multilayer plastic vial & syringe with excellent oxygen … has developed a new plastic medical...
TRANSCRIPT
Multilayer Plastic Vial & Syringe
with Excellent Oxygen Barrier
Researcher
Haruka Okazaki
CPhI Worldwide InnoPack Speaker’s Corner24th October, 11:50 – 12:20
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Mitsubishi Gas Chemical (MGC)
• Belonging to Mitsubishi Group
• Head Office: Tokyo, Japan
• Established in Jan.1918
• Net Sales: US$ 5.5 billion(On a Consolidated basis, Mar. 2017, US$1=\100)
• Employees: approx. 8000(On a Consolidated basis, Mar. 2017)
• Main Products
・ Methanol
・ Hydrogen Peroxide
・ Polycarbonate
・ Nylon-MXD6
・ Oxygen Absorber (AGELESS® )
etc.
Japan;
2 sales offices, 7 productions,
3 research centers
Overseas;
5 sales offices, 19 productions
2
Nylon-MXD6
• Polyamide Resin
• Features
-Good Gas-Barrier (O2, CO2, etc.)
• Applications
Nylon-MXD6
Injection Blow Molding Extrusion Molding
‣Soda Bottles ‣Beer Bottles ‣Food Packaging
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AGELESS®
• Sachet Type of Oxygen Absorber
• Features-Prevents oxidation
-Preserves flavor and nutrition
• Applications-Used in Gas-barrier packaging
AGELESS®
Food ProductsMedical Products
Enclosed
MGC is a leading company in the field of
oxygen barrier material and oxygen absorber.4
Today’s Overview
✓ Features of Glass and Plastics
~Various good aspects of Plastics~
✓ Excellent Oxygen and
Water Vapor Barrier Ability of OXYCAPTTM
✓ Concept of OXYCAPTTM
~Two key technologies;
New Oxygen Absorbing Resin
& Multilayer Configuration~
✓ Technical Data of OXYCAPTTM
5
Today’s Overview
6
✓ Features of Glass and Plastics
~Various good aspects of Plastics~
✓ Excellent Oxygen and
Water Vapor Barrier Ability of OXYCAPTTM
✓ Concept of OXYCAPTTM
~Two key technologies;
New Oxygen Absorbing Resin
& Multilayer Configuration~
✓ Technical Data of OXYCAPTTM
Glass vs Plastics
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Glass Plastics (COP)※Cyclo Olefin Polymer
Oxygen Barrier Excellent(Permeation = Zero)
Poor
Water Vapor Barrier Excellent(Permeation = Zero)
Excellent(Permeation = very low)
Resistance to Breakage Poor Favorable
Inorganic Extractables Much Low
Organic Extractables Low Low
pH Stability Bad Good
UV Barrier Poor Poor
Transparency Excellent Excellent
Weight Heavy Light
Protein Adsorption Much Low
Disposability Difficult Easy
Today’s Overview
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✓ Features of Glass and Plastics
~Various good aspects of Plastics~
✓ Excellent Oxygen and
Water Vapor Barrier Ability of OXYCAPTTM
✓ Concept of OXYCAPTTM
~Two key technologies;
New Oxygen Absorbing Resin
& Multilayer Configuration~
✓ Technical Data of OXYCAPTTM
Plastic has poor oxygen and water vapor barrier
compared with glass.MGC has developed a new plastic medical container
with excellent oxygen and water vapor barrier.G
oo
d←
Oxyg
en
Barr
ier
→P
oo
r
Good ← Water Vapor Barrier → Poor
OXYCAPTTM ~OXYCAPTTM Vial & Syringe~
Oxygen and Water Vapor Barrier
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Glass Plastic s(COP)※Cyclo Olefin Polymer
OXYCAPT™
Oxygen Barrier Excellent(Permeation = Zero)
Poor Excellent(Permeation = very low)
Water Vapor Barrier Excellent(Permeation = Zero)
Excellent(Permeation = very low)
Excellent(Permeation = very low)
Resistance to Breakage Poor Favorable Favorable
Inorganic Extractables Much Low Low
Organic Extractables Low Low Low
pH Stability Bad Good Good
UV Barrier Poor Poor Favorable
Transparency Excellent Excellent Excellent
Weight Heavy Light Light
Protein Adsorption Much Low Low
Disposability Difficult Easy Easy
OXYCAPT™
OXYCAPT™ has the best properties
both of Glass and Plastics container.
10
Today’s Overview
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✓ Features of Glass and Plastics
~Various good aspects of Plastics~
✓ Excellent Oxygen and
Water Vapor Barrier Ability of OXYCAPTTM
✓ Concept of OXYCAPTTM
~Two key technologies;
New Oxygen Absorbing Resin
& Multilayer Configuration~
✓ Technical Data of OXYCAPTTM
OXYCAPT™ Technology
◇New Oxygen Absorbing Resin
・Excellent Oxygen Barrier
・Retains Strength
・Low Extractables
◇Multilayer Configuration
・Improves the properties
・Co-injection molding
+
◇OXYCAPT™ Vial & Syringe・ Plastic containers with excellent oxygen barrier
・ Suitable for oxygen sensitive drugs
12
Oxygen absorbing resin has excellent oxygen barrier
as it absorbs oxygen from outside.
<passive barrier resin> <oxygen absorbing resin>
Oxygen Absorbing Resin
13
Example1. The oxidation of ether with transition metal
Example2. The oxidation of butadiene with transition metal
Existing oxygen absorbing resins’ problems
・High levels of low-molecular-weight extractables
・Lose structural strength
+ +
Degradation!Existing OA resins’ film
after oxygen absorbing
Existing Oxygen Absorbing Resin
from other company
14
~Retain Strength~ ~Low Extractables~<Tensile Strength Test>
・Sample : The 10mm wide film.
・Measurement device : tensile testing machine
The films(SA:200cm2) were soaked in
100mL water and stored for 1week at 60℃
<TOC Analysis>
~Does not Degrade~
New Oxygen Absorbing Resin
15
OXYCAPT™ Syringe- injection molding -
OXYCAPT™ Vial- injection blow molding -
Drug Contact & WV Barrier Layer
COP
Water Vapor(WV) Barrier Layer
COP
Oxygen Absorbing Layer(middle)
New Oxygen Absorbing (OA)
Resin
‣ 3 Layers(COP / New OA Resin / COP)‣ COP (Cyclo Olefin Polymer)
・Low Water Vapor Permeability
・Low Protein Adsorption
・Material of container for biological drug~OXYCAPTTM Vial & Syringe~
Multilayer Configuration
16
OXYCAPTTM has advantages of both new oxygen absorbing resin
and COP, and achieves glass-like gas barrier !
Today’s Overview
17
✓ Features of Glass and Plastics
~Various good aspects of Plastics~
✓ Excellent Oxygen and
Water Vapor Barrier Ability of OXYCAPTTM
✓ Concept of OXYCAPTTM
~Two key technologies;
New Oxygen Absorbing Resin
& Multilayer Configuration~
✓ Technical Data of OXYCAPTTM
Features of OXYCAPT™ Vial & Syringe
<Features>・Excellent Oxygen Barrier
・Excellent Water Vapor Barrier
・Extremely Low Extractables
・Low Protein Adsorption
・High Transparency
・High Breakage Resistance
・Good pH Stability
・Easier Disposal than Glass
・Much Lighter than Glass
Water Vapor Barrier Layer(made of COP)
Drug Contact & WV Barrier Layer(made of COP)
Oxygen Barrier Layer
(made of Oxygen Absorbing Resin)
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Nest & Tab
0.000
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
COP Glass OXYCAPT™
Ox
yg
en
Pe
rme
ab
ilit
y(c
c/p
kg
/da
y/0
.21
atm
)
Stopper
Barrel wall
Tip Cap
0.000
0.005
0.010
0.015
0.020
0.025
0.030
0.035
0.040
COP COP/PA Glass OXYCAPT™
Oxyg
en
Perm
eab
ilit
y(c
c/p
kg
/day/0
.21atm
) Closure
Vial body
Oxygen Barrier
OXYCAPT™ has excellent oxygen barrier,
and can protect drugs just like glass.
<Oxygen Permeability>
10ml Vial
・Measurement device : MOCON OX-TRAN® 2/61
・Condition : 23℃ / In 100%RH, Out 50%RH
1mL Long Syringe
Similar to Glass
Oxygen
Permeability from
barrel ≒ZERO
Extremely low
(Over 100 times
better than COP)
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OXYCAPT™ keeps excellent oxygen barrier like glass.
<The color of gel>
No oxidation Oxidation
~ Before (0 day) ~
GlassCOP OXYCAPTTM
~ After (40℃, 6 months) ~
GlassCOP OXYCAPTTM
~ After (5℃, 18 months) ~
Storage Test with Oxygen Sensitive Gel
GlassCOP OXYCAPTTM20
Oxygen Concentration in Headspace
0.0
5.0
10.0
15.0
20.0
0 30 60 90 120 150 180
Co
nc
en
tra
tio
no
fO
xyg
en
[%
]
Storage Period [day]
Glass
COP
OXYCAPT™
10ml Vial
Headspace
(Zero oxygen
concentration)
O2
O2
<Test method>
- Filled with 5mL water
- Freeze degassing
→N2 gas introduction
→Freeze degassing again
⇒Zero oxygen concentration
in headspace
- Stored at 25℃・60%RH
- Analysis; oxygen analyzer
OXYCAPT™ keeps Zero oxygen concentration
in its headspace just like glass for a long time.
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Water Vapor Barrier
OXYCAPT™ has excellent water vapor barrier like COP.
0.0000
0.0020
0.0040
0.0060
0.0080
0.0100
PET COP OXYCAPT™
WV
TR
(c
c/p
kg
/day)
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
COP OXYCAPT™
WV
TR
(c
c/p
kg
/da
y)
・Measurement device : MOCON PERMATRAN-W® 3/33
・Condition : 40℃ / In 100%RH, Out 5%RH
10ml Vial 1ml Long Syringe
Similar
To
COP
Similar
To
COP
22
<Water Vapor Permeability>
Organic Extractables
0
0.2
0.4
0.6
0.8
1
PET PP COP OXYCAPT™
TO
C(p
pm)
OXYCAPT™
100mL Vial
<Test method>
- Filled with 100mL water
- Stored for 3 month at 40℃- Analysis; TOC
OXYCAPT™ has low organic extractables like COP.
TOC:Total Organic Carbon
23
Extractable Study
10mL Vial
Extractables from OXYCAPTTM are same
to that from COP.
Materials Solvent GC-MS (for volatile impurity) LC-UV-MS (for non-volatile impurity)DI water
50% Ethanol
DI water
50% Ethanol
1% PS-80
5M NaCl
0.5N NaOH
0.1M Phosphoic acid
DI water
50% Ethanol
1% PS-80
5M NaCl
0.5N NaOH
0.1M Phosphoic acid
Glass Not detected Not detected
COP Not detected Not detected
OXYCAPTTM Not detected Not detected
<Test method>
・GC-MS and LC-UV-MS
・6 solvents recommended by BioPhorum Operations Group were selected.
・6 solvents : DI water, 50% Ethanol, 1% PS-80, 5M NaCl, 0.5M NaOH, 0.1M H3PO4
・Prepared 2mL-solvents were put in vials and stored at 40oC, 25%RH for 70 days.
・The duration is necessary to support 3 year storage time at 0 ℃.
-The studies were conducted by American CRO, Frontage Laboratories, Inc.(Exton, PA).
*ASTM F1980-07 “Standard Guide for Accelerated Aging of Sterile Medical Devices”24
Elemental impurity
10mL Vial
*These elements were selected based on ICH Q3D.
Extractables from OXYCAPTTM are same
to that from COP.
0
5
10
15
20
25
30
Li V Cr Co Ni Cu As Se Mo Ru Rh Pd Ag Cd Sn Sb Ba Os Ir Pt Au Hg Tl Pb
Extr
acta
ble
s [n
g /
vial
] Type 1 Glass VialCOP VialOXYCAPT Vial
<Test method>
・ICP-MS
・ 1% HNO3 recommended by CRO was selected
25OXYCAPT is suited to medical containers.
0
10
20
30
40
50
60
70
80
90
100
250 300 350 400 450 500 550 600 650 700 750 800 850
Tra
nsm
itta
nce
(%)
Wave Length(nm)
OXYCAPT™
COP
Glass TypeⅠ
Ultraviolet-Visible Absorbance
OXYCAPT™ shields UV light below 300nm.
⇒ OXYCAPT™ vial can protect UV-sensitive drug.
OXYCAPT™
10mL VialUltraviolet range
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OXYCAPTTM Glass TypeⅠ
Test method1. 5wt% albumin solution was put into
vials and stored for 24h.
2. Dyed with “Coomassie brilliant blue
R-250” solution for 6h.
3. Rinsed with methanol 4 times.
Deeper Blue = more protein residue.
Protein Adsorption
27
OXYCAPTTM has low protein adsorption,
reducing unwanted residues of protein.
Laminated Stopper for OXYCAPT™ Syringe
<Feature of laminated stopper> Slight silicone-coat or Silicone-Free
Light break-loose and gliding force
Low extractables
Meet JP, EP, USP requirementJP 7.03/EP 3.2.9./USP <381>
Sterilized by ETO
Inspection of endotoxin and bioburden
Chlorinated butyl rubber
Full-Laminated
(fluorinated film)
<Components of OXYCAPTTM Syringe>
OXYCAPTTM Syringe barrel
・Silicone-free
Tip types
・Luer Cone
・Luer Lock
Stopper
・PTFE-laminated butyl rubber
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Gliding Force of OXYCAPT™ Syringe
OXYCAPT™ syringe can minimize silicone oil and
decrease the break-loose force and glide force.
<Test method>
- 1 mL long Syringe
(27G×1” needle was attached)
- Filled with 1mL distilled water
- Stroke device : INSTRON® 5967
- Stroke rate : 200 mm/min
<OXYCAPT™① ~standard~>
※Gliding force increases gradually due to its inner draft angle.
Silicone-freeSiliconization
<OXYCAPT™② ~optional~>
Silicone-freeSilicone-free
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0
5
10
15
20
0 10 20 30
Glid
ing
Fo
rce(
N)
Distance (mm)
OXYCAPT™ (stopper with silicone)
OXYCAPT™ (stopper without silicone)
OXYCAPTTM (stopper without silicone)
OXYCAPTTM (stopper with silicone)
Glass
Sample Availability
Type Size Sample Supply Remarks
Vial 2mL From April 2018 ISO 8362-1
6mL Already started ISO 8362-1
10mL Already started ISO 8362-1
Syringe 1mL Long Already started ISO 11040-6
2.25mL Already started ISO 11040-6
(10mL Vial for initial evaluation) (1mL Long Syringe for initial evaluation)
(Other Sizes)
(Samples with Nest & Tub)
※Sterilized by gamma-ray.※These samples are trial products, not guaranteed.※Only for compatibility testing (e.g. 6 months storage)
RTU Syringe RTU Vial
Sample supplying has been started.
If requested, custom-made containers are available.
Closure
Crimp-Seal
Lure Cone
and
Lure Lock
30
Product Area Requirement Status
Oxygen
Absorbing
Resin
USA USP 661.1(Physicochemical) Meet Requirements
USA USP 87/88 (Biological Test) Meet Requirements
USA Drug Master File No.27495
Europe EU-Directive(PIM) Completed
Europe EP (for Polyolefin) Meet Requirements
COP(for drug contact layer)
Japan JP7.02 (as Container) Meet Requirements
USA USP 661.1(Physicochemical) Meet Requirements
USA USP 87/88 (Biological Test) Meet Requirements
USA Drug Master File No.14084 & 27657
Europe EP (for Polyolefin) Meet Requirements
Vial
Japan JP7.02 Meet Requirements
USA USP661.2 In Progress (expected to be completed by 4Q 2017)
USA USP671 Meet Requirements
USA Drug Master File No.30669
Europe EP3.2.2.1 Meet Requirements
Syringe
Japan JP7.02 In Progress (expected to be completed by 4Q 2017)
USA USP661.2 In Progress (expected to be completed by 4Q 2017)
USA USP671 In Progress (expected to be completed by 4Q 2017)
USA Drug Master File In Progress (expected to be completed by 2Q 2018)
Europe EP3.2.2.1 Meet Requirements
- ISO13485 (Bulk) Meet requirements
- ISO13485 (RTU) In Progress (expected to be completed by 4Q 2017)
Regulatory works of bulk vial are expected to be completed by 4Q 2017.
All regulatory works are expected to be completed by 2Q 2018.
Regulatory Compliance
31
• MGC has developed “OXYCAPT™ Vial & Syringe”
for bio drugs.
• OXYCAPTTM Vial & Syringe have
greatest features of both Glass and Plastics.
Glass-Like oxygen and water vapor barrier,
Low levels of inorganic and organic extractables,
Low protein adsorption,
High resistance to breakage, etc.
• Custom-made OXYCAPTTM containers are
available.
Summary
32