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Barrier Systems & Requirements
for Sterile Manufacturing –
Annex 1 Draft
Date : 14th July 2020
2
COPYRIGHT © PDA 2020
▪ Senior Consultant
Aseptic Processing & Containment @ SKAN AG
▪ PDA: Preventing Contamination and
Cross Contamination
▪ PDA Isolator Expert Group
▪ PDA Program Committee for the EU ATMP
and Bio Conference
▪ ISPE Chair CoP Containment and Chair Robotics
▪ ISPE CoP SPP Sterile Product Processing
▪ ISPE Chair Containment Guide
▪ PICs/Annex 2 – 2A ISPE Comments Team
▪ ISO TC 198 Aseptic Processing and Isolators
Your Presenter: Richard Denk
3
COPYRIGHT © PDA 2020
• Under Revision
• 6400 Comments back from the Industry.
• Complete new write of the document.
• Annex 1 is an European Document but with
global involvement.
Version 7 Publish Dec. 2017
Regulatory Annex 1 Draft 2017- 2020
4
COPYRIGHT © PDA 2020
• New Round of Comments to stakeholders
like ISPE, PDA to specific chapters.
• Lessons learned from the first draft.
Version 12 Draft Febr. 2020
Regulatory Annex 1 Draft 2017- 2020
5
PDA Points to Consider Published June 2020
COPYRIGHT © PDA 2020
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• Contamination Control Strategy CCS
• Quality Risk Management QRM
• Keep Operators out of critical Aseptic
Operations
• Barrier Solutions the preferred technology.
What are the :major driver for the
new Annex 1
Regulatory Annex 1 Draft 2017- 2020
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Conventional
Aseptic
Processing
Highest risk of
human
intervention
RABS «Restricted
Access Barrier
System»
Reduced risk of
human intervention
Isolators
Lowest risk of
human intervention
Regulatory Annex 1 Draft 2017- 2020
COPYRIGHT © PDA 2020
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Conventional
Aseptic
Processing
Highest risk of
human
intervention
Conventional Solution
▪ Operator have access to critical areas
▪ No Barrier
▪ Contamination Risk on the Curtain.
▪ Intensive Training and Monitoring
▪ Technology should be replaced to Barrier Solutions.
Regulatory Annex 1 Draft 2017- 2020
COPYRIGHT © PDA 2020
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RABS «Restricted
Access Barrier
System»
Reduced risk of
human intervention
RABS “ Restricted Access Barrier
System”
▪ Operator have access to critical areas
▪ Barrier but doors can be opened
▪ Decontamination inside of the door before closing.
▪ Intensive Training and Monitoring
▪ More and more poor designed RABS on the market.
Regulatory Annex 1 Draft 2017- 2020
COPYRIGHT © PDA 2020
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Regulatory Annex 1 Draft 2017- 2020
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Isolators
▪ Operator have no direct access to critical areas
▪ Surrounding Class C/D
▪ Validated and integrated decontamination system
with vH2O2
▪ Suitable for high potent products
RABS
▪ Operator have direct access to critical areas
▪ Surrounding Class B
▪ Decontamination together with the room
▪ Not suitable for high potent products
Regulatory Annex 1 Draft 2017- 2020
COPYRIGHT © PDA 2020
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Isolators
Lowest risk of
human intervention
Isolators
▪ Operator have no direct access to critical areas
▪ Validated and accepted decontamination system
with
H2O2
▪ Reduced Clean Room requirements outside of the
Isolator (ISO 7/8 Class C/D)
▪ Less Gowning of the Operator
▪ More and more poor designed Isolators on the
market.
High risk to the product
Regulatory Annex 1 Draft 2017- 2020
COPYRIGHT © PDA 2020
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The Olympic Rings for Annex1 Compliance in Isolators
Contamination Control Strategy
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Contamination Control Strategy
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Contamination Control Strategy
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Stainless steel not polished Aluminium
Influence of Cleaning and Decontamination on different surfaces
Contamination Control Strategy
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Contamination Control Strategy
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Grade A - Air Supply and Surface Decontamination
Contamination Control Strategy
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Contamination Control Strategy
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Contamination Control Strategy
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Contamination Control Strategy
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Service covers
Vaporizer plate for H2O2Intake air from air handling unit
Recirculation fan
Unidirectional air flow
Differential pressure indicator
HEPA filter
Diffusor membrane
Return air
through double door
RTP
Critical zone
“Classified working zone”
Critical Zone for Surface Decontamination
Contamination Control Strategy
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dosing unit
vaporizer plate
Surface Decontamination
with vH2O2
Contamination Control Strategy
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H2O2 SolutionFlash
Vaporizer
H2O2 vapour
Carrier gas
HEPA filter
Isolator chamber
Surface Decontamination
with vH2O2
Contamination Control Strategy
COPYRIGHT © PDA 2020
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0 1 2 3 4
Leak Test Pre-Conditioning Conditioning Decontamination Aeration
Decontamination effect
Cycle phases
Surface Decontamination with vH2O2
Contamination Control Strategy
COPYRIGHT © PDA 2020
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Fastest H2O2 cycles with state-of-the-art SKANFOG® decontamination
technology
▪ Micro-nebulization of H2O2
▪ Fastest decontamination process
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Contamination Control Strategy
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Cycle phases
Surface Decontamination with atomized H2O2
Contamination Control Strategy
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Surface Decontamination with atomized H2O2
Contamination Control Strategy
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Proof of Surface Decontamination with Biological Indicators
Contamination Control Strategy
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• Defined test organism
• Defined initial population
• Carrier material
• Primary packaging
• Inactivation method
• e.g. Geobacillus
stearothermophilus
• e.g. 1.0 x 106 [spores/carrier]
• e.g. stainless steel
• e.g. Tyvek
• e.g. gaseous H2O2
Contamination Control Strategy
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Worst Case Study with Biological Indicators
Contamination Control Strategy
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Sterility Test
Contamination Control Strategy
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Contamination Control Strategy
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There will be a PDA Paper about Quality Risk Management for Isolator Gloves together with the BPOG.
Isolator Glove Test
Contamination Control Strategy
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Visual Test Physical Test Glove Quality Risk Management
Contamination Control Strategy
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Contamination Control Strategy
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Contamination Control Strategy
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GMP Cleaning and Operator SafetyContamination Control Strategy
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Validation of the cleanliness of
non-product-contact surfaces
has increased in popularity
since the EMA proposed the
following measures in order to
demonstrate effective
management of the cross-
contamination risk (in Chapter
5.21 of Part 1 of its GMP
guidelines): “Depending on
the contamination risk,
verification of cleaning of non-
product contact surfaces and
monitoring of air within the
manufacturing area [...] in
order to demonstrate
effectiveness of control
measures against airborne
contamination or
contamination by mechanical
transfer.”
Contamination Control Strategy
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•
Contamination Control Strategy
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Contamination Control Strategy
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Automation with Robotics
Contamination Control Strategy
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Automation with Robotics
▪ Human intervention only possible with
the Robot
▪ New Requirements for Viable
Monitoring needed based on automation
and real time release.
▪ Automated Transfer of Stoppers, Caps
etc.
▪ Ready to Use (RTU) End to End design
( Sustainability)
▪ ISPE DACH SIG Robotic
Contamination Control Strategy
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