Photo courtesy of Texwipe NextPharma Technologies Geneviève Motte, PhD VP Sterile Product Development Advanced Aseptic Manufacturing Solutions for Clinical Trial Material Paris, 26 – 27 January 2010

Introduction  Market and Clinical Pipeline  Challenges of NCEs  Manufacturing Solutions NextPharma Technologies

Market outlook  World pharmaceutical market forecast is $750bn in 2009 Expected growth rate: 3 – 6% per year through 2013  Weight of biomedicines: $127bn by 2012 (more than 15%) Expected growth rate: 12% per year  Anticancer drugs: $80bn by 2012 Expected growth rate: 12% per year  Injectables: $147bn (20% of the entire market) Expected to grow at 11% per year through 2012 (26% of market) NextPharma Technologies

Clinical pipeline  Over the last 4 years, 30% of NCE were biomedicines The number of biologics in Phase I has been multiplied by 6, in contrast to only 2 for small molecules  Top targeted disease area is cancer which represents 30% of the global pipeline and 35% of biologics  More than half of the drugs in development are for parenteral administration of which 75% of all biologics NextPharma Technologies

Source : Leem Biotech Bioproduction 2008

NextPharma Technologies Source: Leem Biotech Bioproduction 2008

NextPharma Technologies Source: Availability of medicines and supporting therapies in pediatric oncology -- Warsaw – Oct. 14, 2009

Challenges - Biologics  Minimal quantities of API available (g vs kg)  Unknown toxicity  Stability issue  Solubility issue  Controlled-release formulations to extend half-life and to reduce dose-related side-effects NextPharma Technologies

Challenges - Anticancer drugs  Extremely high potency levels and/or toxicity  Tumor-targeting formulations  Fast-track development programs and high failure rates  Small batch size NextPharma Technologies

How to address these challenges?  Facility Design  Highly flexible manufacturing from Formulation Development to Clinical Trial Material and Commercial Supply  Innovative drug delivery systems NextPharma Technologies

Solubilization and stabilization Targeted and sustained drug delivery systems Lyo cycle development Process parameters Formulation labs at NextPharma NextPharma Technologies

Manufacturing and supply of Phase I to Phase III Clinical Trial Material Cytotoxic and biologics/conventional drugs in segregated units (Toxicity 4) Clinical Trial Packaging, labeling and storage Scaling-up, validation, registration and commercialization Development Center and Commercial Manufacturing NextPharma Technologies

Flexibility  2-100ml glass and plastic vials handled on standard trays  Washing machine  Oven  Filling line  Freeze-dryer  Capping  Automatic tool-free filling and stoppering machine (  – 52 mm) NextPharma Technologies

Flexibility  Temperature control through the manufacturing process  Oxygen control in solution + head space  Light control in RABS  Compatibility with material  stainless steel or glass vessels, flex bags EVA et PE  PES, PVDF, Nylon ® filters  Pt silicone, Teflon ® tubings NextPharma Technologies

Innovative Drug Delivery Systems  Solvent-based formulations  Controlled release matrix  Nanoscale drug carriers  Conjugated APIs NextPharma Technologies

Case study 1 - Oxygen control Filling machine: Head space in the vials: Current process N2 Filling Stoppering NextPharma Technologies

Filling machine: Head space in the vials Improvement N2 FillingStoppering Case study 1 - Oxygen control NextPharma Technologies

Case study 2 - Quantity of API  Lyo cycle development and Phase I clinical trial material  800mg API available for lyo cycle development  Determination of freeze-drying parameters on small vials (2R) oFreezing oSublimation oSecondary drying  Transposition to the final dosage form (10R vials) - adjustment of phases length only, with same pressure and t° parameters NextPharma Technologies

Case study 3 – Fast to Clinic  Freeze-dried drug product for First In Humans  Fast to clinic  Aseptic manufacturing and IPC  Clinical trial packaging and labeling  Final release testing  QP release 3 weeks after manufacturing date NextPharma Technologies

 Sterile depot formulation in PFS for intra-articular administration  Rheumatoid arthritis  Semi-automatic filling of syringes with peristaltic pump  Stopper placement unit under vacuum  ml PFS Case study 4 - Prefilled syringes NextPharma Technologies

 Allow clients to use a new technology  Minimize investment costs  Offer key advantages for patient quality and ease of use to pharmaceutical companies  Create partnership with Aseptic Technologies  Leverage both EMEA approved / FDA registered facility and preliminary R&D setting Case study 5 – Closed Vial Technology NextPharma Technologies

New concept of Crystal ® Sterilization (Gamma irradiation) Molding & Closing (Class ISO 5) Assembly (Class ISO 8) CappingLaser re-sealingFilling Filling line under barrier (Class ISO 5) MOLDING SITE IRRADIATION UNIT PHARMACEUTICAL SITE Clean & Sterile ready- to-fill vial

EMEA approved 2 DMF filed at FDA Approved for recombinant viruses Clinical line in Class ISO8 at Aseptic Technologies Offer in-house ad-hoc contract manufacturing for small quantities of GMP material (e.g., stability batches), especially to client interested to test the concept Authority approved filling facility

Clinical line and lyo unit in Class ISO8 at Aseptic Technologies Offer in-house ad-hoc contract manufacturing for small non-GMP quantities to perform R&D investigation Preliminary R&D filling facility

Filling of GMP batches: –Filling of 3000 vials for stability tests with two vaccines –Filling of 3 recombinant viruses for stability tests Ad-hoc R&D projects: –Filling of 4 x 10 vials (2ml) with a protein to investigate reasons for lack of stability in glass vials –Filling of 2 x 400 vials (1ml) of an antibody to investigate stability in oxygen free condition and in presence of oxygen –Filling of 300 vials (1ml) to investigate stability of a recombinant virus in accelerated conditions –Filling of 500 vials to investigate stability on 2 year basis with a recombinant protein Examples of filling performed

Case study 6 - Controlled release matrix  Injectable depot formulation for Phase I clinical trial  Lipid-based sterile solution  Cyclic peptide  800 vials – 1,4ml fill volume  High sensitivity to water => oAnhydrous formulation oEthanol rinse of equipments and pipes oNitrogen flush  High viscosity of excipients => oCompounding with viscosity-controlled stirring oLarger tubing for dispensing NextPharma Technologies

Case study 7 - Nanoparticles  Injectable nanoscale drug carrier of a cytotoxic drug for Phase II clinical trial  API entrapped in nanoparticles  Freeze-dried sterile formulation  Dissolution of API and sterile filtration of the solution  Aseptic addition of monomer => emulsion (isolator)  In situ polymerization – control of particle size!  Aseptic filling and freeze-drying NextPharma Technologies

Conclusions  Facility Design and equipments adapted to highly sensitive and highly potent drugs  Cost and Time efficiency  Advanced manufacturing solutions NextPharma Technologies