interphex 2013 presentation-highly potent and poorly soluble product manufacturing contract with...

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


10 Modern 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


15 NanoCrystal 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 Case Study: Highly Potent, Poorly Soluble Product

Manufacturing Contract 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 Case Study: Highly Potent, Poorly Soluble Product



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







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 ?



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




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

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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

[email protected]

[email protected]

www.alkermes.com/contract


interphex 2013 presentation-highly potent and poorly soluble product manufacturing contract with...

Health & Medicine

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