Nordmark – Your Partner in Biological Drug Development and Production

Welcome Benvenuto Bienvenue Bienvenido

Willkommen bei Nordmark

Willkommen bei Nordmark

Nordmark – The Specialist for Biological APIs

Nordmark Biotech

Bioprocess development and production

> Cell line/strain development> Process development> GMP production> Analytical development> Validation> Regulatory support> Formulation> Fill & finish

Nordmark Biological APIs

Market leading manufacturer of biological APIs

Extraction from biological materials> Pancreatin> Pepsin> Heparin (low-molecular weight) > Liver extract> Tannin albuminate

Biotechnological production> Collagenase> Erythropoietin* (EPO)

Nordmark Pharma

Finished drug products based on biological APIs

Manufacturing of finished drug products for partners and Nordmark proprietary brands> Granulation and film-coating > Compression and encapsulation> Microtablets> Ointments and sterile ointments> Primary and secondary packaging

Nordmark Group

Combining manufacturing excellence with commercialization know-how

* Norbitec, JV with BIOCEUTICALS Arzneimittel AG 2

Nordmark – Family-owned Business with Long Tradition

Founded: > 1927

Headquartered in Uetersen: > nearHamburg,Germany

Solid revenue base: > EUR75m(2014)

Number of employees: > ~500

~ 40 long-standing international partners > fromthepharmaceutical andbiotechnologyindustry

Fully integrated pharmaceutical company with proven track record

1927Foundation Nordmark Werke

1928LaunchHepatrat

1930LaunchEnzynorm

1943Complete relocation to new manufacturingsite in Uetersen

1950Launch

Thrombophob

1969Launch

Panzynorm forte

1968Take over by

BASF AG

1975BASF acquired

Knoll AG

1987Launch Panzytrat

(film-coated microtablet)

1993LaunchClivarin

2001MBO Nordmark

Independent

1996Launch Iruxol

2007Launch Silapo

and Collagenase NB11

2003Foundation

Norbitec

2010Foundation

Viprinex

2012Acquisition

BIBITEC

2015Launch Collage-

nase AF11

Nordmark History – Nearly 90 Years of Experience

Long tradition in biological APIs and finished drug products

1 Biochemical reagent, distributed exclusively via SERVA Electrophoresis GmbH 4

Nordmark Uetersen – Sufficient Room for Expansion

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|1Biocenter|2Administration|3Pharm.development|4Norbitec|5APIproduction,Pancreatin,Extracts,Collagenase,Heparin|6Qualitycontrol|7Processdevelopment(API)|8Pharm.production,Semi-soliddrugforms|9Engineeringandpowerstation|10Analyticaldevelopment|11Pharm.production,Soliddrugforms|12Packaging|13Warehouse

Nordmark Biotech at a Glance

> Leadingserviceproviderfordevelopment andmanufacturingofbiopharmaceuticalAPIs > Non-recombinantproteins > Monoclonalantibodies(mAb) > Otherrecombinantproteins

> Entirevaluechainfromdevelopment tomarketeddrugs

> Significanttrackrecordinprocessdevelopment andproduction

> State-of-the-artGMP-certified manufacturingfacilities

> Higheststandardsinqualitycontrol

> Vastexperienceininternationalregulatory approvalprocessesandprograms

> Commercializationknow-how basedonowndrugs

> Benefittingfromknow-how ofentireNordmarkGroup

Tailor-made packages to turn your innovation into marketed drugs

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Nordmark Biological APIs – Market Leading Manufacturer of Biological APIs

FERMENTATION/CELL CULTURE

Microbial fermentation> Collagenase for wound debridement> Purified collagenase as biochemical for cell isolation (several grades)

CHO cell culture (Norbitec)> Erythropoietin for anaemia

Porcine origin> Pancreatin> Heparin (low-molecular weight) > Pepsin

Bovine origin> Liver extract

Other origin> Tannin albuminate

BIOLOGICAL EXTRACTS

Pancreatin> Capsules with pellets or microfilmtablets> Film-coated tablets

Collagenase> Ointment

Others> Sugar-coated tablets> Effervascent tablets

Nordmark Pharma – Finished Drug Products for Partners and Own Brand

FOR PARTNERS NORDMARK BRAND

Pancreatin> Pankreatan®, > Helopan®

Heparin> Thrombophob®

Pepsin Ph. Eur. > Enzynorm® f

Liver extract> Prohepar®

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Fully Integrated Pharmaceutical Company

Nordmark provides the complete value chain to meet your drug development needs all the way through to commercialization

BIOPROCESS DEVELOPMENT(USP AND DSP)

GMP-COMPLIANTAPI PRODUCTION

FORMULATION FILL & FINISH

ANALYTICS AND QUALITY CONTROL

REGULATORY AFFAIRS

Mammalian cell lines* and microbial strains> Screening> Clone selection > Clone optimization> Genetic engineering> Cell banking under cGMP> Master Cell Bank (MCB)> Working Cell Bank (WCB)

Scalable Process Development

Processing techniques > Fractionation by solvent > Precipitation (heat, acid)> Crystallization> Filtration> Chromatography> Vacuum drying> Spray drying> Freeze drying> Milling

Upstream processing> Batch, fed-batch, perfusion> Parallel cultivation systems> Process optimization> Lab to production scale> Scale-down studies

Downstream processing> Chromatography and filtration> HCP, DNA and virus removal> Scale-up and scale-down studies

* With partners

CELL LINE DEVELOPMENT PROCESS DEVELOPMENT BIOLOGICALS DEVELOPMENT

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Upstream Development

* With partners

Strain Selection/Cell Line Development> Bacteria> Yeasts> CHO and others*> Hybridoma*

Genetic Engineering> Recombination> Codon usage> Mutagenesis

Expression Studies> Screening studies> Characterization> Clone selection> Research cell bank

Media Optimization> Screening studies> Multivariate (DoE) studies> Final host selection

Process Development> Multivariate (DoE) studies > Parallel bioreactor system> Up to 2 L scale (cell culture)> Up to 42 L scale (microbials)

MCB and WCB> cGMP conditions> Qualified and monitored storage

Scale Up> Up to 200 L scale (cell culture)> Up to 500 L scale (microbials)> Process adaptation

Process Transfer> In-house engineering> Process setup

Production at Pilot Scale> Up to 500 L> Clinical supply> cGMP conditions

Commercial Production> Supported production > cGMP conditions

Downstream Development

Cell Removal> Filtration> Centrifugation

Purification> Development of purification and filtration steps> Process optimization > Evaluation of process robustness and reproducibility (Design Space)> Optimization of storage conditions

Analytical Development (IPKs)> Activity-assays> Aggregates (SEC)> Identity and purity (SDS-PAGE; HPLC/UPLC) > HCPs (ELISA); DNA (qPCR)> Protein A/L, leachables> Isoforms (CE)> Protein concentration (UV-Assay)

Virus Reduction> Nanofiltration> Chromatography> Physical treatment> Virus validation studies

Production: Pilot Scale> ÄKTA pilot systems> Bioprocess systems> Clinical trial supply> cGMP conditions

Scale Up> Up to 100 L batch scale> Process adaptation

Process Transfer> In-house engineering> Process setup> Process optimization> Trainings> Production support

Production: Full Scale> Up to > 1000 L scale> Market supply> cGMP conditions

cGMP SERVICES

Process development and validation for Biological APIs originating from:> Animal organs and fluids (e.g. snake venom)> Bacteria and yeasts (recombinant and non recombinant)> Mammalian cell cultures (mAbs and other recombinant proteins)

Clinical supply up to PH III

Commercial supply

Certified cGMP Production

Tailor-made packages to turn your innovation into marketed drugs

Clinical trial manufacturing> Stainless steel stirred bioreactors> Single use bioreactors

Commercial manufacturing> Stainless steel stirred bioreactors> Industrial chromatography systems

cGMP PRODUCTION FACILITIES

Formulation Development and Characterization of Biologicals

Protein unfolding temperature (Tm) via μDSC> High-through-put screening of liquid formulations> High-through-put prediction of storage stability

Protein secondary structure via FT-IR (ATR)> Evaluation of liquid and solid formulations> Determination of changes in protein structure

Subvisible particles in solutions via dynamic light scattering (DLS)> Particle size distribution in nm-range> Detection of soluble protein aggregates

Subvisible particles in solutions via light obscuration (LO)> Particle count in μm-range> Detection of insoluble protein aggregates> Pharmacopoeial method

PROTEIN STRUCTURE PROTEIN AGGREGATION

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Photo: © Wyatt Technology CorpPhoto: © TA Instruments

Photo: © PAMASPhoto: © Bruker

Solids> Granulation and film-coating> Compression and encapsulation> Micro-tablets

Semi-solids> Ointments and sterile ointments

Liquids> Oral and parenteral*

Manufacture of Clinical and Commercial Supplies

Solids> Bottles and blisters

Semi-solids> Sterile and standard tube

Liquids> Oral and parenteral*> Glass & blow-fill-seal vials*

Secondary packaging> Art works, cartons and PLI> Commercial and clinical trial medication

* With partners

MANUFACTURE FILL & FINISH

Characterization and method development> Biological activity assays> Cell culture based assays> ELISA> Glycostructure analysis> Mass spectrometry> Chromatography (TLC/HPLC/UPLC/GC)> GLP-compliant studies

Cutting Edge Analytics and Quality Control

According to international guidelines > ICH (Int’l Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use)> EMA (Europ. Medicines Agency)> WHO (World Health Organization)

In-process control> Expression system> Fermentation

Release testing according to USP and Ph. Eur.> Protein identification, purity and content

Adventitious agents> Viral safety, impurities

Nordmark’s cutting-edge analytics guarantee consistently high quality of your products

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PROTEIN ANALY TICS QUALIT Y CONTROL STABILIT Y TESTING

Wealth of Regulatory Experience

Based on our experience we can contribute to your success in drug product development

> Preparation of registration documentation

> Support of registration processes (worldwide)

> Regulatory consulting services from early development to registration

> Strategic advice

> Project management

> Lifecycle management/maintenance for existing products

Customer support through all stages of approval process up to registration

BfArM Health Canada

KFDAJMHLW

FDAMEB

LaSD Schleswig Holstein

EMAANVISA

MPA Ministerio da Saude

Timeline

2001-2007

2011-2014

2013

ongoing

ongoing

ongoing

ongoing

Project

Process development, GMP-production of clinical material Phase III, Planning, building & operationally running the GMP production site

Process development and GMP-production of preclinical and clinical material PH I

Purification process development and GMP production

Process development and GMP production

Process development PHI/II and GMP production, formulation and primary packaging development

Process development PHI/II and GMP production, formulation and primary packaging development

Process development and GMP production, formulation and primary packaging development

Partner

Bioceuticals

advanceCor

Ticeba

CT Atlantic

Nordmark proprietary

Nordmark proprietary

Nordmark proprietary

Process

CHO cell line

CHO cell line

Hybridoma technology

CHO cell line(transient)

Extraction from snake venom

Microbial fermentation

Microbial fermentation

Product

EPO-Biosimilar

Recombinant fusion protein

Monoclonal antibody

Monoclonal antibody

Ancrod, non-recombinant protein

Burlulipase, non-recombinant protein

Collagenase, non-recombinant protein

Proven Expertise in Bioprocess Development

Track record, selected projects:

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Successful Project Development & Technology Transfer

With our expertise we bring products to market

Process development clinical Phase III

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Example: Industrial manufacturing of Erythropoietin (EPOzeta)

Establishment of new production site

EMEA approval EPOzeta

Process development industrial scale

Market supply EU (Silapo®, Retacrit®, EPOBEL®)

Start of approval process USA (Hospira)

Joint Venture with BIOCEUTICALS Arzneimittel AG

Ancrod is> a highly active fibrinogenase isolated from venom of malayan pit viper bred in Nordmark’s own snake farm.

Ancrod can> favorably improve blood viscosity.

Ancrod has successfully passed> extensive preclinical tests.> clinical studies PH I.

Ancrod is currently in clinical studies PH II.

New Biological APIs under Development

Burlulipase is> a pure, liquid, animal- and virus-free, highly active and acid stable lipase-only product from bacterial fermentation with a favorable safety profile.

Burlulipase can> effectively improve fat absorption in patients with exocrine pancreatic insufficiency (EPI).

Burlulipase has successfully passed> extensive preclinical tests.> clinical studies PH I and IIa (PoC).

ANCROD BURLULIPASE

Structure determined in cooperation with DESY*

* X-ray analysis by Deutsches Elektronen-Synchrotron DESY, Hamburg, Germany 20

Worldwide Business Relationships

Partnering with Nordmark is about achieving your goals. Together!

Partner References

Our long-term relationships demonstrate the satisfaction and trust of our partners

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Nordmark Arzneimittel GmbH & Co. KG info@nordmark-pharma.de+49-(0)4122 712-0www.nordmark-pharma.de

projects@nordmark-biotech.de +49-(0)4122 712-907 www.nordmark-biotech.de

Nordmark – Your Partner of Choice

Keys to our success are competence, quality,

responsibility and reliable long-term relationships

> Leading manufacturer of high quality biological APIs based on nearly 90 years of experience

> Proven track record in development and manufacturing

> Family-owned business in which your projects are handled as if they were ours

> Extensive regulatory experience adds significant value for our partners

> Strong commitment to long-term partnerships built on trust, reliability and execution

> Fast and simple decision-making processes

> Open to various collaboration models

> Drug product development and manufacture from scratch to batch and beyond

> Whatever size your project – your success is our priority

Contacts