Photo courtesy of Texwipe NextPharma Technologies Geneviève Motte, PhD VP Sterile Product Development Advanced Aseptic Manufacturing Solutions for Clinical.

Photo courtesy of Texwipe

NextPharma TechnologiesGeneviève Motte, PhDVP Sterile Product Development

Advanced Aseptic Manufacturing Advanced Aseptic Manufacturing Solutions for Clinical Trial Solutions for Clinical Trial

MaterialMaterial

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 2012Expected growth rate: 12% per year

Injectables: $147bn (20% of the entire market)Expected to grow at 11% per year through 2012 (26% of market)


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


Traditional Drugs and Biologics by Clinical Phase

0

500

1000

1500

2000

2500

3000

3500

Total Phase I Phase II Phase III

Biologics

Small Molecules


Source : Leem Biotech Bioproduction 2008

Biologics by Therapeutic Class

18027%

18427%

7211%

17326%

599%

Mabs

Vaccines

Oligonucleotides

Therapeutic Proteins

Gene and cell therapies


Source: Leem Biotech Bioproduction 2008

Anticancer Drugs by Therapeutic Class

32

6

40

27

18

67

on the market in development

%

Targeted

Cytotoxic

Hormonal


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


Challenges - Anticancer drugs

Extremely high potency levels and/or toxicity

Tumor-targeting formulations

Fast-track development programs and high failure rates

Small batch size


How to address these challenges?

Facility Design

Highly flexible manufacturing from Formulation Development to Clinical Trial Material and Commercial Supply

Innovative drug delivery systems


Solubilization and stabilization

Targeted and sustained drug delivery systems

Lyo cycle development

Process parameters

Formulation labs at NextPharma


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


Flexibility

2-100ml glass and plastic vials handled on standard trays

Washing machineOvenFilling lineFreeze-dryerCapping

Automatic tool-free filling and stoppering machine ( 14.25 – 52 mm)


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


Innovative Drug Delivery Systems

Solvent-based formulations

Controlled release matrix

Nanoscale drug carriers

Conjugated APIs


Case study 1 - Oxygen control

Filling machine: Head space in the vials:Current process

N2 N2Filling

Stoppering


Filling machine: Head space in the vialsImprovement

N2 N2Filling Stoppering

Case study 1 - Oxygen control


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)o Freezingo Sublimationo Secondary drying

Transposition to the final dosage form (10R vials) - adjustment of phases length only, with same pressure and t° parameters


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


Sterile depot formulation in PFS for intra-articular administration

Rheumatoid arthritis

Semi-automatic filling of syringes with peristaltic pump Stopper placement unit under vacuum 0.5-20ml PFS

Case study 4 - Prefilled syringes


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


New concept of Crystal®

Sterilization

(Gamma irradiation)Molding & Closing

(Class ISO 5)Assembly

(Class ISO 8)

Capping Laser re-sealing Filling

Filling line under barrier (Class ISO 5)

MOLDING SITE IRRADIATION UNIT

PHARMACEUTICAL SITE

Clean & Sterile ready-to-fill vial

EMEA approved2 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 =>o Anhydrous formulationo Ethanol rinse of equipments and pipeso Nitrogen flush

High viscosity of excipients =>o Compounding with viscosity-controlled stirringo Larger tubing for dispensing


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


Conclusions

Facility Design and equipments adapted to highly sensitive and highly potent drugs

Cost and Time efficiency

Advanced manufacturing solutions


Photo courtesy of Texwipe NextPharma Technologies Geneviève Motte, PhD VP Sterile Product Development Advanced Aseptic Manufacturing Solutions for Clinical.

Documents

nextpharma technologies

formulation development

clinical trial material

clinical trial packaging

development programs

flexible manufacturing

challenges anticancer

year anticancer drugs