Transcript Document

Advanced Aseptic Manufacturing
Solutions for Clinical Trial
Material
NextPharma Technologies
Geneviève Motte, PhD
VP Sterile Product Development
Photo courtesy of Texwipe
Paris, 26 – 27 January 2010
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Introduction
 Market and Clinical Pipeline
 Challenges of NCEs
 Manufacturing Solutions
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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)
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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
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Traditional Drugs and Biologics by Clinical Phase
3500
3000
2500
2000
Biologics
1500
Small Molecules
1000
500
0
Total
Source : Leem Biotech Bioproduction 2008
Phase I
Phase II
Phase III
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Biologics by Therapeutic Class
59
9%
173
26%
180
27%
Mabs
Vaccines
Oligonucleotides
Therapeutic Proteins
72
11%
Source: Leem Biotech Bioproduction 2008
Gene and cell therapies
184
27%
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Anticancer Drugs by Therapeutic Class
18
%
67
40
32
Cytotoxic
Hormonal
27
6
on the market
Targeted
in development
Source: Availability of medicines and supporting therapies in pediatric oncology -- Warsaw – Oct. 14, 2009
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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
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Challenges - Anticancer drugs
 Extremely high potency levels and/or toxicity
 Tumor-targeting formulations
 Fast-track development programs and high failure rates
 Small batch size
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How to address these challenges?
 Facility Design
 Highly flexible manufacturing from Formulation
Development to Clinical Trial Material and Commercial
Supply
 Innovative drug delivery systems
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Formulation labs at NextPharma
Solubilization and stabilization
Targeted and sustained drug
delivery systems
Lyo cycle development
Process parameters
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Development Center and Commercial
Manufacturing
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
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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 ( 14.25
– 52 mm)
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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
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Innovative Drug Delivery Systems
 Solvent-based formulations
 Controlled release matrix
 Nanoscale drug carriers
 Conjugated APIs
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Case study 1 - Oxygen control
Filling machine: Head space in the vials:
Current process
Filling
N2
N2
Stoppering
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Case study 1 - Oxygen control
Filling machine: Head space in the vials
Improvement
N2
Filling
N2
Stoppering
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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 Freezing
o Sublimation
o Secondary drying
 Transposition to the final dosage form (10R vials) - adjustment of phases
length only, with same pressure and t° parameters
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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
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Case study 4 - Prefilled syringes
 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
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Case study 5 – Closed Vial Technology
 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
New concept of Crystal®
MOLDING SITE
Molding & Closing
(Class ISO 5)
IRRADIATION UNIT
Sterilization
(Gamma irradiation)
Assembly
(Class ISO 8)
PHARMACEUTICAL SITE
Filling line under barrier (Class ISO 5)
Clean & Sterile readyto-fill vial
Capping
Laser re-sealing
Filling
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
Preliminary R&D filling facility
Offer in-house ad-hoc contract manufacturing for small non-GMP
quantities to perform R&D investigation
Clinical line and lyo unit in Class ISO8 at Aseptic Technologies
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 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
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Case study 6 - Controlled release matrix
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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 formulation
o Ethanol rinse of equipments and pipes
o Nitrogen flush
 High viscosity of excipients =>
o Compounding with viscosity-controlled stirring
o Larger tubing for dispensing
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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
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Conclusions
 Facility Design and equipments adapted to
highly sensitive and highly potent drugs
 Cost and Time efficiency
 Advanced manufacturing solutions