds

Facility on 40-acre site, FDA/EMA licensed

Formulation to scale-up to full-scale manufacturing

Multiple products manufactured and/or packaged

Global markets – supply product to 100+ markets including U.S.,

European, Asian and BRIC territories

Equipped capacity of 2 billion solid oral dosages annually

Currently manufacturing two highly potent compounds for partners

Installed capability to handle APIs to potency of 0.1µg/m3


5 Modern Facilities to Fit Your Precise Product

Requirements

Modern Solid Oral Dose Facilities in Athlone

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

− Tableting

− Film coating and sugar coating

− Encapsulation (powder, bead, dual fill)

− Finished product packaging including cold chain

capability

− Release testing – EU QP Service available for U.S.

clients doing business in Europe


Category 1: Low toxicity

Category 2: Intermediate toxicity

Category 3: Potent

− 3A (default)

− 3B

Category 4: Highly potent

Alkermes Compound Categorization 6


Alkermes Compound Categorization 7


Understand the risks – toxicity, eco-toxicity, process safety etc.

Use “banding” systems intelligently to deal with early stage materials or to direct us to a control strategy

Design and build well

Use skilled and experienced staff

Measure the effectiveness of our controls and “verify” that our banding system actually delivers

Apply a systematic, science-based approach to safety

Our Approach to Managing Potent Compounds 8

Category 3 Criteria*

(default category) • High acute and chronic

systemic effects

• Irreversible effects

• High potency

• “Genic” materials and/or

sensitizers (Carcinogenic,

Mutagenic, Teratogenic,

Developmental Tox,

Reproductive Tox)

• Poor or no warning

properties

• High degree of medical

intervention required

• Immediate and delayed

onset of symptoms

• Well absorbed by mucous

membranes, via inhalation or

by the skin

* One or more of the above criteria

may place a material into this category


Installed capability to handle APIs to potency of 0.1µg/ m3:

− At commercial high volume scale

− At development scale (discovery to phase III)

All new product introductions (NPIs) assessed and project managed in an integrated, risk management lifecycle approach:

− Occupational health, safety & toxicology

− Process safety

− Environmental and sustainability

− Security

Our Approach to Managing Potent Compounds 9


New Product Introduction Model Safety Risk Management

– developed and executed on-site 10


Closed and Contained Process for Potent

Compounds

Nova Septum sampler – used to removed in process liquid samples in a contained manner

IH monitoring results achieved <0.1µg/m3.

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Products handled at commercial scale

Category Typical OELs (µg/m3)

Types of technologies applied

1 500 • LAF booths • LEV • High shear granulation (aqueous and solvent) • Bead coating (aqueous and solvent) • Milling • Screening • Blending • Tablet compression & coating • Encapsulation

2 10-500

3a 2 • High containment dispensing, transfers & sampling • NanoCrystal Colloidal Dispersion® (NCD) products • Dispending, screening, fluid bed coating • Encapsulation

3b 0.15-0.5 • Isolator, High shear granulation, blending, compression and coating • NCD products

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Project History

Donor site capacity issue where the company was seeking an

outsourcing manufacturing partner for commercial supply

Product was classed as a highly potent compound and had an

Occupational Exposure Limit (OEL) of 0.5 µg/m3, an Adverse Drug

Event (ADE) level of 5µg/day, and exhibited teratogenic and eco-

toxic properties

The product had a low Minimum Ignition Energy (MIE) of <3mJ

Manufacturing required contained dispensing, high shear

granulation with microwave drying, blending, compression and

coating processes

Case Study: Potent API, High Volume Process 13


Procedures

The following steps were undertaken to ensure containment

procedures were in place to manage the safe manufacture of the

HPAPI product:

Determination of OELs and compound categorization scheme

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



The Result

The HPAPI product has been successfully tech-transferred onto

the Alkermes Athlone, Ireland site. From our involvement with

this project, a number of significant milestones were realized.

− Execution of a robust containment strategy:

− Primary: high containment primary processing areas, high containment

transfers and sampling areas were built (or established)

− Secondary: segregated processing rooms were built

− Tertiary: dedicated segregated suite, security access controlled,

Closed Circuit Television (CCTV) remote monitoring, Heating

Ventilation and Air Conditioning (HVAC) single pass air (safe change in

room), double High Efficiency Particulate Air (HEPA) exhaust, pressure

cascade and fogging shower were all put in place



The Result (Continued)

− Organisation of contained and dedicated waste water facilities

− Bringing on-site Personal Protection Equipment (PPE) and Respiratory

Protection Equipment (RPE) suitable for HPAPI handling

− Establishment of segregated, high containment dust extraction systems

− Undertaking of extensive training & competence development for all staff

involved in the manufacture and handling of the highly potent product

− Establishment of medical surveillance, proactive IH & environmental

monitoring

− Enforcement of an integrated life-cycle risk management approach using a

New Product Introduction (NPI) model (Next Slide).



New Product Introduction (NPI) Model Safety Risk Management

– developed and executed on-site

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Success

The Highly Potent API (HPAPI) product has been successfully tech-

transferred onto the Alkermes Athlone, Ireland site

The use of the NPI model allowed for a robust approach to be

followed when bringing HPAPIs onto the site and proved effective in

implementing tech-transfers and commercial manufacture of all

products including highly potent compounds for partners

As a result of this partnership, the Alkermes Athlone site now has

the capability to handle APIs to potency of 0.1 µg/ m3 at

development (Discovery to Phase III) and commercial high volume

scale

Alkermes now successfully handles two commercially available

potent compounds on its multi-product facility in Athlone for partners.



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Our Legacy of Quality

Recent successful regulatory audits from, US FDA, UK MHRA, Brazil’s ANVISA and South Korean KFDA

Exceptional compliance track record no major observations from last set of

audits, including no 483s from last US FDA audit on-site.


Highly skilled workforce

Capability to scale-up and optimize formulation to commercial scale including

difficult to make solid oral products

On-site tech transfer to commercial manufacturing

Experience, proven track record, infrastructure and capacity in solid oral

dosage form manufacture including high potency and difficult to make

compounds

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World-Class Facilities through to Commercial Scale

Process

Optimization

Process

Scale Up

Product

Launch

Commercial

Supply

Manufacturing Services

Quality Assurance


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Analytical Capabilities

We offer a complete range of analytical capabilities

to support CMC activities

Our highly qualified chemists and scientific staff

operate in fully equipped, best-in-class facilities that

include:

− Raw Material, In-Process and Finished Product release

testing laboratories

− Microbiology laboratories

− Bioanalytical laboratories

− Stability incubators and testing facilities

− Physiochemical characterization

− Method Development laboratories

− Method Validation laboratories

Full range of analytical technologies available

Analytical Technologies

Chromatography

• HPLC-UV, HPLC-PDA,

HPLC-RI, UPLC-UV, UPLC-

PDA

• GC-FID, GC-TCD, GC-MS

Dissolution

• Automated UV and HPLC

• Fibre Optic UV and HPLC

Characterization

• Particle Size e.g. Malvern,

Coulter, Camsizer, HIAC

• DSC and TGA

• Viscosity

Physical

• Moisture Analysis –

Volumetric and Coulimetric

• Disintegration, Hardness,

Friability

Microbiological

• Endosafe

• Vitek 2

• Rapid Micro System


22 Lean 6 Sigma/Operational Excellence Initiative

- Driving Excellence in Everything We Do

Operational Excellence (OE) Initiatives

− Trained Problem Solvers (Black Belts, Green Belts & Yellow Belts) who anticipate,

overcome and improve workflow challenges

− Value Stream Structure

− Standardized Workflows

− Process Mapping

− Improved Set-Up/Turnaround Times

− Lean Lab

− Energy Conservation

A suite of performance metrics are measured and available to you. OE Program now running for five years.

4

black

belts

40 green belts

350 yellow belts

Strategic OE Staff Training Plan


23 Our Collaborative Approach

– Our Promise to You

Experience and Expertise

• 45 years providing contracting services to our partners

Exceptional Compliance Track Record

• Successful audits from all regulatory agencies including US

FDA, EMA, Anvisa, Japanese regulatory agency

Compliant, Reliable and Cost Efficient Supplier

• Embedded Operational Excellence and Lean 6 Sigma

• Established Key Performance Metrics (KPIs) tracking product

performance

World Class Modern Facility

• Established record in solid oral dosage manufacturing

• Experience in high potency manufacturing

• Located in low tax jurisdiction (LSJ)

Committed to your manufacturing needs

• Long term commitment to manufacturing your outsourcing

requirements

45 years experience and

expertise manufacturing and

developing products for our

partners


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Contact Us

Alkermes Contract Pharma Services

Monksland

Athlone

Co Westmeath

Ireland

Fidelma Callanan

Snr Director Commercial Development

[email protected]

Phone: +353 9064 95126

Website: www.alkermes.com/contract

Health & Medicine

Alkermes high potency capabilities