Advanced Aseptic Manufacturing Solutions for Clinical Trial Material

1
Advanced Aseptic Manufacturing Solutions for
Clinical Trial Material
Paris, 26 27 January 2010
2
Introduction
NextPharma Technologies

• Market and Clinical Pipeline
• Challenges of NCEs
• Manufacturing Solutions

3
Market outlook
NextPharma Technologies

• 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)

4
Clinical pipeline
NextPharma Technologies

• 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

5
NextPharma Technologies
Source Leem Biotech Bioproduction 2008
6
NextPharma Technologies
Source Leem Biotech Bioproduction 2008
7
NextPharma Technologies
Source Availability of medicines and supporting
therapies in pediatric oncology -- Warsaw Oct.
14, 2009
8
Challenges - Biologics
NextPharma Technologies

• 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

9
Challenges - Anticancer drugs
NextPharma Technologies

• Extremely high potency levels and/or toxicity
• Tumor-targeting formulations
• Fast-track development programs and high failure
  rates
• Small batch size

10
How to address these challenges?
NextPharma Technologies

• Facility Design
• Highly flexible manufacturing from Formulation
  Development to Clinical Trial Material and
  Commercial Supply
• Innovative drug delivery systems

11
Formulation labs at NextPharma
NextPharma Technologies

• Solubilization and stabilization
• Targeted and sustained drug delivery systems
• Lyo cycle development
• Process parameters

12
Development Center and Commercial Manufacturing
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

13
Flexibility
NextPharma Technologies

• 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 (? 14.25 52 mm)

14
Flexibility
NextPharma Technologies

• 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

15
Innovative Drug Delivery Systems
NextPharma Technologies

• Solvent-based formulations
• Controlled release matrix
• Nanoscale drug carriers
• Conjugated APIs

16
Case study 1 - Oxygen control
NextPharma Technologies

• Filling machine Head space in the vials
• Current process

Filling
N2
N2
Stoppering
17
Case study 1 - Oxygen control
NextPharma Technologies

• Filling machine Head space in the vials
• Improvement

N2
N2
Filling
Stoppering
18
Case study 2 - Quantity of API
NextPharma Technologies

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

19
Case study 3 Fast to Clinic
NextPharma Technologies

• 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

20
Case study 4 - Prefilled syringes
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
• 0.5-20ml PFS

21
Case study 5 Closed Vial Technology
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 RD setting

22
New concept of Crystal
MOLDING SITE
IRRADIATION UNIT
Sterilization (Gamma irradiation)
Molding Closing (Class ISO 5)
Assembly (Class ISO 8)
PHARMACEUTICAL SITE
Filling line under barrier (Class ISO 5)
Clean Sterile ready-to-fill vial
Capping
Laser re-sealing
Filling
23
Authority approved filling facility
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
EMEA approved 2 DMF filed at FDA Approved for
recombinant viruses
Clinical line in Class ISO8 at Aseptic
Technologies
24
Preliminary RD filling facility
Offer in-house ad-hoc contract manufacturing for
small non-GMP quantities to perform RD
investigation
Clinical line and lyo unit in Class ISO8 at
Aseptic Technologies
25
Examples of filling performed

• Filling of GMP batches
• Filling of 3000 vials for stability tests with
  two vaccines
• Filling of 3 recombinant viruses for stability
  tests
• Ad-hoc RD 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

26
Case study 6 - Controlled release matrix
NextPharma Technologies

• Injectable depot formulation for Phase I clinical
  trial
• Lipid-based sterile solution
• Cyclic peptide
• 800 vials 1,4ml fill volume
• High sensitivity to water gt
• Anhydrous formulation
• Ethanol rinse of equipments and pipes
• Nitrogen flush
• High viscosity of excipients gt
• Compounding with viscosity-controlled stirring
• Larger tubing for dispensing

27
Case study 7 - Nanoparticles
NextPharma Technologies

• 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 gt emulsion
  (isolator)
• In situ polymerization control of particle
  size!
• Aseptic filling and freeze-drying

28
Conclusions
NextPharma Technologies

• Facility Design and equipments adapted to highly
  sensitive and highly potent drugs
• Cost and Time efficiency
• Advanced manufacturing solutions