Implementation of a robust Manufacturing Process for a unique liquid formulated Alpha1

proteinase Inhibitor (Human), the recently FDA approved – GLASSIA®

Avi Baziz Kamada Ltd. Israel

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Contents: 1. Introduction 2. The shift 3. Company Strategic Mile Stones History 4. Engineering projects- Plant upgrade 5. Building QA Force and Regulatory Department 6. BLA, CMC, FDA audit, all the way to approval 7. Kamada Unique Purification Process- visiting card 8. Kamada Unique Purification Process - AAT 9. Main AAT Process steps 10. AAT- Main product attributes and advantages 11.Clinical pipeline 12. Next Generation (AAT) Inhaled

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The evolution of Paste IV-1 as a disposable raw material to … an important product for the manufacturing of a highly pure and

unique product The common product in market is lyophilized, mainly because of stability and shelf life constraint of a liquid protein solution. GLASSIA ® is the first liquid formulated product of it’s kind and is robust in a sense that the process is capable to utilize Cohn Fraction IV-1 as well as IV1+4 or even different Various suppliers (Plasma Fractionation sites), will be further detailed.

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Kamada Manufacturing

Facility

$30-$50

~$300

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Fraction IV or IV-1 From Human plasma

The shift

Company Founded

• Company’s Foundation

• Flag Product - Albumin

• Strategy Change

Strategy Change

• Strategic agreements with the American Red-Cross (ARC)

IPO

• Israel’s First public BIO company

• Over 50% of company products are strategic

• Increasing investment in R&D

Entering the US Market

Sales and Marketing US & EU

• Pivotal clinical study ongoing

2012-2013

Inhaled AAT - US & Europe Clinical development & submission

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Engineering projects- Plant upgrade : Goal: System equipment and structure must reach the highest standards required by experienced Auditors.

• Three main upgrades between 2005 and 2009,

Construction and equipment. • Additional Expenses- Projects scope included Sewage

treatment Facility, software/ Hardware/ PLC and control system and validations

• End of project is defined Only when finishing all related Validations

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The Bet Kama Site (~4.5 Acres)

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TO Company • Leaned to Quality and Production • Integrated • Process directed activities • 300 employees • Continuing improvement

FROM Company • Leaned to Production and Quality • Tasks ambiance • Consequential directed activities • 100 employees • Preservation capabilities

HR, the key to success

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• Identifying of needs and corporate culture- GMP compliance, guidance and working • Qualified employee, fostering personal liability • organization structure • Working procedure (not SOP)- Team leaders, coordination between managers and departments. Synchronization of routine work depends first on will and drive of people, only than on good project plan

Building QA Force and Regulatory Department

• Recruit and develop experienced QA & RA managers and staff

• Good Development Practice

– Ongoing Collaboration with R&D

– Establish Technology Transfer Procedures

– Continuous Training

• Establishing work teams and team work (Production; QA; QC; RA and R&D)

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BLA, CMC, FDA audit, all the way to approval

• Comprehensive Product Development Report by R&D

• Establishment of Two Major Projects

• Institute CPO Unit

• Perform Detailed Gap Analysis vs. BLA Chapters, Consultants references, Audits and inspections findings & cGMP Guidelines.

• Create a General Work Plan

• Generate a Detailed Work Plan

• Perform Internal Audits and Mock FDA Inspections as part of the detailed work plan

• Create Sub-teams Manage it as a Project, with

Engineering tools

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Unique, in house developed, patented process, based on

chromatographic purification.

Able to extract highly pure, stable, ready to use (Liquid),

specialty proteins (AAT, Albumin, Transferrin,

immunoglobulin and others).

Kamada Unique Purification Process- visiting card

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Kamada Unique Purification Process - AAT

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Kamada has the knowledge, experience and ability to adjust its manufacturing

process to :

- Assorted fraction pastes (Filter Press, Centrifuge)

- Various suppliers (Plasma Fractionation sites)

- Raw materials from different stages of fractionation (Fr IV or Fr IV-1)

- Final product, Liquid solution ready to use (injection or inhalation).

Using classic methods of protein purification (precipitation, ion-exchange columns, ultra filtration, diafiltration ,filtration…).

Main AAT Process steps

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Pretreatment

Heat treatment

Precipitation

Centrifugation or filter press for removal of insoluble materials

Protein purification

Chromatography purification steps ultrafilteration / diafiltration steps

Viral elimination steps (nanofiltration)

Viral inactivation steps (solvent / detergent treatment)

Final polishing step

DS

Final 0.2µ sterile filtration

DP

Formulation

Aseptic filling

AAT- Main product attributes and advantages

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1. Batch continues production

2. Each batch started with 100 to 200 kg of paste (Reference, without FA) and finished as a concentrated liquid DS

3. Tight bio-burden limits all along the process

4. Extremely high safety standards (two viral inactivation steps).

5. significant High yields

6. High specific activity –Avr. 0.9

7. Distribution of molecular size- MT 90%.

8. 2% Active Alpha-1 Proteines Inhibitor ready to use

9. Stabilizer and preservative free

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The Next Generation (AAT) Inhaled

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• In Phase 2-3 in the EU

• Current production capacity MT 1,000 patients by IV

• production capacity MT 4,000 patients by Inhalation

• AAT process as other IP are protected under patents in EU,

North America…

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Thanks

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Appendices Topics mentioned along the presentation

o New controlled Facility Layout plans- Manufacturing area (partial) o List of required Validation protocols (Partial) o Before- After, illustration o General Layouts- after reconstruction o Kamada Product Line o Alpha-1 Antitrypsin (AAT), Augmentation Therapy o Additional Indications o AAT Potential Market o Intellectual Property

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Drawing. No. Title

D-20001/96 Layout

D-1131/00 CD Production Area Pressure Cascade

D-1132/00 Production Layout & Room Classification

D-1134/00 CD Production Area – Dirty Equipment Flow

D-1135/00 CD Personnel Flow Into Prod. Areas

D-1101/03 Process Flow in Prod. Area AAT Drug Substance/Product

D-1101/05 IgG Process

D-01001/96 Parenteral Drug Process

D-1141/00 CD Production Area - Clean Equipment Flow

D-11300/96 CD Production Area – HVAC AC- 2203

CD Production Area – HVAC AC- 2204

CD Production Area – HVAC AC- 2205

CD Production Area – HVAC AC- 2206

CD Production Area – HVAC AC- 2207

CD Production Area – HVAC AC- 2256

CD Production Area – HVAC AC- 2284

New controlled Facility Layout plans- Manufacturing area (partial)

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Machine / System CC URS DQ IQ OQ

AC-2203 (Pretreatment Area) - - + + +

AC-2204 (Filling Suite 1) + + + + +

AC-2205 (Filling suite 2 ) + + + + +

AC-2206 (Buffers) + + + + +

AC-2207 (Controlled corridors & Peripherals, Prep. Room, Gowning Areas) + + + + +

AC-2208 (Second Viral Elimination Room) + + + + +

AC-2209 (Gowning to filling rooms) + + + + +

AC-2256 (First Viral Elimination Room) + + + + +

AC-2284 (General Production Room) + + + + +

Clean Room Facility Monitoring System - - + + +

New Autoclave (ACL-1402) + + + + +

New Depyrogenation Oven (SO-1403) + + + + +

Existing Autoclave (ACL-2005) - - + + +

Vessel (T-56) + + + + +

Vessel (T-57) + + + + +

Vessel (T-59) + + + + +

Vessel (T-60) + + + + +

Vessel (T-61) + + + + +

Vessel (T-70) + + + + +

Vessel (T-71) + + + + +

Vessel (T-72) + + + + +

Vessel (T-73) + + + + +

Vessel (T-63) 80L + + + + +

Vessel 80 L( T-93) + + + + +

Vessel 80L (T-64) + + + + +

Vessel 80 L (T-94) + + + + +

Vessel (T-99) 250L + + + + +

Vessel 250L( T-69) + + + + +

Vessel (T-92) 300L + + + + +

Vessel 300L( T-62) + + + + +

Vessels screen - - + + +

Heating/cooling system for vessels + + + + +

Uniformity of filling vials - - + + +

Media Fill - - + + +

Filling Machine 1 + + + + +

Filling Machine 2 + + + + +

Gowning Validation - - + + +

Nitrogen System + + + + +

Oil Free Compressed Air System + + + + +

Clean Steam Production and Distribution System + + + + +

WFI Distribution System + + + + +

RO Distribution System + + + + +

NaOH Distribution System + + + + +

List of required Validation protocols (Partial)

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General Layouts- after reconstruction

Southern Building Northern Building

Central Building

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Kamada Product Line Category Product

Respiratory

Intravenous AAT (Glassia®) – Alpha 1 Deficiency

A1- AAT (IH) for Alpha 1 deficiency*

B1- AAT (IH) for Bronchiectasis*

C1 – AAT (IH) for Cystic Fibrosis*

Diabetes D1 – AAT (IV)

Immunoglobulins

KamRAB

KamRho- D IM

KamRho -D IV

Varitect **

Hepatect **

Megalotect**

Pentaglobin **

Critical Care

IVIG**

Heparin sodium injection **

Heparin Lock Flush

Kamacaine

Kamacaine Adrenaline

Protosol

Snake antiserum*

Albumin**

Coagulation Factors

Factor IX**

Factor VIII, VWF**

Additional Specialty Proteins Human Transferrin (Diag.)

Human Transferrin (Pharm.) * * Under development

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Alpha-1 Antitrypsin (AAT)

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• Protein derived from human plasma (fraction IV)

• Indicated for chronic treatment of genetically deficient alpha 1 patients

• Regulates the activity of Neutrophil Elastase (NE) - excess of which may

cause chronic inflammatory state, lung tissue damage and decrease in lung

function

• Treatment with AAT controls the excess NE activity by restoring the

enzyme/inhibitor balance

AAT

AAT

AAT

AAT

AAT

AAT

AAT

Augmentation Therapy

Alpha 1 Patient

Healthy or treated patient

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Additional Indications

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Diseases related to

inactive AAT

COPD, Diabetes, IBD

Vasculitis, Wegener’s

Panniculitis

Diseases with

overwhelming inflammation

Sinusitis, Bronchiectasis

Cystic Fibrosis, IBD

Chronic Infections

Diabetic Foot

AAT Potential Market

• 1: 2,500 potential patients world-wide

• ~100,000 in the US

• ~100,000 in the EU

• Current market

• 5,000 identified and treated

• 6,000 identified, 1,000 treated

• ~$500 Million

• significant growth of the AATD market

• potential and additional indications

• Baxter is the leading company in the US specializing in identification of

new patients

• Average cost of therapy is $100,000 / patient / year

• Orphan indication to support premium pricing

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Intellectual Property

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PATENT: “Large Scale Preparation of Alpha1 Proteinase Inhibitor and Use Thereof “ Granted: USA, EU, Australia

PATENT: “Method for purification of alpha1 proteinase inhibitor”

Granted: USA

PATENT: “Ultrapure Transferrin for Pharmaceutical Compositions “ Granted: USA

PENDING PATENT: “Large Scale Preparation of Alpha1 Proteinase Inhibitor and Use Thereof“

National stage: Israel, Canada, Argentina

PENDING PATENT: “Pulmonary Delivery of Alpha1 Proteinase Inhibitor” National stage: USA, EU, Australia, Canada, Israel, Mexico, Brazil, Russia

PENDING PATENT: “Alpha1 Antitrypsin for Treating Exacerbation Episodes of Pulmonary

Diseases” National stage: USA, EU, Australia, Canada, Israel, Mexico, Brazil, Russia

ORPHAN DRUG DESIGNATIONS in US and EU for inhaled AAT for:

AAT Deficiency, CF and Bronchiectasis indications (Bronchiectasis only in the US)