Appendix 1 URS For Isolator and Safety Cabinets PDF

Client: Centre for Process Innovation (CPI) Validation Doc Number: na
Project: National Biologics Manufacturing Validation issue: na

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Title: URS – Isolators and Safety Cabinets Version: 2.0 Page: 1 of 31
CPI – NBMC
URS – ISOLATOR and SAFETY CABINETS

Abstract
Centre for Process Innovation (CPI) is setting up the National Biologics Manufacturing Centre
(NBMC) in Darlington. This will undertake process development projects for the UK
biopharmaceutical industry. Although this will not be a licenced GMP Facility, it will use
internationally recognised standards for operation to ensure that the processes and results of
experiments are transferable elsewhere.
Two types of Isolator and Safety Cabinets are required as follows:

 Negative pressure Safety Cabinets for operator & environment protection from cytotoxics
 Postive pressure Isolator for product protection for mimicking final finishing operation
This URS defines the performance requirements for both Isolator and Safety Cabinets and will
enable the vendor to design, specify, fabricate, install and commission the equipment.
Author Organisation & Responsibility Signature Date
Andrew Provan Process Consultant – eXmoor Pharma 20th Dec 2013
Approved By Organisation & Responsibility Signature Date
Robert Haugh Project Manager – eXmoor
Lucy Foley Project Engineer - CPI
Harvey Branton Process and Technical Manager-CPI
Jerry Cooper Project Manager - CPI
DOCUMENT HISTORY
Version Verification Reason for Issue Date
Issue
1.0 n/a For Client Review 12th Dec 2013
2.0 n/a Inc client comments – ready for ITT 20th Dec 2013

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CONTENTS
1. INTRODUCTION................................................................................................................... 3
1.1 Background ................................................................................................................. 3
1.1 Scope and Purpose of this Document ......................................................................... 3
1.2 Definitions .................................................................................................................... 4
1.3 Purpose of the Isolator and Safety Cabinets ............................................................... 4
2 REGULATORY REQUIREMENTS ......................................................................................... 5
2.1 Design ......................................................................................................................... 5
2.2 Qualification Requirements ......................................................................................... 5
3 DOCUMENTATION REQUIREMENTS .................................................................................. 7
3.1 Documentation General ............................................................................................... 7
3.2 Documentation Pre-Delivery ........................................................................................ 9
3.3 Documentation Post-Delivery ...................................................................................... 9
4 GENERAL REQUIREMENTS ................................................................................................. 9
4.1 Design Codes/Standards ............................................................................................. 9
4.2 Mechanical Design ...................................................................................................... 9
4.3 Electrical Design ........................................................................................................ 10
4.4 Site Safety ................................................................................................................. 10
5 LOCATION, UTILITIES AND CONNECTIONS ..................................................................... 11
6 SCOPE OF SUPPLY ............................................................................................................ 11
7 GLOSSARY AND REGULATORY FOCUS .......................................................................... 12
7.3 Health and Safety ...................................................................................................... 12
7.4 Glossary .................................................................................................................... 12
Appendix 1 –Layout of the Isolators 1st Floor Process CPI-NBMC .............................................. 13
Appendix 2 - SPECIFIC REQUIREMENTS ................................................................................. 14
A2.1 Isolator and Safety Cabinets Operation and Performance ........................................ 14
A2.2 Isolator and Safety Cabinets Controls and Instrumentation ...................................... 17
A2.3 Isolator and Safety Cabinets Ancillaries .................................................................... 19
A2.4 Isolator and Safety Cabinets Construction ................................................................ 19
A2.5 Isolator and Safety Cabinets Air Handling Units ........................................................ 22
A2.6 Isolator and Safety Cabinets Sterilisation .................................................................. 23
A2.7 VHP Generator Operation and Performance ............................................................. 25
A2.8 Cleanroom Sterilisation ............................................................................................. 26
A2.9 VHP Generator Controls ............................................................................................ 27
A2.10 VHP Generator Construction ..................................................................................... 29
APPENDIX 3 –3-WAY VALVE OPERATION ............................................................................... 31

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1. INTRODUCTION
1.1 Background
The Centre for Process Innovation (CPI) is setting up the National Biologics Manufacturing
Centre (NBMC) in Darlington UK to support, develop and progress the biopharmaceutical
manufacturing industry in the UK. It will be involved in process development, analytical methods,
training, new equipment, new technologies, showcasing equipment and technology, funding,
advisory support and act as a centre of collaboration and cross fertilisation of ideas in the UK.
The NBMC comprises 5,000m² flexible laboratory facility for process, analytical and technology
development, small scale production areas for process demonstration and pre-clinical
requirements, clean rooms for GMP simulation of process and equipment and flexible, open-plan
areas where new facility design concepts can be developed and tested.
In addition to the technical facilities, the Centre will provide training and conferencing facilities
together with office and meeting spaces.
The NBMC will not be a licenced GMP facility, and therefore will not be producing pharmaceutical
material for Clinical Trials nor for sale. Therefore none of the equipment nor processes needs to
be qualified or validated according to standard practice in the pharmaceutical industry.
However it is a requirement that any experiments or process development work is undertaken to

internationally recognised standards, so that the processes can be transferred to manufacturing
sites, and the experiments and results are reproducible elsewhere.
This will employ the same design, specification, installation and commissioning standards as
that for a licenced GMP facility. However it will not be qualified (IQ/OQ) but instead will undergo a
process of Documented Commissioning (DocCom), and DV, IV, OV and PV (Design, Installation,
Operation and Performance Verification).
This will employ many of the standards and technique as for Installation Verification (IV) and
Operational Verification (OV), but will not be subject to review by regulatory agencies.
The building design, construction and commissioning will be undertaken by others on a separate
contract, and will include the shell, clean room and laboratory fit out, HVAC, mechanical services,
electrical and other services.
The process equipment package (of which the Isolator and Safety Cabinets are part of) will be
specified and purchased separately by CPI.
1.2 Scope and Purpose of this Document

This specification covers the design, manufacture, installation, testing and documentation of the
Isolator and Safety Cabinets for the CPI-NBMC Centre. A total of two 4-glove Isolator and Safety
Cabinets are required as follows;
 1 negative pressure Safety Cabinets for cytotoxic production
 1 positive pressure Isolator for final finishing and formulation.
 1 vHP mobile generator to sterilise both Isolators/Safety Cabinets and Clean Room
Both Isolator and Safety Cabinets must be designed for automated VHP Sanitisation.

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Appendix 2 of this User Requirement Specification (URS) contains requirements, which relate to
current Good Manufacturing Practice (GMP) and hence will be qualified according to the
requirements of Section 2. User requirements in other sections and appendices relate to Good
Engineering Practice (GEP) and safety or provide information and so will not be qualified but will
become contractual requirements.
This URS will provide a basis for:

 Manufacture of the Isolator and Safety Cabinets by Supplier.
 Definition of performance testing requirements to be undertaken by the Supplier.
 Technical basis of contractual arrangements between the Supplier and the Purchaser
1.3 Definitions
The definitions employed in this document are as follows:
Purchaser Centre for Process Innovation

Project Manager Jerry Cooper, CPI
Main Contractor A design and build contractor, to be appointed
Process and GMP eXmoor Pharma Concepts, appointed by the Purchaser to carry
Consultant out process design and oversee GMP compliance and
qualification.
Supplier The designer and manufacturer of the Isolator and Safety
Cabinets
Must/Will The word “must” or “will” denotes that the requirement is
mandatory.
Should The word “should” denotes that the requirement is good
practice/highly recommended, but is not mandatory. Where the
Supplier does not meet this requirement it must be agreed with
the Purchaser.
May “May” is used where information is provided to assist the
Supplier, and no requirement is implied.
The Supplier of the Isolator and Safety Cabinets is required to adhere to the content of this
document; any deviations proposed must be clearly identified and justified by the Supplier.
Compliance with the agreed contents must be a contractual requirement of the purchase order
and any costs associated with meeting the agreed requirements must be included in the
purchase price.
Not withstanding anything to the contrary in this specification, the Supplier must be responsible
for ensuring that the Isolator and Safety Cabinets are “fit for purpose” and in particular for
achieving the performance set forth in this specification.
1.4 Purpose of the Isolator and Safety Cabinets
The Isolator and Safety Cabinets each comprise an aseptic process chamber, its loading and
unloading devices and any built-in equipment. The Isolator and Safety Cabinets are required to

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maintain a Grade A micro-environment in which the various ‘open’ processing stages of

individual aseptic batches can be carried out and which is continuously particle monitored.
The specific User Requirements detailed in Appendix 2 of this document have been derived from
the documents stated above
The Isolator and Safety Cabinets are to be used for both aseptic and contained bio processing of
microbial fermentation, mammalian cell cultures, purification and conjugation. These activities
support the development of CPI-NBMC processes and product developmemt for clinical use,
however no clinical material will be generated at the CPI-NBMC Centre and therefore any
products manufactured within the Isolator and Safety Cabinets will not be used for human
application.
The VHP necessary to sterilise the Isolator and Safety Cabinets will be generated by an
individual mobile VHP Generator system.
The processes to be carried out in the Isolator and Safety Cabinets are manual, may be
repetitive and may involve frequent material transfers in and out of the Isolator and Safety
Cabinets, thus ergonomics is a major design factor.
Hydrogen Peroxide Vapour (VHP) is hazardous to health, so the Isolator and Safety Cabinets
must incorporate appropriate safeguards for CPI-NBMC, maintenance and engineering
personnel.
2 REGULATORY REQUIREMENTS
2.1 Design
2.1.1. The Isolator and Safety Cabinets will be used in a GMP-like environment, therefore,
design, construction and installation does not have to comply with current Good
Manufacturing Practice, as referenced in Section 7, but should try to meet requirements
where possible.
2.1.2. The Isolator and Safety Cabinets must be designed, tested, supplied and commissioned
in accordance with a documented quality assurance system implemented by the
Supplier
2.2 Qualification Requirements
2.2.1. All qualification activities must conform to the requirements set out in the Facility and
Equipment Verification Plan, ####
2.2.2. The Isolator and Safety Cabinets have been assessed as ‘Direct Impact’ systems
requiring the following qualification stages. This qualification is required even though the
unit does not have to comply with cGMP because the gassing cycle development will not
be able to be completed without the unit being verified.
 Functional Design Specification (FDS)
 Design Verification (DV) including Verifictaion Traceability Matrix (VTM)
 Factory Acceptance Test (FAT)
 Commissioning

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 Installation Verification (IV)

 Operational Verification (OV)
 Gassing Cycle Development (GCD)
 Performance Verification (PV)
2.2.3. To support qualification the Supplier must provide a cross reference matrix (Verification
Traceability Matrix (VTM)) between this URS document, the Functional Design
Specification and specific tests to be carried out during Installation and Operational
Qualification. Appendix 2 is set out in the format of the VTM.
2.2.4. The qualification process will follow the principles set out in the ISPE Baseline Guide
Vol. 5, Commissioning and Qualification.
2.2.5. All Supplier testing of critical items will be carried out following pre-approved protocols
and test sheets and witnessed by the Purchaser.
2.2.6. The Supplier is responsible for providing all necessary documentation. Where test
sheets need to be completed, the Supplier must follow pre-approved documentation
procedures, according to pharmaceutical industry standards and take responsibility for
the correct completion of the test sheets, follow up actions and close-out of the testing
2.2.7.
The Supplier must, at the DV/VTM stage, complete a copy of the matrix given in
Appendix 2 in the following way.
Where “Required” is entered in the DV row, the Supplier must replace this with a statement
which confirms design compliance or not with the URS and gives a documentary reference
to the Suppliers Functional Design Specification which relates to the subject.
Where “Required” is entered in the IV row, the Supplier must replace this with a test
reference from their IV protocol.
Where “Required” is entered in the OV row, the Supplier must replace this with a test
reference from their OV protocol.
Where N.A. is entered in any row, this may be ignored.
Note: Appendix 2 is set out to be printed and used as A3 landscape.
2.2.8. The following table summarises the responsibilities for Supplier qualification services.
Responsibilities for Qualification

Prepare Approve Execute Write Report Approve
Protocol Protocol Protocol Report
FDS Supplier Approval by n.a. n.a. n.a.
Purchaser is
integral with
DV
DV (inc. VTM) Supplier Purchaser Supplier & Supplier Purchaser
Purchaser
FAT (i) Supplier Purchaser Supplier. Supplier Purchaser
Purchaser to
witness
Commissioning Supplier Supplier Supplier. Supplier Purchaser

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(i) Purchaser to
witness
IV Supplier Purchaser Supplier. Supplier Purchaser
Purchaser to
witness
OV Supplier Purchaser Supplier. Supplier Purchaser
Purchaser to
witness
GCD Supplier Purchaser Supplier. Supplier Purchaser
Purchaser to
witness
PV Purchaser Purchaser Purchaser Purchaser Purchaser
(Supplier to (Supplier to
advise) advise)
(i) Correctly documented FAT and / or Commissioning results may be leveraged into IV and OV
by agreement, if FAT and commissioning is undertaken to pre-approved Procedures and
included in the Supplier’s Quality Assurance System
3 DOCUMENTATION REQUIREMENTS
3.1 Documentation General
3.1.1. All documentation, including software printouts, must be in English.

3.1.2. Documentation must meet, as a minimum, the following requirements:
Providing all the details necessary so that the Isolator and Safety Cabinets can be
qualified
Providing ‘as built’ records and drawings.
Providing information so that operating and maintenance procedures can be prepared.
3.1.3. Plant items must be uniquely identified on schematic diagrams.
3.1.4. All documentation must be identifiable by the Purchaser item number, which is ZNNN.
All validation documentation must be numbered as follows: NBMC.ZNNN.Vnn.XX,
where nn = version number and XX = document type (FD = Functional Design
Specification, DV = Design Qualification, IV = Installation Qualification, OV = Operational
Qualification etc.)
3.1.5. The final issue by the Supplier of any piece of documentation is to be marked and
certified as the “As-built” or “As installed” version. The “As-built” and “As-installed”
document is defined as the document which accurately represents the system at
Handover, having passed through FAT, DV, Commissioning, IV and OV with all
documentation discrepancies cleared and final data verified.
3.1.6. The supplier must provide one paper copy and one digital copy of the Operation and
Maintenance Manual relevant to the specific Isolator and Safety Cabinets. (Copies of a
generic manual covering numerous models are not permitted).

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The supplier must provide one paper copy and one digital copy of all other
documentation relevant to the specific Isolator and Safety Cabinets, as listed below.
Digital copies must be delivered on CDROM, DVD or read-only USB Flash-Drive and
must be recoded in industry standard software packages such as Microsoft Office,
Adobe pdf and AutoCad for drawings.

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3.2 Documentation Pre-Delivery
3.2.1. Functional Design Specification (FDS), machinery and controls.

3.2.2. General arrangement drawings and schematics
3.2.3. Parts list with component specifications
3.2.4. Material certificates for all product contact parts or certificates of conformity to the
specification for all parts not provided with individual material certificates or other quality
assurance documents
3.2.5. Control schematics with control panel layouts and wiring diagrams
3.2.6. Instrumentation list with calibration certificates for critical instruments
3.2.7. Operating and Maintenance manuals
3.2.8. Preventative maintenance schedule and recommended spares list for 2 years
3.2.9. Executed FAT protocol and qualification protocols for approval, as noted in Section 2
3.2.10. Commissioning Procedure for comment and approval prior to execution
3.2.11. Qualification protocols for approval, as noted in Section 2
3.3 Documentation Post-Delivery
3.3.1. Any documentation which was issued as “preliminary”, “draft” or “for construction” or any
other documentation which requires revision as a result of commissioning and
qualification must be certified “As Installed” and re-issued.
3.3.2. Executed Commissioning Procedure approved by the Purchaser with a list of
commissioning spares replaced.
3.3.3. Calibration certificates for all test equipment used at any stage.
3.3.4. Executed qualification protocols and qualification reports for approval, as noted in
Section 2.
4 GENERAL REQUIREMENTS
4.1 Design Codes/Standards
4.1.1. The Isolator and Safety Cabinets must be permanently CE Marked to confirm
compliance with all relevant EU Directives, and a suitable conformance certificate must
be provided.
4.1.2. The Isolator and Safety Cabinets s must be safe to operate and comply with the
Provision & Use of Work Equipment Regulations, 1998.
4.2 Mechanical Design
4.2.1. The Isolator and Safety Cabinets must be designed as a complete, stand alone, unit
comprising process chamber, transfer hatch, air handling units (complete with fans and

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HEPA filters), VHP connections, controls (with intuitive HMI), powered height adjustment,
sleeves and gloves.
4.2.2. The Isolator and Safety Cabinets must be ergonomically designed to allow ease of use,
cleaning and maintenance.
4.2.3. Sensing devices must be easily accessible and removable for calibration and
maintenance purposes.
4.2.4. Supplier to confirm automated valves are equipped with open/closed limit switches as
standard.
4.2.5. The Isolator and Safety Cabinets must have adequate temporary protection suitable for
transporting to site and for on site storage and protection once installed up to and
including the commissioning stage.
4.3 Electrical Design
4.3.1. All electrical equipment, documentation and installation must comply with all local
regulations in the UK (the current edition of BS7671, IEE Wiring Regulations) and
EN60204 Safety of Machinery.
4.3.2. Electrical equipment must only be connected to a single source of supply. The machine
must be equipped with an isolation switch that completely isolates the machine from the
mains electricity supply. Any other voltages and frequencies must be produced from
within the equipment. Power supply for instrumentation and control must be 24V DC.
4.3.3. All electrical components and connectors must be compatible with those used in the UK
4.3.4. All electrical components must be contained in protective enclosures, having Ingress
Protection suitable for cleanroom which are frequently cleaned with lIVuid products and
also sterilised with VHP.
4.3.5. Access to electrical enclosures must only be permitted by use of a key or tools. Panel
doors must be interlocked to disconnect power from exposed equipment when the door
is opened. It is permissible to allow low voltage (24V) circuits to remain powered when
the door is open if mains voltage equipment is strictly segregated and effectively
protected from accidental contact.
4.3.6. All Isolator and Safety Cabinets metalwork must be securely earthed and an earth
continuity test carried out.
4.3.7. Adequate short circuit protection must be installed to guard against failure of individual
electrical circuits.
4.3.8. Clear labelling must be fitted to each fixed component and termination, labelling must
correspond to that used on wiring diagrams and parts lists.
4.3.9. An Electrical Safety Test must be carried out and documented to confirm safe
installation.
4.4 Site Safety
4.4.1 Where any site work (offloading, unpacking, moving into position, re-assembly,
installation, connection to services, cleaning, commissioning, testing, calibrating etc.) is
to be carried out by the Supplier, this will be under the direct control of the Main
Contractor, although the Purchaser may inspect or witness the work. The Site Rules of

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the Main Contractor and GSTT must be followed and Risk Assessments and Method
Statements for the work must be submitted and approved before starting work. All
Supplier’s staff working on site will be required to undergo Site Induction by the Main
Contractor.
5 LOCATION, UTILITIES AND CONNECTIONS

5.1. The Isolator and Safety Cabinets will be located in the following location at CPI-NBMC;
 Negative contained Safety Cabinets – Cytotoxic laboratory – Room 1.20
 Positive pressure Isolator – GMP Simulation – Room 1.33 or Room 1.34
5.2. The Isolator and Safety Cabinets will be floor standing, the ceiling is 2700 mm above
FFL.
5.3. The room temperature is controlled at 20 ± 3 oC and humidity will not be controlled
5.4. The route from the goods unloading area is via a goods lift and internal corridors
constrained by doors with an effective opening of 1800 mm wide and 2500 mm high, with
restricted turning space.
5.5. Utility Parameters Connection
Power 13 A, 230 V, 1 Phase, 50Hz 13A UK type socket
CO2 2 bar 0.5 inch quick connect
Vacuum Hospital vacuum 0.5 inch quick connect
6 SCOPE OF SUPPLY
The scope of supply must comprise.
6.1. Detailed design, manufacture, installation, commissioning and qualification of the Isolator
and Safety Cabinets
6.2. Packing and delivery to site, including insurances and customs duties etc.
Offloading, unpacking and moving into position.
6.3. Re-assembly and installation, including connection to services, which will terminate
approximately 2m away from the machines.
6.4. Commissioning including supply of all consumables, spare parts, labour and calibrated
test equipment used in the tests. Note that commissioning and qualification may be
scheduled several weeks after installation.
6.5. Qualification services listed in Section 2
6.6. Comprehensive training in both operation and maintenance, with Training Certificates
issued to Purchaser’s staff who have completed the course.
6.7. Documentation, as listed in Section 3.
6.8. Handover will be achieved when a Handover Certificate (prepared by the Supplier) is
signed by the Purchaser.
The Handover Certificate will confirm the completion of the following:
 Equipment is installed, commissioned and operating without snags or faults
 O & M Manual has been delivered and its content approved

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 DV, IV and OV protocols have been executed and unconditionally approved

 GCD has been completed and unconditionally approved
 Training has been completed and training certificates issued
 All other documentation listed in Section 3 has been delivered
 Spare parts ordered with the contract have been delivered
6.9. Minimum 12 months Warranty from date of Handover, covering on-site repair and
replacement of defective parts with re-qualification, if necessary 48 hour maximum
response time required.
6.10. One year’s on-site planned maintenance contract, with defined rates for labour and
parts. Tenderer to provide an option to extend the planned maintenance contract,
including a 48 hour maximum response time breakdown service, for years 2 to 3.
6.11. Supplier must provide a minimum of 1 spare HEPA filter for each model number of filter
used in the Isolator and Safety Cabinets. For example should an Isolator or Safety
Cabinets use 1 off 300 x 300mm H14 and 1 off 600 x 600mm H14 and there are 6
Isolator and Safety Cabinets all the same then commissioning consumables must be 6
off 300 x 300mm H14 and 6 off 600 x 600mm H14.
The commissioning spares are to be shipped with the equipment and identified as an
individual line item for costing purposes.
7 GLOSSARY AND REGULATORY FOCUS
7.3 Health and Safety

o Control of Substances Hazardous to Health (COSHH) Regulations Schedule 3 2002
o Genetically Modified Organisms (Contained Use) Regulations 2000 (GMO(CU))
o Genetically Modified Organisms (Contained Use) (Amendment) Regulations 2002
o Advisory Committee on Dangerous Pathogens (ACDP) Approved List of Biological
Agents 2004
o Pressure Systems Safety Regulations 2000
7.4 Glossary
o BMS – Building Management System
o EMS - Environmental Monitoring System
o HMI – Human-Machine Interface
o N.A. – Not applicable
o TBA – To be advised or to be agreed

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Appendix 1 –Layout of the Isolators 1st Floor Process CPI-NBMC


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Appendix 2 - SPECIFIC REQUIREMENTS

A2.1 Isolator and Safety Cabinets Operation and Performance
Requirement Fulfilment Sign / Date
A2.1.1. The Isolator and Safety Cabinets must accommodate the following ‘generic’ process steps (Note that specific DV Required
loads and operations will be defined by individual processes and the two typical loads, identified by the batch
sequence diagrams, will be used to inform VHP gas cycle development): IV To be demonstrated at Mock-up stage
a) Preparation
OV N.A.
Manual cleaning
Glove testing
Assemble racking and fixed equipment parts, as necessary.
b) Loading
Load stock boxes of disposable items
Load initial single-use disposable tubing sets’or well-plates or centrifuge tubes or transfer bags or culture
flasks
Load ‘tools’ and static equipment (eg battery powered balance, tube welder) to be used in the process
c) Pre-Process VHP Cycle
Sterilisation of all internal surfaces and items placed inside the Isolator and Safety Cabinets
d) Transfers
Load extra equipment items via Transfer Hatch
Load extra WFI, media and buffer solutions via Transfer Hatch
Introduce blood-bag, cell culture bag, tube or culture flask containing cells
e) Processing
Carry out process manipulations
Remove disposable tubing sets via Transfer Hatch.
Remove wastes via Transfer Hatch.
Return tubing sets via Transfer Hatch.
Introduce new reagents and disposable equipment via the Transfer Hatch
f) Processing and Transfers
Steps (d) – (e) may be repeated several times, with subtle variations
g) Remove Final ‘Product’
Remove final ‘product’ bag or cryo-vial via Transfer Hatch
h) Open, Clean and Tidy
(Note: If viral vectors have been used, it will be necessary to run a VHP sterilisation cycle before opening)
Remove wastes
Manually clean

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A2.1.2. The ‘working area’ (that which is accessible to the operator using the glove-ports) must accommodate the DV Required
following removable items, whilst leaving adequate space to work
Blood bags, tubing sets, product and buffer bags IV To be demonstrated at Mock-up stage
Wastes (discard) container (200 mm dia.)
OV N.A.
Bottles or bags of media (1 to 5 L)
1 No. Centrifuge racks for 25 mm tubes (150 mm x 80 mm)
2 L container (130 mm dia.)
2 No. Gilsons-type pipettes in rack (300 mm x 100 mm)
2 No. Pipette tip boxes (80 mm x 80 mm)
Sharps container (100 mm x 100 mm)
Syringe and needles
Sample containers
Packs of dry or wet wipes and other minor consumables
Tube welder
Settle plates
A2.1.3. It must be possible to move in or out all the removable items either via the front opening window (prior to or after a DV Required
process batch) or via the Transfer Hatch (during a process batch).
It must be possible to fully open the Isolator and Safety Cabinets window to the same internal width and height of IV To be demonstrated at Mock-up stage
Isolator and Safety Cabinets chamber to manually clean inside and to clean and maintain any built-in equipment.
OV N.A.
A2.1.4. In order to satisfy A2.1.1 and A2.1.2 it is likely that the ‘working area’ (that which is accessible to the operator DV Required
using the glove-ports) of the Isolator and Safety Cabinets may be approximately 2000 mm x 600 mm. The working
area must be supplemented with a perorated storage shelf, 70 mm wide mounted on the ‘back’ wall of the Isolator IV Required
and Safety Cabinets and a ‘x-y-hanging rail grid with hooks for sterile bags etc.
OV N.A.
A2.1.5. 10” gloveports must be sited to suit the process with optimum ergonomics. DV Required
IV To be demonstrated at Mock-up stage
OV N.A.
A2.1.6. An Isolator and Safety Cabinets must maintain a Grade A environment at all times during a production run, which DV Required
may last several days.
IV N.A.
OV Required
A2.1.7. A downward vertical unidirectional velocity of 0.45 + 20 % m/s must be maintained at the expected level of open DV Required
processing, which is understood to be an area approximately 100 mm off the internal walls and approximately 300
mm off the base (to be qualified with the Isolator and Safety Cabinets empty). IV N.A.
OV Required
A2.1.8. The equivalent air flow rate in the Isolator and Safety Cabinets must be at least 500 air changes per hour. DV Required
IV N.A.

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OV Required
A2.1.9. It must be possible to sterilise, with VHP, the Isolator and Safety Cabinets, its equipment and full load of DV Required
disposable items using a cycle of approximately 90 minutes duration, and ideally as short as possible.
“Sterilisation” is defined in Section A2.6. IV N.A.
For clarification of the time, the 90 mins refers to the time from initiating the VHP cycle on the generator until
aeration is completed i.e. H2O2 is below 1ppm. This 90 mins will include the initial gassing, dew point, dwell time OV Required + Gas Cycle Development
and aeration.
A2.1.10. It must be possible to sterilise items placed in the Transfer Hatch either by a ‘short’ VHP cycle (less than 60 DV Required
minutes in total) or by manual wiping down or by ethanol spraying.
IV N.A.
OV Required
A2.1.11. The lighting level in the Isolator and Safety Cabinets must not be less than 600 lux at the ‘working area’ level. DV Required
IV N.A.
OV Required
A2.1.12. When in ‘production’ mode the Isolator chamber must be maintained at a pressure at least 25 Pa higher than that DV Required
of the Transfer Hatch and the Transfer Hatch must be maintained at a pressure at least 50 Pa higher surrounding
IV N.A.
room. This applies to the Isolators;
 GMP Simulation in 1.20 OV Required
A2.1.13. When in ‘production’ mode the Safety Cabinets chamber must be maintained at a pressure at least 200 Pa lower
than that of the Transfer Hatch and the Transfer Hatch must be maintained at a pressure at least 50 Pa higher
surrounding room. This applies to the negative pressure safety cabinets;
 Cytoxics in 1.20
A2.1.14. The temperature in the Isolator and Safety Cabinets chamber must not be more than 4 °C above the surrounding DV Required
room temperature when in ‘production’ mode.
IV N.A.
OV Required
A2.1.15. The positive pressure Isolators must pass a leak test. The test criterion is a pressure decay of less than 25 Pa in DV Required
1.5 minutes when the pressure is raised to +250 Pa with the Isolators sealed. {This represents ≤1% volume loss
IV N.A.
per hour as per Isolator Class 3, ISO 10648-2 and ISO 14644-7 draft}.
OV Required
A2.1.16. The negative ressure Safety Cabinet must pass a leak test. The test criterion is a pressure decay of less than 25 DV Required
Pa in 1.5 minutes when the pressure is lowered to -250 Pa with the Isolator and Safety Cabinets sealed. {This
IV N.A.
represents ≤1% volume loss per hour as per Isolator Class 3, ISO 10648-2 and ISO 14644-7 draft}.
OV Required
A2.1.17. The noise from the Isolator and Safety Cabinets in operation must be no more than 65dB at 1m away. DV Required
IV N.A.
OV Required

Centre (NBMC)
A2.2 Isolator and Safety Cabinets Controls and Instrumentation
Requirement (applies to all Isolator and Safety Cabinets unless indicated) Fulfilment Sign / Date
A2.2.1. The Isolator and Safety Cabinets control panel (HMI) must indicate: DV Required
 Isolator and Safety Cabinets and Hatch Pressures (digital)
 Air Flowrate or Velocity in the Isolator and Safety Cabinets, annotated in Air Changes per Hour or m/s. IV Required
 Terminal and exhaust HEPA filter pressure-drops (Magnahelic or digital).
OV Required
 Gassing cycle status
 Hatch door status
 Alarms
A2.2.2. The HMI requirements of the built-in equipment have been listed in A2.3. These controls should be incorporated DV Required
in the same panel as the Isolator and Safety Cabinets controls, if this is not possible, they must be mounted close-
by. IV Required
OV N.A.
A2.2.3. Settable high and low alarms must be fitted for DV Required
 Pressure (independent chamber and hatch)
 Flow/velocity IV Required
 Seal failures
OV Required
Alarms must be annunciated by audible and visible means.
Alarms must be latched, ie. alarms can only be cleared by manual intervention once the excursion has been
corrected.
Additionally, the Isolator and Safety Cabinets must receive, display and annunciate a common VHP Generator
alarm and a particle counter.
Alarm noise to be noticeable, but not with a disturbing or distracting intonation or volume.,
A2.2.4. The control system must log all alarms (alarm type, time of alarm, time acknowledged and time cleared) and retain DV Required
these for operator information at the end of a batch. These alarms are independent of any EMS alarms.
IV Required
OV Required
A2.2.5. The required range and accuracy of the instrumentation is given in the table below. DV Required
Instrument Range Accuracy Precision
Air Flow 0 – 900 Ach/h + 5 Ach/h 5 Ach/h IV Required
Air Velocity 0 – 10 m/s + 0.1 m/s 0.1 m/s
Pressure -300 to +600 Pa + 5 Pa 10 Pa
HEPA filter DP 0 – 500 Pa + 5 Pa 10 Pa OV N.A.
Hydrogen Peroxide Conc. (low) 0 – 10 ppm + 0.5 ppm 0.5 ppm


Centre (NBMC)
A2.2.6. The Isolator and Safety Cabinets control system must monitor an ‘extract healthy’ signal either from the BMS or DV Required
directly and display and annunciate it.
Furthermore, the Isolator and Safety Cabinets control system must not allow a VHP cycle to start if this signal is IV Required
not present and it must go into a ‘safe-hold’ state if the signal drops out during the aeration phase of a gassing
cycle. OV Required
A2.2.7. The control system must manage and report automatic leak tests: DV Required
 leak test on demand
 A pre-gassing leak test as part of the VHP sterilisation cycle IV N.A.
 Glove leak test.
OV Required
The Isolator and Safety Cabinets must be supplied with a glove leak-test device for semi-automatic operation.
A2.2.8. Control systems must be protected from power failure by a dedicated UPS with capacity for 30 minutes operation. DV Required
UPS to be alarmed for failure or low battery. The UPS must also include power surge protection.
The Isolator and Safety Cabinets will be connected to a ‘maintained’ supply, therefore power interruptions are IV Required
anticipated to be momentary.
OV Required
In the event of power failure, the Isolator and Safety Cabinets must restart automatically to its previous set point,
with no operator intervention.
A2.2.9. The inner door of the Transfer Hatch must be controlled so that a variable delay is applied after the outer door is DV Required
closed until the inner door may be opened. This is to allow alcohol vapour to be swept away and Grade A
conditions to re-establish. IV N.A.
OV Required
A2.2.10. The control system must be password protected, with at least three levels of entry (Operator, Supervisor and DV Required
Engineer). If the selected control system falls within the guidance of Annex 11 (Computerised Systems) of the EU
GMP regulations, then password protection must comply with sections 8 and 10 of Annex 11 of the EU GMP IV N.A.
regulations. This states that all actions carried out under password control must be logged, with the identity of the
person initiating the actions. OV Required
A2.2.11. All instruments must be clearly labelled in English with their function. DV Required
IV Required
OV N.A.

Centre (NBMC)
A2.3 Isolator and Safety Cabinets Ancillaries
Requirement (applies to all Isolator and Safety Cabinets unless specifically noted) Fulfilment Sign / Date
The Isolator and Safety Cabinets must incorporate a built in peltier-type cold/heat block.
The cold block must be sealed into the base plate of the Isolator and Safety Cabinets. The cold block must have a
A2.3.2 cover that is flush with the base of the Isolator and Safety Cabinets, with a removable magnetic handle in order to
maximise the working area in the Isolator and Safety Cabinets when the cold/hot block is not being accessed. The
cold block must be 30cm x 20cm x 20 cm. The cold hot block must be able to maintain temperatures between -20°
C to 37° C. The cold block must be supplied filled with proprietary heat transfer beads.
A2.4 Isolator and Safety Cabinets Construction
Requirement (applies to all Isolator and Safety Cabinets unless specifically noted) Fulfilment Sign / Date
A2.4.1. The CPI-NBMCIsolator and Safety Cabinets configuration comprises the Isolator and Safety Cabinets chamber DV Required
and a Transfer Hatch at the right-hand end.
IV Required
OV N.A.
A2.4.2. The overall external dimensions of the Isolator and Safety Cabinets, should not exceed 2400 mm (w) x 1200 mm DV Required
(D)x 2100 mm high.
Note should also be made of the access route limitations shown on the layouts in Appendix 1; IV Required
 Equipment lift – 2.4m wide, 3.4 long, 2.5m high (to be confirmed) OV N.A.
 Corridors on process floor – 2.5m wide
 Doors into process rooms – 1.8m wide
A2.4.3. The internal surfaces of the Isolator and Safety Cabinets must be constructed in 316L stainless steel (minimum DV Required
thickness 3mm).
IV Required
OV N.A.
A2.4.4. All internal surfaces must be finished smooth and crevice free. “Folded” metal construction is not permitted, joints DV Required
must be welded, with the welds ground smooth and polished to match the base metal sheet. Internal corners
must be radiused (at least 20mm recommended). IV Required
Internal finish < 0.8 micron Ra. External finish < 1.8 micron Ra.
OV N.A.
A2.4.5. The internal height of the Isolator and Safety Cabinets must be approximately 800 mm. DV Required
IV Required
OV N.A.
A2.4.6. The Isolator and Safety Cabinets base plate height must be approximately 900 mm above floor level, with ±150 DV Required
mm powered adjustment.
IV Required
OV N.A.

Centre (NBMC)
A2.4.7. The Isolator and Safety Cabinets chamber must be equipped with 2 No. power sockets (5 A rating) for removable DV Required
equipment. These should be covered power sockets that will need to be opened during VHP gassing. The
IV Required
location of the sockets should not interfere with the operation inside the Isolator and Safety Cabinets.
The Isolator and Safety Cabinets chamber must be equipped with 2 No. USB bulkhead sockets. One to be type A OV N.A.
on the inside and type B outside and the other vice versa.
Power and data sockets provided in the Isolator and Safety Cabinets must be sealed, allowing no leakage path for
air into/from the Isolator and Safety Cabinets chamber.
A2.4.8. The Isolator and Safety Cabinets must be equipped with at least one permanently installed particle sampling point DV Required
(isokinetic nozzle) for connection to a particle counter at working height (300mm) in a position that doesn’t
IV Required
interfere with the processing.
The head must be connected with “Bev-a-Line” tubing to the particle counting head which must be mounted on the OV N.A.
Isolator and Safety Cabinets. The particle counter should be positioned inside the Isolator and Safety Cabinets
cladding, and be accessed by a removable panel,
Note: Isokinetic nozzle and Bev-a-Line tubing to be supplied and installed by Isolator and Safety Cabinets
Supplier, particle counting head to be supplied by the EMS Supplier. Bev-a-line must be installed to the
manufacturers recommendations. The tubing must be positioned and maintained without any kinks to ensure
particles cannot get trapped inside.
A2.4.9. The Isolator and Safety Cabinets must be equipped with at least one sealable port for the introduction of a low DV Required
concentration H2O2 sensor. (Sensor will be included in the VHP Generator scope of supply).
IV Required
OV N.A.
A2.4.10. The clear aperture of the door between the Transfer Hatch and the Isolator and Safety Cabinets chamber must DV Required
not be less than 400 mm x 400 mm. Likewise the outer door of the Transfer Hatch should be a matching size.
IV Required
The inner and outer doors of the Transfer Hatch must be interlocked, so that only one door can be open at any
time. This interlock may be inactivated when the Isolator and Safety Cabinets is open for cleaning or OV N.A.
maintenance.
A2.4.11. It is intended that the Isolator and Safety Cabinets be installed against the wall of the cleanroom and therefore DV Required
operational or maintenance access will not be available from the rear of the Isolator and Safety Cabinets.
IV Required
Supplier must confirm that this is acceptable or suggest alternatives. For example the Isolator and Safety Cabinets
may be on rollers to allow for access for cleaning or maintenance. OV N.A.
A2.4.12. The support frame must be rigid, fabricated from stainless steel or white powder-coated steel and mounted on DV Required
height adjustable cleanroom-type feet. The support frame must be within the footprint of the main body of the
IV Required
Isolator and Safety Cabinets and allow for wall to floor coving in the room.
The support frame must be designed so that operators of different statures can work at the gloveports; exact OV N.A.
details and specification of any height adjusting devices necessary to be agreed during ergonomic trials.
A2.4.13. The enclosure for the fan/filter unit and controls must be fabricated from polished stainless steel or white powder DV Required
coated steel.
IV Required
OV N.A.
A2.4.14. Doors and windows must be constructed in laminated safety glass or clear cast acrylic, with 316 L stainless steel DV Required
frames.
IV Required
Doors and windows must be interlocked (Isolator and Safety Cabinets can’t run in “production” or “gassing” mode
if the outer doors or windows are open or not locked). OV N.A.
Windows may slope back for operator comfort
A2.4.15. Windows must be interlocked (Isolator and Safety Cabinets can’t run in “production” or “gassing” mode if the DV Required

Centre (NBMC)
windows are open or not locked). IV Required

Windows must be safely self-supported when open.
OV N.A.
A2.4.16. Opening windows and doors must be sealed with retained inflatable or vacuum seals. A 0.22 μm filter must be DV Required
installed to filter the compressed air which is used for the inflatable seals. Vacuum seals must be protected with
IV Required
non-return valves to maintain vacuum in the event of pump failure.
Seal pressures must be continuously monitored, when operational, with a local alarm. OV N.A.
A2.4.17. If mechanical devices are used to secure door and window seals, lockable over-centre latches are preferred, DV Required
screw-down closure devices are not acceptable.
IV Required
The holding hook for the transfer hatch door should be angled up so that the door can not fall off when
suspended. OV N.A.
A2.4.18. Seals for doors and windows must be fabricated using pharmaceutical industry approved elastomers, including DV Required
silicone rubber, PTFE, EPDM and viton, which must be VHP resistant.
IV Required
OV N.A.
A2.4.19. Four glove-ports (10 inch port diameter) must be equally spaced, low, in the Isolator and Safety Cabinets to suit DV Required
the process with optimum ergonomics.
IV Required
OV N.A.
A2.4.20. Gloveport sleeves must fit securely onto the shoulder rings (double O-rings preferred) and must be easy to DV Required
change when required.
IV Required
OV N.A.
A2.4.21. Gloveport sleeves must be tough but flexible and resistant to the effects of VHP. They must be of the double-layer DV Required
type, self-indicating of leakage.
IV Required
OV N.A.
A2.4.22. The cuff assembly must allow for safe change of the gloves, without breaking sterility or containment. DV Required
IV Required
OV Required
A2.4.23. Gloves are considered consumable but the Isolator and Safety Cabinets supplier must provide gloves sufficient for DV Required
commissioning and validation. Gloves may be recommended by the supplier, but these must be of material
IV Required
resistant to VHP, available in various sizes, non-allergenic and widely available.
OV N.A.
A2.4.24. All internal surfaces and fittings inside the Isolator and Safety Cabinets must be compatible with VHP sterilisation DV Required
and manual cleaning with proprietary cleaning products (75% IMS), Shield Medicare biocides X, Klercide A, B &
IV Required
C. Virkon and Chlorsept disinfectant tablets may be used inside of the Isolator and Safety Cabinets. Use of these
tablets within the Isolator and Safety Cabinets will be limited and the surface will be cleaned with water following OV N.A.
contact and subsequent sterilisation.
All external surfaces of the Isolator and Safety Cabinets must be compatible with VHP sterilisation of the room in
which it is located and manual cleaning with the same range of cleaning products as used inside. There must be
space allowance for a tool for cleaning of far walls and sides of the Isolator and Safety Cabinets. The casters and
some of the external surfaces of the Isolator and Safety Cabinets must be compatible sporicides including
Sporklenz, Clearklens Bi Spore.

Centre (NBMC)
A2.4.25. The Isolator and Safety Cabinets must be identified with a permanently fixed “tag”, the tag having an engraved DV Required
number corresponding to its identification
IV Required
OV N.A.
A2.4.26. All the documentation listed in Section 3 of this URS must be delivered with the Isolator and Safety Cabinets. DV Required
IV Required
OV N.A.
A2.4.27. There must be a sealable port to allow a peristaltic pump tubing (diameter of tubing to determined) to be inserted DV Required
into the Isolator and Safety Cabinets (before VHP gassing) to allow a peristaltic and/or vacuum pump to be kept
IV Required
outside the Isolator and Safety Cabinets, and pump/remove fluid into/out of the Isolator and Safety Cabinets.
OV Required
A2.4.28. A non-slip bar to act as a foot rest will be fitted to allow the operator to sit down in an ergonomic manner when DV Required
using the Isolator and Safety Cabinets.
IV Required
Foot switches to be provided for:
OV Required
 Inner hatch door open/close
 Centrifuge stop/start
A2.5 Isolator and Safety Cabinets Air Handling Units
A2.5.1. The Isolator and Safety Cabinets chamber and Transfer Hatch must re-circulate air internally, but must use DV Required
conditioned air from the room for pressure and temperature control purposes.
IV Required
OV N.A.
A2.5.2. When in operation, it is expected that a constant volume of air, 120 +0/-20 L/s, will be drawn from the room into DV Required
the Isolator and Safety Cabinets and exhausted via a flexible duct (Supplier to install) to a ceiling spigot (105 mm)
and onwards to a building a extract fan. The exhaust pressure at the outlet of the Isolator and Safety Cabinets IV N.A.
must be 0 Pa ± 50 Pa.
When the Isolator and Safety Cabinets is shut down or during the gassing phases of a VHP cycle, the Isolator and OV Required
Safety Cabinets controls must open an automatic damper to divert directly to exhaust the same quantity of room
air as is normally lost via the Isolator and Safety Cabinets.
A2.5.3. All air fed and recirculated to the internal space of the Isolator and Safety Cabinets chamber and Transfer Hatch DV Required
must be terminal HEPA filtered, using H14 grade filters. Inlet and recirculated air must be pre-filtered to prolong
the life of the terminal HEPA filters. IV N.A.
OV Required
A2.5.4. Double exhaust HEPA filters are to be fitted to the Isolator and Safety Cabinets, but safe change of the primary DV Required
exhaust filter is not required.
IV Required

Centre (NBMC)
OV N.A.
A2.5.5. Test ports must be fitted for independent testing of all HEPA filters and their seals. This means the provision of DV Required
test aerosol inlet points, aerosol challenge sampling points (e.g. in plenum chambers) and downstream sampling
points. IV Required
OV N.A.
A2.5.6. Automatic shut-off valves must be provided to permit leak testing by pressure decay. These valves must be fitted DV Required
ahead of the inlet HEPA filters and after the exhaust HEPA filters.
IV Required
OV N.A.
A2.5.7. The air handling unit must be mounted integrally above, below or behind the Isolator and Safety Cabinets DV Required
chamber, within the room.
IV Required
OV N.A.
A2.5.8. The ventilation system of the Transfer Hatch must be compatible with alcohol spraying of process equipment and DV Required
product containers which are placed in it.
IV Required
OV N.A.
A2.6 Isolator and Safety Cabinets Sterilisation

A2.6.1. The Isolator and Safety Cabinets and built-in equipment must be engineered for automatic sterilisation by VHP DV Required
treatment.
IV Required
Rotating or static gas distribution nozzles and stirring fans must be installed in the process chamber and hatch as
required by the VHP System supplier. OV Required
It must be possible to completely seal the Isolator and Safety Cabinets and/or Transfer Hatch from the room
during sterilisation.
A2.6.2. The Isolator and Safety Cabinets must have a VHP inlet and a VHP outlet port. Additionally, signal ports and gas DV Required
sampling ports must be fitted to suit the VHP System.
IV Required
The gas inlet and outlet ports must be configured so that the (heavy) VHP hoses do not impart high bending
moments on the ports. OV N.A.
A2.6.3. The Isolator and Safety Cabinets must control the VHP sterilisation sequence. DV Required
Therefore the Isolator and Safety Cabinets controller must first check that an ‘exhaust fan healthy’ signal is being IV N.A.
received from the BMS. If this is not present, the Isolator and Safety Cabinets controller must stop and alarm.
OV Required
If the exhaust fan is OK, the Isolator and Safety Cabinets controller must send a ‘start’ signal to the VHP
Generator (once a successful leak test has been completed), stop its fans and shut its isolation valves.
The Isolator and Safety Cabinets controller then waits for an ‘aeration’ signal from the VHP Generator, at which
point it must restart its fans and aerate the enclosure to finish the cycle.
Finally, the Isolator and Safety Cabinets controller then waits for a “successful cycle completion” signal from the
VHP Generator and then reverts to “Normal Operation”.
Furthermore, the Isolator and Safety Cabinets must send signals to the EMS to close its particle counter/vacuum
valves during VHP sterilisation and suspend particle counting.

Centre (NBMC)
A2.6.4. All valves which must be operated before, during or after a VHP sterilisation cycle must be automated. DV Required
IV Required
OV Required
A2.6.5. Glove hangers must be supplied to hold up sleeves during VHP sterilisation. DV Required
IV Required
OV N.A.
A2.6.6. Prior to an aseptic process batch it must be possible to place the necessary items, typically listed in A2.1.2, in the DV Required
Isolator and Safety Cabinets and carry out a VHP sterilisation cycle (from start to completion of aeration) in
IV N.A.
approximately 90 minutes. In this context sterilisation is defined as a minimum of a 6-log reduction of spore
forming microorganisms. OV Required (CGD)
A2.6.7. It must be possible to VHP sterilise the Transfer Hatch independently from the process chamber, whist carrying DV Required
out process operations in the chamber (Zero VHP leak in the chamber can be tolerated).
IV N.A
The total VHP sterilisation cycle time must be less than 60 minutes.
OV Required (GCD)
A2.6.8. It is proposed that Geobacillus stearothermophilus (ATCC # 12980) will be used as the test organism, prepared on DV Required
proprietary biological indicator (BI) strips
IV N.A.
The Supplier must demonstrate equivalence of Geobacillus stearothermophilus (ATCC # 12980) to typical viruses
that may be processed in the suite. OV Required (CGD)
A2.6.9. A typical Isolator and Safety Cabinets and/or Hatch sterilisation sequence must be carried out as follows: DV Required
 Operator prepares load in Isolator and Safety Cabinets and/or Hatch. IV N.A.
 Operator moves VHP Generator to the Isolator and Safety Cabinets and connects gas hoses, sample tube
and communications cables OV Required (CGD)
 Operator plugs in VHP Generator to the mains and loads it with H2O2 solution.
 Operator places VHP Generator in run mode
 Operator selects gassing cycle (if there are different cycles validated for different loads) and initiates the
gassing cycle at the Isolator and Safety Cabinets HMI.
 Isolator and Safety Cabinets controller sends signals to the EMS to indicate that it is gassing
 Isolator and Safety Cabinets controller controls the gassing cycle and aerates the enclosure at the end of the
sterilisation period
 Isolator and Safety Cabinets controller indicates a successful cycle and goes into normal operation mode
(sends signal to EMS to indicate normal operation)
 Operator stops the VHP Generator and removes the printout for batch records
 Operator disconnects hoses and communication cables and returns VHP Generator to its storage position
 Operator may take a manual air sample in the enclosure to confirm < 1ppm H2O2.

Centre (NBMC)
A2.7 VHP Generator Operation and Performance

A2.7.1. A minimum total of one mobile VHP Generator must be supplied to produce a stream of Hydrogen Peroxide DV Required
Vapour in conditioned air (“gas”) to match the stated sterilisation requirements of the Isolators.
IV Required
OV N.A.
A2.7.2. Mobile VHP Generators must be used to sterilise both Isolators and Safety Cabinet. DV Required
IV Required
OV N.A.
A2.7.3. Mobile VHP Generators (if chosen) will be used to sterilise the following rooms and suites of rooms; DV Required
 1.18 – Viral Vectors 122m³ room volume
IV Required
 1.20 – Cytotoxics 97m³ room volume
 1.33 – GMP Simulation – Grade D 200m³ room volume OV N.A.
 1.34 – GMP Simulation – Grade C 144m³ room volume
A2.7.4. A VHP Generator must draw air from the room in which it is located. DV Required
IV Required
OV Required.
A2.7.5. A VHP Generator must produce concentrations of hydrogen peroxide and vapour temperatures and DV Required
H202humidities within their set-point ranges.
IV N.A
OV Required
A2.7.6. The VHP Generators must produce the required environmental conditions and hydrogen peroxide vapour at a DV Required
sufficient rate so that the total Isolator sterilisation cycle times stated in Section A2.6
If a VHP Generator alone cannot achieve the required cycle time then the following equipment must be included if IV N.A
required
 Catalytic H2O2 destruction units. Such units may be included in the VHP Generator cabinet or be separate OV Required
mobile or fixed units incorporating appropriate circulation or exhaust fans.
 Separate distribution fans if appropriate.
A2.7.7. The VHP Generators must use 30% H2O2 solution to produce VHP. DV Required
IV Required
OV N.A.
A2.7.8. The VHP Generators must control the cycle so that the cycle completion point is when there is a concentration of DV Required

Centre (NBMC)
less than 1ppm H2O2 in the enclosure being sterilised. IV N.A
OV Required
A2.8 Cleanroom Sterilisation

Requirement (applies to all VHP Generators unless specifically noted) Fulfilment Sign / Date
A2.8.1. Isolator VHP sterilisation will not take place at the same time as room VHP sterilisation. DV N.A
IV N.A
OV N.A.
A2.8.2. The following rooms may be gassed using the vHP DV Required
• 1.18 – Viral Vectors 122m³ room volume 20 air changes per hour IV N.A
• 1.20 – Cytotoxics 97m³ room volume 20 air changes per hour
OV Required (GCD)
• 1.33 – GMP Simulation – Grade D 200m³ room volume 20 air changes per hour
• 1.34 – GMP Simulation – Grade C 144m³ room volume 30 air changes per hour
The vHP Generator will be placed in room during gassing.
This operation will be carried out on an occasional basis, i.e. once or twice a year, but may have to be done in an
‘emergency’ following a major spill or other incident.
A2.8.3. It must be possible to VHP sterilise any one of the occasionally gassed rooms in a total cycle time of DV Required
approximately 8 hours
IV N.A
OV Required
A2.8.4. A typical cleanroom sterilisation sequence must be carried out as follows: DV Required
 Operator places VHP Generator in the room to be gassed, in the validated position (previously determined IV N.A
during room gassing cycle development), loads it with H2O2 solution and plugs it into the mains.
OV Required (GCD)
 Operator props open inner doors to any Pass Through Hatches in the room(s) and props open any doors
to adjoining rooms to be gassed.
 Operator assembles the room gassing nozzle and connects the gas hose between the VHP Generator and
it
 Operator connects the communications cable from the VHP Generator to the gassing socket in the room
wall.
 Operator places VHP Generator in run mode.
 Operator checks rooms for personnel, leaves the room and tapes up all the outer doors and any other
known air transfer paths such as transfer grilles or spool pieces.
 Operator posts warning notices.
 Operator connects the remote controller to power and to the gassing wall socket in the safe room outside
the room(s) to be gassed.
 Operator selects the validated gassing cycle for the room(s) to sterilised and initiates the gassing cycle.
 Remote controller sends a signal to the EMS to indicate that it is gassing the rooms
 Remote controller sends a signal to the BMS to request that inlet and exhaust dampers are shut to the
rooms
 Remote controller waits for a signal from the BMS to confirm that the requested inlet and exhaust dampers

Centre (NBMC)
are shut.
 Remote controller starts the VHP Generator and monitors the gassing cycle.
 At the end of the sterilisation period, the remote controller sends a signal to the BMS to request aeration
(i.e. opening the inlet and exhaust dampers for once through aeration of the room(s).
 At the end of aeration, the remote controller indicates a successful cycle and sends a signal to EMS to
indicate normal operation.
 Operator takes a manual air sample in the room to confirm < 1ppm H2O2.
 If safe, operator removes tape from outer door, enters room, stops the VHP Generator and removes the
printout for batch records and dismantles the gassing equipment and returns it and the VHP Generator to
storage.
A2.8.5. In order to facilitate room VHP sterilisation, the Supplier must provide a communications wiring detailed design to DV Required
the Main Contractor and free issue communications sockets, so that the Main Contractor may install the
IV Required
necessary wiring between the communications sockets in the rooms to be gassed, the communications sockets in
the ‘safe’ rooms and the BMS and EMS OV N.A
The Supplier must label all communications sockets in the walls.
A2.8.6. It is proposed that Geobacillus stearothermophilus (ATCC # 12980) will be used as the test organism, prepared on DV Required
proprietary biological indicator (BI) strips
IV N.A
For rooms S21 to S26 the Supplier must demonstrate equivalence of Geobacillus stearothermophilus
(ATCC # 12980) to typical viruses being processed in the suite. OV Required (GCD)
A2.9 VHP Generator Controls

Requirement (applies to all VHP Generators unless specifically noted) Fulfilment Sign / Date
A2.9.1. The control system of the VHP Generator must consist of a PLC with a fixed and a remote Human-Machine DV Required
Interfaces (HMI).
IV Required
OV N.A.
A2.9.2. The fixed HMI must comprise a membrane keypad or touchscreen, an alphanumeric display and a printer. The DV Required
fixed HMI must be integrated within the VHP Generator cabinet.
IV Required
OV N.A
A2.9.3. The HMI must be used to initiate and monitor fully automated VHP sterilisation cycles in an Isolator DV Required
IV N.A
OV Required
A2.9.4. The remote HMI must be capable of communicating with the BMS and EMS, via a communication cable ‘gassing’ DV Required
sockets located in each ‘safe’ room immediately outside the room or suite of rooms to be gassed.
IV N.A
The remote HMI must be capable of sending a signal to the BMS and EMS which identifies the room(s) being
gassed. OV Required
The remote HMI must be capable of communicating with any VHP generator via communications cables and a
‘bulkhead’ type socket in the wall between the ‘safe’ room and the room being gassed where the VHP Generator
is located.

Centre (NBMC)
A2.9.5. The VHP Generators must be equipped with the following instruments/sensors DV Required
 H2O2 solution weight or volume
IV Required
 H2O2 vapour concentration
 H2O2 vapour temperature OV N.A
A2.9.6. Data viewable on the alphanumeric display must include: DV Required
 Alarms IV Required
 Machine status (ready, in-use, not ready) OV N.A
 H2O2 solution weight or volume
 H2O2 vapour concentration
 H2O2 vapour temperature
A2.9.7. The printed cycle report must include: DV Required
 Batch No. IV Required

 Operator ID OV Required
 Equipment Treated (Tag. No.)
 Time and date start cycle
 Time and date finish cycle
 Settings used for the cycle
 H2O2 solution weight or volume used
 H2O2 vapour concentration and temperature at phase transitions, with time
 Alarms during the cycle, with time
 Summary, i.e. “Cycle Successful” or “Cycle Aborted”
A2.9.8. The HMI system must be password protected at least three levels DV Required
 Operator,
IV N.A
 Supervisor,
OV Required
 Administrator/Engineer/Validator
A2.9.9. The controller must provide the following alarm systems. DV Required
 Out of H2O2 solution IV Required

 Gas concentration or temperature out of specification. OV Required
 Catalytic converter out of specification (if included).
A2.9.10. The controller must provide the following interlock systems, which must be both hardware and software DV Required
implemented.
IV Required
 VHP generation must not start if Isolator leak test fails
 VHP generation must not start if room dampers are not closed OV Required

Centre (NBMC)
 VHP generator goes to aeration if the “Abort” button is pressed.
A2.9.11. The required range and accuracy of the instrumentation is given in the table below. DV Required
Instrument Range Accuracy Precision
Weight/Volume 0 – 250 g/mL + 0.1 g/mL 0.1 g/mL IV Required

H2O2 Concentration (low range) 0 – 5 ppm + 0.5 ppm 0.1 ppm
Temperature 0 – 100 oC + 1 oC 1 oC OV N.A.
A2.9.12. Settable high and low alarms must be fitted to all analogue instruments. Alarms must be annunciated by audible DV Required
and visible means.
IV Required
Alarms must be latched, i.e. alarms can only be cleared by manual intervention once the excursion has been
corrected.
OV Required
A2.9.13. Both the fixed and remote HMI’s must have an “Abort” button, which has the function of stopping a gassing DV Required
sequence and driving the Isolator or room HVAC to full aeration.
IV Required
OV Required
A2.9.14. All instruments must be clearly labelled in English with their function DV Required
IV Required
OV N.A
A2.9.15 If the selected control system falls within the guidance of Annex 11 (Computerised Systems) of the EU GMP DV Required
regulations, then password protection must comply with sections 8 and 10 of Annex 11 of the EU GMP
regulations. This states that all actions carried out under password control must be logged, with the identity of the IV Required
person initiating the actions.
OV Required
A2.10 VHP Generator Construction

A2.10.1. The VHP Generator’s (if mobile rather than built in) overall footprint must not exceed 700 mm x 900mm. DV Required
IV Required
OV N.A.
A2.10.2. Materials and design of construction must enable easy and effective cleaning to be performed. All functional parts DV Required
of the VHP Generator must be enclosed in a single cabinet, with secure access doors for maintenance. All items
requiring observation, maintenance or calibration must be located so as to allow easy and safe access. IV Required
The external finish of the machine cabinet must be powder coated steel or equivalent.
The Mobile VHP Generator must be mounted on four cleanroom type castors, at least two of which must be OV N.A.
lockable.
A2.10.3. The HMI for the VHP Generator must be ergonomically sited and must be between 800 mm and 1200 mm above DV Required
floor level.
IV Required

Centre (NBMC)
OV N.A
A2.10.4. The mobile VHP Generator be supplied with two “gas” hoses; one for supply to the Isolator and the other for return DV Required
from the Isolator.
All “gas” hoses shall be armoured platinum crosslinked silicone tubing with ends to match the nozzles on the IV Required
isolator/ and Room Nozzle
OV N.A
A2.10.5. Each major component or sub-assembly in the system must be identified with a permanently fixed tag, the tag 1 Required
having an engraved or embossed number corresponding to its identification on the P&ID.
IV Required
OV N.A

Centre (NBMC)
APPENDIX 3 –3-WAY VALVE OPERATION
Exhaust
1 –Exhaust Stack – Normal and post vHP stack tp
atmosphere
From
From room
Room
Isolator
vHP
Generator
Exhaust
stack to
2 – Exhaust Stack – During vHP Gassing atmosphere
From
From room
Room
Isolator
vHP
Generator

Appendix 1 URS For Isolator and Safety Cabinets PDF

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Appendix 1 URS For Isolator and Safety Cabinets PDF

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Client: Centre for Process Innovation (CPI) Validation Doc Number: na

Project: National Biologics Manufacturing Validation issue: na

URS – ISOLATOR and SAFETY CABINETS

Two types of Isolator and Safety Cabinets are required as follows:

Author Organisation & Responsibility Signature Date

Andrew Provan Process Consultant – eXmoor Pharma 20th Dec 2013

Approved By Organisation & Responsibility Signature Date

Robert Haugh Project Manager – eXmoor

Lucy Foley Project Engineer - CPI

Harvey Branton Process and Technical Manager-CPI

Jerry Cooper Project Manager - CPI

Project: National Biologics Manufacturing Validation issue: na

Project: National Biologics Manufacturing Validation issue: na

However it is a requirement that any experiments or process development work is undertaken to

1.2 Scope and Purpose of this Document

 1 negative pressure Safety Cabinets for cytotoxic production

 1 positive pressure Isolator for final finishing and formulation.

Project: National Biologics Manufacturing Validation issue: na

This URS will provide a basis for:

The definitions employed in this document are as follows:

Purchaser Centre for Process Innovation

1.4 Purpose of the Isolator and Safety Cabinets

Project: National Biologics Manufacturing Validation issue: na

maintain a Grade A micro-environment in which the various ‘open’ processing stages of

2.2 Qualification Requirements

Project: National Biologics Manufacturing Validation issue: na

 Installation Verification (IV)

Responsibilities for Qualification

Project: National Biologics Manufacturing Validation issue: na

3.1 Documentation General

3.1.1. All documentation, including software printouts, must be in English.

Project: National Biologics Manufacturing Validation issue: na

Project: National Biologics Manufacturing Validation issue: na

3.2 Documentation Pre-Delivery

3.2.1. Functional Design Specification (FDS), machinery and controls.

3.3 Documentation Post-Delivery

4.1 Design Codes/Standards

4.2 Mechanical Design

Project: National Biologics Manufacturing Validation issue: na

4.3 Electrical Design

4.4 Site Safety

Project: National Biologics Manufacturing Validation issue: na

5 LOCATION, UTILITIES AND CONNECTIONS

Project: National Biologics Manufacturing Validation issue: na

 DV, IV and OV protocols have been executed and unconditionally approved

7 GLOSSARY AND REGULATORY FOCUS

7.3 Health and Safety

Project: National Biologics Manufacturing Validation issue: na

Appendix 1 –Layout of the Isolators 1st Floor Process CPI-NBMC

Project: National Biologics Manufacturing Validation issue: na

Appendix 2 - SPECIFIC REQUIREMENTS

Requirement Fulfilment Sign / Date

Project: National Biologics Manufacturing Validation issue: na

IV To be demonstrated at Mock-up stage

Project: National Biologics Manufacturing Validation issue: na

Project: National Biologics Manufacturing Validation issue: na

A2.2 Isolator and Safety Cabinets Controls and Instrumentation

Instrument Range Accuracy Precision

Air Flow 0 – 900 Ach/h + 5 Ach/h 5 Ach/h IV Required

Air Velocity 0 – 10 m/s + 0.1 m/s 0.1 m/s

Pressure -300 to +600 Pa + 5 Pa 10 Pa

HEPA filter DP 0 – 500 Pa + 5 Pa 10 Pa OV N.A.

Hydrogen Peroxide Conc. (low) 0 – 10 ppm + 0.5 ppm 0.5 ppm