Nordmark – Your Partner in Biological Drug Development and Production

Welcome Benvenuto Bienvenue Bienvenido

Willkommen bei Nordmark

Willkommen bei Nordmark

Nordmark – Family-owned Business with Long Tradition

Founded: > 1927

Headquartered in Uetersen: > near Hamburg, Germany

Solid revenue base: > EUR 90 m (2017)

Number of employees: > ~ 550

~ 40 long-standing international partners > in biotech and pharmaceutical industry

Fully integrated pharmaceutical company with proven track record

Nordmark at a Glance

> Leading service provider for development and manufacturing of biopharmaceutical APIs > Biological extracts > Non-recombinant proteins > Monoclonal antibodies (mAb) > Other recombinant proteins

> Entire value chain from development to marketed drugs

> Significant track record in process develop- ment and production

> State-of-the-art GMP-certified manufacturing facilities

> Highest standards in quality control

> Vast experience in international regulatory approval processes and programs

> Commercialization know-how based on own drugs

Tailor-made solutions to turn your innovation into marketed drugs

Nordmark Uetersen – Sufficient Room for Expansion

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| 1 Biocenter | 2 Administration | 3 Pharm. development | 4 Norbitec | 5 API production, Pancreatin, Extracts, Collagenase | 6 Quality control | 7 Process development (API) | 8 Pharm. production, Semi-solid drug forms | 9 Engineering and power station | 10 Analytical development | 11 Pharm. production, Solid drug forms | 12 Packaging | 13 Warehouse

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

Norbitec2010Foun-

dationViprinex

2012Acquisition

BIBITEC

2015Launch Collage-

nase AF11

Nordmark History – More than 90 Years of Experience

Long tradition in biological APIs and finished drug products

1 Biochemical reagent, distributed exclusively via SERVA Electrophoresis GmbH until 2017

2018Take-over

biochemicals distribution

Nordmark – The Specialist for Biological APIs

Nordmark Development

Biologics from lab to market

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

Areas of expertise> Extraction from biological materials> Microbial fermentation> Microbiome> Mammalian cell culture

Nordmark Biological APIs

Market leading manufacturer of biological APIs

Extraction from biological materials> Pancreatin> Pepsin> 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 development and manufacturing excellence with commercialization know-how

* Norbitec, JV with BIOCEUTICALS Arzneimittel AG 6

Nordmark Development – Biologics from Lab to Market

BIOTECH

Mammalian cell lines*/microbial strains> Screening and clone selection> Cell line and strain development> Manufacture of MCB/WCBs (GMP)> Scale-up and scale-down studies> Up- and down-stream processing> Process optimization> Virus studies

Processing techniques> Extraction> Purification> Filtration> Drying> Milling> Virus studies

From lab to production scale

EXTRACTS

* With partners

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> Pepsin

Other origin> Tannin albuminate

BIOLOGICAL EXTRACTS

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

Collagenase> Ointment

Others> Sugar-coated tablets> Effervescent tablets

Nordmark Pharma – Finished Drug Products for Partners and Own Brand

FOR PARTNERS NORDMARK BRAND

Pancreatin> Pankreatan®

Heparin> Thrombophob®

Pepsin Ph. Eur. > Enzynorm® f

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

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Bioprocess Development – Upstream

* 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

Bioprocess Development – Downstream

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)

For clinical up to commercial supply

Certified cGMP Production

Tailor-made solutions 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> Lyophilization

cGMP PRODUCTION FACILITIES

Pharmaceutical Development

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Photo: © PAMASPhoto: © Bruker

Formulation Development> Protein-based liquid, semi- solid and solid formulations> Live biotherapeutic (micobiota) based formulations> DoE based studies

Primary packaging development

Scale up and technology transfer

Subvisible Particles in Solutions via Dynamic Light Scattering (DLS) > Particle size distribution in nm-range> Detection of soluble protein aggregatesSubvisible Particles in Solutions via Light Obscuration (LO)> Particle count in µm-range> Detection of insoluble protein aggregates> Pharmacopoeial method

Protein UnfoldingTemperature (Tm) via µDSC> High-trough-put screening of liquid formulations> High-trough-put prediction of storage stabilityProtein Secondary Structure via FT-IR (ATR)> Evaluation of liquid and solid formulations> Determination of changes in protein structure

DEVELOPMENT PROTEIN STRUCTURE PROTEIN AGGREGATION

Photo: © Wyatt Technology CorpPhoto: © TA Instruments

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

Proven Expertise in Bioprocess Development

Track record, selected projects:

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Partner Timeline Projekt Product Process

advanceCor 2011-2014 Process development, GMP-production of preclinical and clinical material PH I

Recombinant fusion protein

CHO cell line

Ticeba 2013 Purification process development, GMP production Monoclonal antibody

Hybridoma technology

Greenovation 2015/16 Technology transfer, GMP production of clinical material PH I

Enzyme Moss cultivation (P. patens)

MATHIASConsortium

2017 Process development, GMP production Monoclonal antibody

CHO cell line

HelmholtzZentrum

2017/18 Process development, GMP-production of preclinical and clinical material PH I

Fab antibody fragment

CHO cell line

US partner ongoing Microbiome Live Biothera-peutic Product

Microbials

Nordmarkproprietary

ongoing Process development, GMP production, formulation, pri-mary packaging development

Several non- recombinant proteins

Microbial fermentation

Nordmarkproprietary

ongoing Process development, GMP production, formulation, pri-mary packaging development

Ancrod, non- recombinant protein

Extraction from snake venom

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

New Biological APIs under Development

Structure determined in cooperation with DESY*

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

Ancrod is ... ... a highly active fibrinogenase isolated from venom of malayan pit viper bred in Nordmark‘s own snake farmAncrod can ... ... favorably influence blood viscosityAncrod has successfully passed ... ... extensive preclinical tests ... clinical studies PH I ... and is currently in PH II

ANCROD BURLULIPASE COLLAGENASE

Burlulipase is ... ... a pure, liquid, animal- and virus-free, highly active, acid stable lipase-only product from bacterial fermentation with a favorable safety profileBurlulipase can ... ... effectively improve fat absorption in EPI** patientsBurlulipase has successfully passed ... ... extensive preclinical tests ... clinical studies PH I and IIa (PoC)

Collagenase is ... ... an enzyme obtained from fermen- tation with Clostridium histolyticumCollagenase is used for tissue dissociation... ... e.g. in wound healing, edema- tous fibrosclerotic panniculopathy (cellulite), Dupuytren‘s contracture and tissue-engineeringCollagenase development by Nordmark: ... animal-free collagenase

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 more than 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