Aseptic toxic fill-finnish isolator pharma pharmaceuticals skan engineering h2o2 decontamination manufacturing vial syringe ebeam lyo lyophilisation

1. Manufacturing fill-finnish
with aseptic toxic
pharma Isolators
1
18.04.2023 Reinraum-Lounges 2023 – SKAN - Frank Lehmann

2. SKAN
1. Introduction
Myself
SKAN
2. Challenge
Comparison to purely aseptic processing
Comparison to aseptic toxic processing
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18.04.2023

3. Introduction
Frank Lehmann
Since 2005 with SKAN
25 years cleanroom technology
20 years Isolator technology
Today ”Head of Strategic Product Management”
Book, chapters,
papers,
Patents
S
Roboterlösungen in der aseptischen Herstellung 3
19.04.2023

4. What we are standing for:
Together always one step ahead
We support our customers
in improving their products
and manufacturing them
even more efficiently.
Relying on our industry expertise,
we collaborate with our customers to find the
best solution for every application
We act as a reliable partner
for our customers and employees
S
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18.04.2023

5. Facts and figures 2022
S
> 50 years
Experience in
Isolators
> 1000
Highly skilled
employees
Multinational
Worldwide
connected
200M
turnover
Market Leader
CoC
Center of
Competence
> 1000
Running
Isolators
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6. SKAN
SKAN Core Competences
Sterility Testing Filling Isolator
skanfog® SARA VARIOSYS
skanfog®
Technology
NANOX®
Catalytic Converter
WirelessGT SKAN BI
INTEGRA
ebeam Transfer System
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7. SKAN
Global presence
SKAN AG Headquarters Allschwil Switzerland
SKAN Germany
SKAN US
SKAN Stein Switzerland
SKAN Japan
Aseptic Technologies Belgium
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8. SKAN
Challenge
Comparison to purely aseptic processing
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9. Purely aseptic
Protect the product of potential contamination
from outside.
Humans are the biggest
source of contamination!
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10. SKAN
Pressure Cascade (sample aseptic)
Depyrogenation Tunnel
+
Filling & Stoppering
+++
Capping
+
Lyo
Loading
/
Unloading
++
Lyophilizer
~12 Pa 40 Pa 20 Pa
30 Pa
Process
Process Process
20 Pa
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11. SKAN
Aseptic-Toxic – classification
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12. Aseptic-Toxic
Protect the product of potential contamination
from outside.
Protect the outside of potential contamination
from the product.
Get reliably rid of residuals from Product A,
when afterwards dealing with Product B.
S
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13. SKAN
Pressure Cascade (sample aseptic, toxic )
Depyrogenation Tunnel
+
Filling & Stoppering
+++
Capping
+
Lyo
Loading
/
Unloading
++
Lyophilizer
~12 Pa 40 Pa 20 Pa
25 Pa
Air flow
20 Pa
30 Pa -10 Pa
Infeed
++++
Washing
-
Air flow
Air flow
Air flow
Air
flow
Air flow
Air
flow
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14. SKAN
Requirements for return
air filter concepts
Big air flow from over the base plate
needs to be filtered
Safe, simple and low contamination filter
change
Area between working chamber and filter
needs to be cleanable
- automatic cleaning system for
inaccessible areas
- cleaning with glove and spray gun
in the working area
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15. SKAN
Execution of highly potent isolator
Slide 15
Isolator for aseptic processing of highly potent products

16. SKAN
Execution of highly potent isolator
Slide 16
Isolator air handling (aseptic/toxic)
• No extra space for BIBO filters in technical area required
• Return air ducts protected with cartridge filters do not require
wash down (cleaning validation)
• Manual spray guns for wetting and cleaning
• Special cartridge filters (FIPA) located close to filling area

17. SKAN
Execution of highly potent isolator
Slide 17
Air Handling Concept for highly potent product - skanfog
• Innovative Air Handling unit with exhaust back to outside
• Option for return back to room – zero balance issues – energy saving
• Reliable SKAN NANOX catalytic convertor
• skanfog decontamination with nebulized Hydrogen Peroxide and
patented Catalytic Convertor
• SKAN Isolator with unidirectional air flow with controlled conditions
• Patented FIPA safe change return filters
• CLEAN options, spray guns

18. SKAN
Filter concepts
Classic method:
a) Push-push filter system
b) Washable return air filter ducts with bag-in
bag-out (BIBO) filter change.
SKAN filter cartridge box for filling lines:
“FIP -FL” for operator handlings on both
sides of filling line isolators.
Lounges 2023 - Frank Lehmann
Bild: Ausbau eines kontaminierten Bag-in/Bag-out Filter. Lehmann F. und
Lümkemann J.; Safe change filter systems for containments in the
pharmaceutical industry; Pharm. Ind. 73, Nr.9, 1683-1694 (2011
18
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19. SKAN
Execution of highly potent isolator
Slide 19
Filter Cartridge (FiPa)
SKAN patented safe change return air filter
Return air duct (clean area)
Isolator inside (potentially “contaminated” area)
Potentially “contaminated” area
Filter medium
Clean area
Contamination “caught” inside
Contamination «caught» inside

20. SKAN
Handling of “FIP ”
Change of FIPA cartridge filter
invented by SKAN
FIPA service access hermetically
or pneumatically sealed (operated
trough HMI)
FIPA opening / closure
mechanically or with automatic
drive (operated trough HMI)
Slide 20

21. SKAN
Cleaning
Slide 21
Spray guns
▪ For manual cleaning inside the isolator working
chamber (to the boundaries of potential
contamination)
▪ Switchable – initially water, afterwards air
Drains
▪ From inside the isolator working chamber to
the drainage system.
▪ Drains can be protected with perforated grids
in order to not flush potential glass breakage
in.

22. SKAN
How to deal with it
Get reliably rid of residuals from Product A, when afterwards dealing with Product B.
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23. Cross-contamination
PDA Letter Nov 6th, 2017
Isolator Surfaces and Contamination Risks to
Personnel and Patient
Effective cleaning at the end of dealing with a
product is KEY.
Avoid product spread during dealing with a product
is the WAY.
Summarizing the following ways of product spread:
Air flow
S
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24. Cross-contamination
PDA Letter Nov 6th, 2017
Isolator Surfaces and Contamination Risks to
Personnel and Patient
Effective cleaning at the end of dealing with a
product is KEY.
Avoid product spread during dealing with a product
is the WAY.
Summarizing the following ways of product spread:
Air flow
Mechanical transfer
Contact contamination
S
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25. Cross-contamination
PDA Letter Nov 6th, 2017
Isolator Surfaces and Contamination Risks to
Personnel and Patient
Effective cleaning at the end of dealing with a
product is KEY.
Avoid product spread during dealing with a product
is the WAY.
Summarizing the following ways of product spread:
Air flow
Mechanical transfer
Contact contamination
S
Lounges 2023 - Frank Lehmann
Guidelines for Risk Assessments
In line with the EU GMP Guidelines, Chapter 3
and 5, a risk assessment has to be performed
with regard to potential cross-contamination of
one product with another – the objective being
assuring patient safety.
25
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26. SKAN
How we deal with it
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27. SKAN
CLEAN
Your Challenge – Our Solution
How do we deal with it?
well thought out
because the topic has the potential to paralyze
the project
as careful as necessary
but as straight forward as possible
trying to avoid overshoots
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28. CLEAN
Your Challenge – Our Solution
How do we deal with it?
well thought out
because the topic has the potential to paralyze
the project
as careful as necessary
but as straight forward as possible
trying to avoid overshoots
Lounges 2023 - Frank Lehmann
18.04.2023

29. SKAN
SKANalytix
CLEAN - Service Packages
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30. SKAN
Improve your cleaning assessment workflow
Identify with a traceable substance (i.e. fluorescence) the source and
contaminated areas in the filling line during production & failure
mode
Characterize the distribution patterns
Choose the surrogate substance
Determine the more adequate sampling method (swab or rinse
sampling) - based on reproducibility and sensitivity requirements by the
PDE
Set up tailor-made MOC coupon spiking studies to achieve more
realistic recovery factors estimation
Force contaminate the filling line, test the efficacy of the cleaning
SOPs and check for possible airborne residues
Test effectiveness of the containment equipment during challenging
operations by measuring airborne emissions and surface contamination
Operator
safety
Contamination
mapping
Surrogate
selection
Material and
recovery studies
Cleaning
simulation
Contamination
mapping
Surrogate
selection
CLEAN - workflow
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31. SKAN
Typical contamination locations in fill & finish processes
Filling
Vials
crush
Mechanical
transfer
Contamination spread
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32. SKAN
CLEAN - Contamination Mapping
Simulation of filling with worst case parameters (highest speed and volume)
Simulation of worst case scenarios – vial break, contamination distribution, spillage in FIPA,
splashes on RTP ports, etc.
Delineation of practical contamination level risk sub-areas
Characterization of distributions patterns
Lounges 2023 - Frank Lehmann
Contaminated
vials
Clean
vials
Last detectable
contamination of
conveyor
Vial crush
Contamination
distribution
32
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33. SKAN
CLEAN - Evaluation of cleaning efficacy
Simulation of cleaning procedure
Qualitative
Fluorescent marker
(Riboflavin)
Visual evaluation
Definition of worst-case
positions
Quantitative
Pharmaceutical or surrogate
Recovery and analysis of
residuals
Demonstrated cleanliness
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34. SKAN
1 2 3 4 5
Manual wiping: Measure and quantify cleanness
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Understand and quantify the cleaning kinetic of different materials and pharmaceutical soils
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35. SKAN
Rinse wash: Measure and quantify cleanness
Lounges 2023 - Frank Lehmann
Understand and quantify the rinsability of different materials and pharmaceutical soils
257.34
83.32
28.58
0
50
100
150
200
250
300
Start 15s 30s
ug/dm2
0.0%
67.6%
88.9%
0%
20%
40%
60%
80%
100%
Start 15s 30s
Cleaning
Efficacy
(%)
Pharmaceutical soil B
212.90
0.21 0.00
0
50
100
150
200
250
Start 15s 30s
ug/dm2
0.0%
99.9% 100.0%
0%
20%
40%
60%
80%
100%
120%
Start 15s 30s
Cleaming
Efficacy
(%)
Pharmaceutical soil A
35
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36. SKAN
Typical contaminations observed in a filling line
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37. CLEAN IP
CLEAN Indicators & Prints
Produce chemical distributions at
predetermined doses
Standardize contamination distribution to
reduce/eliminate variation in the recovery rates
Speedup recovery/cleaning studies: no
waiting times » immediately dry contaminated
surface
Generation of (custom) cleaning performance
indicators (CPIs) to guide your bench and field
studies
S
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38. SKAN
SKANalytix
CLEAN - Service Packages
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39. skan.com
frank.lehmann@skan.ch
Thank you