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RABS & Isolators

Barrier Technology

Gordon Farquharson, May 2016

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• History & perspective

• Advanced aseptic processing concept

• Evolution

• Expectations

Overview

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Nothing new – Isolators designed and used in 1989, 1999/2000

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Photo Courtesy of Bosch Packaging

1989 – ampoule filling isolator with softwall isolator

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In May 2001 US FDA were clear about the potential of the technology

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In2001 lots of debate about killing microbes

What I love is that we are still

debating it today, > 15 years on!

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Where do we still go wrong?

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We still try to put cleanroom equipment

and processes in a small box; operate

like we do in a cleanroom; and use

open cleanroom monitoring techniques

to monitor how well we’re doing !

How can we get better?

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Increasing system integrity

Increased sterility assurance

RABS2000s

Isolators1990s

Evolution - The aseptic processing integrity spectrum”

Advanced aseptic processing2000s

Blow-fill-seal1970s

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Advanced aseptic processing

• This US FDA initiative started the whole RABS debate.

• US FDA suggested that they would favour firms that used ”advanced aseptic processing”.

• Isolators.

• Properly managed “blow fill seal”.

• A number of big pharma and generic firms got grumpy because they didn’t want to be pushed into using isolators because they were unsuitable:

• Dry powder fill.

• Excessive change-over time - Multiple product generic and CMOs.

• The concept of the RABs emerged (restricted access barrier system):

• ISPE got in on the act and agreed a definition with US FDA in 2006.

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GMPs & Barrier Technology

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Maturing technology in EU/PIC-S GMPs – Isolators & RABS

21. The utilization of isolator technology to minimize human interventions in processing areas

may result in a significant decrease in the risk of microbiological contamination of aseptically

manufactured products from the environment. There are many possible designs of isolators

and transfer devices. The isolator and the background environment should be designed so

that the required air quality for the respective zones can be realised. Isolators are

constructed of various materials more or less prone to puncture and leakage. Transfer

devices may vary from a single door to double door designs to fully sealed systems

incorporating sterilization mechanisms.

• Today, we should see Isolators and RABS as essential technology that should at least be considered –improved separation of personnel from process.

• Perhaps the revised Annex 1 (2016/17) will say??????

• “The utilisation of barrier technologies, RABS and Isolators can improve the sterility assurance during open aseptic processing, and should be considered when selecting the most appropriate environmental control solution.”

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Characterising the barrier technologies

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Traditional cleanroom(our GMPs are written around this approach)

© Critical Systems Ltd 201621

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Traditional cleanroom – characteristics

• Grade B/ISO7 Room scale critical environment contains operators

• Critical Grade A/ISO5 Aseptic process Core located in the

Grade B/ISO7 room

• Operators access equipment from surrounding Grade B/ISO7 room

to load the process and intervene using defined SOPs. High reliance

on operator garments

• Bio-decontamination…

‒ Autoclave sterilisation of product contact parts, followed by

aseptic assembly.

‒ Topical disinfection of surfaces

‒ Room fumigation in some cases (rare these days)

• Separation between operators and aseptic process core

‒ Polycarbonate doors

‒ Screens

‒ Curtains

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Conveyor

Vial

Nozzle

Filling

Mechanism

Conventional Clean Room

HEPA Filters

Class 100

(ISO 5)

Grade B

non-UDF

Room

Grade A

UDF Zone

Traditional cleanroom – principles

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Open cleanroom – example unacceptable practice of operators inside Grade A UDF zone

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Conveyor

Vial

Nozzle

FillingMechanism

HEPA Filters

HVAC - Fans

Grade A

UDF Zone

Grade B

non-UDF

Room

Minimum open cleanroom – principles (limited access)

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The minimum acceptable cleanroom practice todayRigid screens separate personnel from the aseptic process.

Highly controlled access to the machine enclosure.

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The “RABS” restricted access barrier system

© Critical Systems Ltd 201627

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Definitions (ISPE) – just be aware of thisA barrier system is:

• “A system of physical partitions that affords Grade A protection

by partially separating its interior from the surrounding

environment utilizing airflow.”

Restricted Access Barrier System (RABS) is:

• “An aseptic processing system that provides an enclosed, but

not closed, environment meeting Grade A conditions utilizing a

rigid-wall enclosure and air overspill to separate its interior from

the surrounding environment.”

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RABS TYPES &Configurations asdefined in PHSSRABS Technical

Monograph 15

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It is considered to qualify as RABS that complywith the PHSS monograph the following design and

contamination control attributes should becombined in a system design:

RABS disinfection method andprocess application

manual or automatic

RABS environmental &

contamination control

attributes + monitoring

The RABS –‘System’

RABS access control for

barrier process transfers and

operator access

Sterilisation processes for

direct and indirect product

contact parts

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RABS types

Grade A

Grade A

Grade B

Grade B

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Annex 1 Grade B

RABS Background

‘Open’ ‘Closed’

RABS with air over spill tothe ISO7 surrounding Area.Photograph courtesy of Boehringer Ingelheim Germany.

Possible HPV high level disinfection

together with the Clean room.

Closed RABS for HPV

gassing with integral air returnpaths and part recirculationPhotograph courtesy of Franz Ziel, Germany for a Pharma project in Ireland.

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Open RABS – characteristics

• The Grade B/ISO7 Room scale critical environment contains operators

• Critical Grade A/ISO5 Aseptic process Core sits in Grade B/ISO7 room

• Operators use glove ports for intervention, and closed component handling from the surrounding Grade B/ISO7 room

• Bio-decontamination…generally as open room

‒ Autoclave sterilisation of product contact parts, followed by aseptic assembly.

‒ Topical disinfection of secondary surfaces

‒ Room fumigation in some cases

• Separation between operators and Grade A/ISO5 Aseptic process core

‒ Polycarbonate doors

‒ Screens

With glove ports and transfer

ports for components

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Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

HVAC

Class10,000(ISO 7)

Grade B

Grade A

Locally increased

UDAF zone to protect door opening for very limited

interventions

Grade B

Room

Passive RABS

In passive RABS

resistance to airflow can

cause lateral flows.

RABS – principles

7-Feb-18 © Critical Systems Ltd 2016

34

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Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

HVAC

Class10,000(ISO 7)

Grade A

Locally increased UDAF zone to protect door opening

for very limited interventionsGrade B

Room

Active RABS

RABS – principles

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Passive Open RABS – example

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RABS – example illustrates problem of aseptic assembly of complex change parts

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Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

HVAC

Class10,000(ISO 7)

Grade BGrade A

This variation has the ability to close a valve to allow a closed system gassing, fumigation or bio-decontamination or surface sterilisation.

HEPA Filters

HVAC

HEPA Filters

HVAC

Closed RABS – principles

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Conveyor

Vial

Nozzle

Filling

Mechanism

HEPA Filters

Class 100

(ISO 5)

HVAC

Class

10,000

(ISO 7)

Grade B Grade A

Closed RABS – principles

This variation has the ability to close a valve to allow a closed system gassing, fumigation or bio-decontamination or surface sterilisation.

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The “Isolator”

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Isolator – characteristics

• Small contained enclosure excludes process operators

• Critical Grade A Aseptic process Core sits in Grade C or D “at rest” room

• Operators only open equipment when off-line. Human access via glove ports, and closed process loading

• Bio-decontamination…

• Sporicidal gas bio-decontamination of product contact parts.

• Steam sterilisation of fluid pathway.

• Separation between operators and aseptic process core

• Isolator shell

• Windows

• Glove ports

• Transfer ports sterilised change-parts & components

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Conveyor

Vial

Nozzle

Filling

Mechanism

Isolator

HEPA Filters

Class 100

(ISO 5)

AirReturn

Class

100,000

(ISO 8)

Isolator – principles

Grade A

Grade C

or min Grade D

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Isolator – examples

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Isolator – examples

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www.pharmsystems.com/ LabServices/LabFacility_...

Half suit (a sterile API application)

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Some final thoughts

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Barrier technology - the future

1. GMPs will expect that we consider the use of RABs and Isolators.

2. We need to get better at the technology.

3. Personal view –

• We need to find a better agent that HPV for bio-decontamination. ClO2, O3, and NO2 seem to offer some exciting opportunities.

4. For many isolators, traditional microbial monitoring presents the greatest aseptic processing risk:

• Getting media IN & OUT.

• Managing the false negative risk of the gassing agent.

5. Technologies we should consider:

• Rapid and instant microbial detectors.

• Take the environment to the detectors, not place the detector in the isolator or RABs.

6. Design the process to be more barrier sympathetic.

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ANY QUESTIONS?

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ANY QUESTIONS?