Download 10-10-19 PDA Sterile Connectors v3

Sterile Connectors:
Selecting your device
Will Waterfield
October 22, 2019
Pharmaceutical Connectors
• Connectors provide a means to join two lines and transfer
fluids from one container to another while maintaining a
sterile pathway
– Enables two separate systems to communicate without
contamination of the fluid by ingress, and of the environment by
egress of potentially toxic leakage
– Typically the connector is pre attached and isolated by either
membranes or valves
• Sterile connectors become a critical process aid
– When biosafety hoods are unavailable,
– Protect operators from product and
– During continuous manufacturing
2
2
In a perfect world the ideal connector needs….
•
•
•
•
•
•
•
•
•
Reduced classified environment requirements
Intuitive ergonomics to reduce errors
Single step connectors to dramatically reduce training
Qualification tests with media-wet tubing
To enable multiple connections/disconnections
To be cost effective
To limit wasted material
To be available with multiple tubing diameters and
Indispensable to enable continuous manufacturing of liquids
or semi liquids, and
• Ultimately to be genderless
3
3
Selecting your CONNECTORS
SINGLE
CONNECTIONS:
MULTIPLE
Removable TABS => No ROC (*) Integrity => “sterile” transfer in ISO 7 or ISO 5
ROC (*) Integrity => sterile transfers in CNC
Data available
Up to 6
(Click for details on the name)
SINGLE STEP or INTUITIVE ?
Tube
WELDER
Aseptiquik
G
3 step
Aseptiquik
DC
3 step
KLEENPAK
10 step +
cradle
Opta
SFT
3 step
for ♂
only
Lynx
S2S
Phaseal
Lynx
CDR
SCOTPS
7 step
12 step
4 step
1 step
bayonet
Once
connected
Once
connected
Once
connected
Data available Data available
Up to 10
Up to 10
SCOTSCV
1 step
bayonet
DROC
1 step
bayonet
WET TUBING
NO LIQUID LEAKAGE
before during and after transfer
NO GERM INGRESS
before during and after transfer
COMPLETELY CLOSED NO INGRESS NO
VAPOR EGRESS before during and after transfer
Once
Once
connected connected
Once
Once
connected connected
?
No post
disconnect
No post
disconnect
Once
connected
Once
connected
?
COST EFFECTIVE
Limited PLASTIC WASTE
1/9 “ or 1/8”
1/4 “
3/8 “
1/2 “ or ¾”
5/8” or 1 “
1½“
GENDERLESS
(*) ROC = Ring of Concern
Enabling
CONTINUOUS
Manufacturing
5
5
Static immersion of separated uncapped male and female
connectors
Number of
units passed/
units tested
Test
Microorganism(s)
Target
Bioburden
Exposed
Surface
Exposure
Time
Dry or Wet
Connector
Kleenpak™
B. diminuta
S. marcescens
6-Log (CFU/ml)
removable
tab
> 1 hour
Dry
2/2
Opta® SFT
(Validation
Guide)
B. diminuta
6-Log (CFU/ml)
removable
tab
30 min
Wet
20 /20
SCOT-PS
B. diminuta
S. marcescens
6-Log (CFU/ml)
Entire,
uncapped
connector,
cavity surface
exposed
 1 hour
Wet
30/30
SCOT-SCV
B. diminuta
S. marcescens
6-Log (CFU/ml)
Entire,
uncapped
connector,
cavity surface
exposed
 1 hour
Wet
30/30
Connector
Notes:
Data provided by INTACT Pharma
Lynx® S25, Lynx CDR, AseptiQuik, Kleenpak and Phaseal are not recommended for use under wet conditions
6
6
Aerosol/Soiling Challenge: Results from Validation Guides
Connector
(Validation
Guide)
Aseptiquik® G
Test
Microorganism(s)
Target
Bioburden
Exposed
Surface
B. diminuta
8-Log
(CFU/mL)
Peel-Off
Membrane
Kleenpak™
S. Marcescens
6-Log
(CFU/m3)
Opta® SFT
B. diminuta
6-Log
(CFU/mL)
Peel-Off
Membrane
Lynx® S25
B. Diminuta
6-Log (CFU/
connector)
removable
tab
removable
tab
Exposure
Time
Dry or Wet
Connection
Number of
units
passed/units
tested
30 seconds or
sprayed
Dry connection
35 / 35
Unknown/
Undefined
Dry connection
in aerosol
chamber,
followed by
media transfer
4 /4
(Exposure time
not provided)
Unknown/
Undefined
Dry connection,
& 10min
immersion
20 / 20
Unknown/
Undefined
Dry connection
in aerosol
chamber,
followed by
media transfer
Unknown
number of units
and unknown
duration
7
7
Aerosol/Soiling Challenge: Results from Suppliers
Connectors
Phaseal™
(from
validation
guide)
Lynx® CDR
(from
validation
guide)
DROC
SCOT-PS
Test
Microorganism(s)
Target
Bioburden
Exposed
Surface
Exposure
Time
Dry or Wet
Connection
98.2% probability of sterile transfer from vial to syringe, 99.7% probability of sterile
transfer from syringe to IV- bag; sterile transfer assurance in ISO 5 environment
B. diminuta
4-6 Log CFU
Number of
units
passed/units
tested
1304/1328
in ISO 5
Tab
Unknown/
Undefined
6 wet
connections in
ISO 7
Unknown/
Undefined
application
B. diminuta,
S. marcescens,
E. aerogenes
4-Log
(CFU/m3)
Entire
connector
15 minutes
10 wet
connections in
CNC
10 / 10
E. aerogenes
4-Log
(CFU/m3)
Entire
connector
15 minutes
Dry
connection in
CNC, then
media transfer
30 / 30
Notes:
DROC and SCOT-PS data provided by INTACT Pharma
8
8
Beware of Vendor Test Protocols
• Specified testing method
– AAMI (Association for the Advancement of Medical
Instrumentation) or
– Producer Testing Method
• Wet or dry
• Challenge limited by tab or to full uncapped container
• Aerosol or Immersion
• Challenge Duration
• Challenge set
• Environment requirement: ISO 5, 7 or 8
• Ring of Concern
9
9
Ring of Concern
• The Ring Of Concern (ROC), is the Microbial barrier
between the outer potentially contaminated, and the inner
sterile surfaces
• The challenge is to transfer the sterile fluid from one closed
container, into another closed sterile container, without
breaching the “ROC” (different from tortuous path or
labyrinth seal , and from tab surface removal)
• Sterile transfer is all about the mechanism used to secure
the ROC Integrity, before, during and after connection
10
10
Augmenting a Connector Test Series to
demonstrate ROC integrity
•
Before connection
– Immerse the uncapped units into broth
– Incubate
– Check for growth in the pouch sealed to the respective connector
•
While Connected
– Fluid transfer while immersed
– Disconnect
– Incubate
– Check for growth in the pouch sealed to the respective connector
•
Connect and disconnect multiple times
– Last connect/disconnect
– Immerse the disconnected units into broth
– Incubate
– Check for growth in the pouch sealed to the respective connector
•
Post second or third connection demonstrate sterile fluid transfer:
– Fluid transfer
– Last connect/disconnect
– Incubate
– Check for growth in the pouch sealed to the respective connector
11
11
ANNEX
Hyperlinks
12
Suppliers of marketed connectors
•
Thermoplastic Tube Welding
– GE Welder, Sartorius Bio-Welder and Terumo STCIIB
•
CPC (Colder Aspetiquick)
– https://products.cpcworldwide.com/en_US/ProductsCat/AseptiQuik-Sterile/
•
Pall Kleenpak
– https://go.pall.com/Kleenpack-presto-3-4.html?utm_source=google&utm_medium=cpc&utm_content=websiteconversions&utm_term=%2Bkpc%20%2Bconnector&gclid=EAIaIQobChMIsqfJc285AIVi4zICh0Fjw88EAAYASAAEgKeBvD_BwE
GE Readymate
– https://www.gelifesciences.com/en/us/shop/liquid-preparation-and-management/single-use-connectors/readymatesingle-use-connectors-p-00257
•
•
Sartorius
– http://microsite.sartorius.com/fileadmin/sartorius_pdf/alle/biotech/Data_Opta_SFT-I_SLO2000-e.pdf
•
Millipore
– http://www.emdmillipore.com/US/en/product/Lynx-S2S-Connector-for-sterile-to-sterile-connection,MM_NF-C9502
•
Closed System Transfer Devices
– https://www.bd.com/en-us/offerings/capabilities/hazardous-drug-safety/phaseal-system
– www.emdmillipore.com/US/en/product/Lynx-ST-Connectors,MM_NF-C9131
•
CPC (Colder) Aseptiquik
– https://products.cpcworldwide.com/en_US/ProductsCat/AseptiQuik-Sterile/
•
Refine Technologies
– https://www.refinetech.com/wp/products/
13
13
Tube Welders
•
•
•
•
Requires capital costs
Wafer cost for each
Genderless
A process to set up and
weld
• Fairly robust. Good tensile
strength and maintains
closed environment
• Small tubing diameter sizes.
Typically used for seed
transfers or other low
volume transfers
• Dry Weld only
Back to overview table
14
14
AseptiQuik® G or S Connector
•
•
•
•
Genderless design
3-step connection
Single use
Requires a controlled environment
to assure absence of contamination
ingress / egress
• Sterile transfers validated with
intentionally contaminated
membrane surfaces to be peeled
off prior to completing the
connection
• Four (4) sizes for G – 1/4“ to 3/4”
• Three (3) sizes for S – 1/8“ to 3/8”
• Dry connect
Back to overview table
15
15
AseptiQuik® DC Connector
•
•
•
•
Gendered
3-step connection
Single Use with Dis-Connect
Absence of contamination
ingress / egress assured in
classified environment
• Sterile transfers also
validated with intentionally
contaminated surfaces
which are peeled off prior
to completing the
connection
• Three (3) sizes – 3/8” to ¾”
• Dry connect
Back to overview table
16
16
Kleenpak™ Connector
• Gendered
• 10-step connection with
cradle
• Single use only
• Absence of contamination
ingress / egress assured in
Classified Environment
• Sterile transfers also
validated with intentionally
contaminated surfaces
which are peeled off prior
to completing the
connection
• Four (4) sizes – ¼” to 5/8”
• Dry Connect
Back to overview table
17
17
Opta® SFT Connector
• Gendered
• 3-step connection with
securing ring
• Single Use only
• Absence of contamination
ingress / egress assured in
classified environment
• Sterile transfers also
validated with intentionally
contaminated surfaces
which are peeled off prior
to completing the
connection
• Two (2) sizes - ¼” & ¾”
• Dry Or Wet Connect
Back to overview table
18
18
Lynx® S2S Connector
•
•
•
•
Gendered
7-step Connection
Single Use only
Absence of contamination
ingress / egress assured in
classified environment
• Sterile transfers also
validated with intentionally
contaminated surfaces
which are peeled off prior
to completing the
connection
• Three (3) sizes – 1/4” to ½”
• Dry connect
Back to overview table
19
19
Towards Closed System Transfer Devices (CSTD)
- Preventing Product to Operators cross
contamination, but
- Seems to increase Patients’ Bacteremia
(Marilyn Hanchett, ICT)
Phaseal™ System: Connector, Injector, Protector
•
•
•
•
•
•
•
Gendered
12-step connection from vial to syringe
8-step connection from syringe to IV-bag
Single use only
Absence of contamination ingress / egress
assured only in Classified Environment;
98.2% probability of sterile transfer from
vial to syringe, 99.7% probability of sterile
transfer from syringe to IV- bag; no ingress
observed between vial and protector
IV tubing size
Dry connect
“Although needleless connectors offer
enhanced safety features, there have been
recurrent concerns about an increased risk of
bacteremia associated with their use” (Marilyn
Hanchett, ICT)
Back to overview table
21
21
Lynx® CDR Connector
•
•
•
•
Gendered
3-step connection
Multiple Use (up to 6 Times)
Absence of contamination
ingress / egress assured in
classified environment
• Sterile transfers also validated:
– with intentionally contaminated
surfaces, then connected in ISO 7
classified environment
– without Intentional Contamination
in CNC environment
• Four (4) sizes – 3/8” to 1” + 1 ½”
Tri clover clamp
• Dry or wet connect
Back to overview table
22
22
SCOT-PS Connector
Piercing
Closed Needle
Pierceable
Septum
Back to overview table
• Gendered
• Completely Closed
• Single continuous bayonet-like
connection
• Single use for Female side
• Multi use for male side
• Absence of contamination ingress /
egress demonstrated for 10 male
connections / disconnections after 15
minute exposure to 10,000 CFU/m3
aerosol environment
• 1/4” and 3/8” size available
• Dry or wet connect
23
23
SCOT-SCV Connector (Self Closing Valve)
Closed Shaft with
Smooth Tip
(not a Needle)
•
•
•
•
Gendered
Completely Closed
Single bayonet connection
Multiple Use:
Absence of contamination
ingress / egress during 10
connections / disconnections
in CNC with 10,000 CFU/mL
incidental contamination of
male unit
3/8” size available, ½” and 1”
sizes tooling under
development
• Dry or wet connect
Back to overview table
24
24
DROC Connector
• Gendered
• Completely closed (or Closed
system design)
• Single continuous bayonet-like
connection
• Multiple use:
– up to 10 connections /
disconnections in CNC after
15 minute exposure to 10,000
CFU/m3 aerosol environment
(closed to environment)
• Relatively small ID - 1/9” size
• Dry or wet connect
Back to overview table
25
25
Seal Integrity – Wet tubing condition
Hermetic Seal
Expected Challenge conditions:
6-Log CFU/m3
≥ 60 minutes (1hr)
BACTERIA
STERILE
PRODUCT
Expected Incubation conditions:
10 – 14 days at 30C followed by GPT (Growth
Promotion Test)
GPT: To prove the Sterile Product was always
able to support bacteria growth if a breach
would have been present. Inoculation of <100
CFU followed by incubation at optimal
temperature (25 or 30C) (3 – 5 days)
26
26
Static Immersion - Separated Uncapped Male & Female
Step 1
Step 2
Uncap
Connectors
Capped
Capped
Male
Female
Filled with Media
Step
6 Log (CFU/ml)
S. marcescens
B. diminuta
60 minutes
Bio-Immersion
with Sterile Media at the seal
Step 4
3
Visual Inspection
(Turbid?)
Uncapped
Male
Uncapped
Male
Incubation
30oC, 10 days
with Sterile Media at the seal
Results
27
27
Transfer of media after connection followed by immersion
1
Female Unit
Male Unit
2
1.
2.
3.
4.
5.
Connection
Immersion
Unclamp
Transfer (Gravity)
Clamp
3
6-Log (CFU/ml)
S. marcescens and B. diminuta
Immersed for 10 minutes
Incubation: 14 days, 30oC
5
4
Results
Visual Inspection
For signs of contamination
Sample if necessary
28
28
Aerosol Challenge: Disconnected/Connected
1
Male Unit
2
Female Unit
3
Aerosol Chamber
Dry challenged surface
in operation environment
Challenge: Exposure Duration &
Chamber concentration TBD
4
1. Connection (SINGLE or
Multiple )
2. Transfer
3. Disconnect, if applicable
5
Must be disconnected for
incubation
6
Visual Inspection:
Turbidity?
If required:
Sample/Streak/Incubation:
Growth?
Connect & Transfer
Incubate
Analysis
29
29