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Methodology to Conduct
Sterile Boundaries Assessment
PDA Midwest Conference
6 OCT 2016
Vicente Ventura
Agenda
• Background
• Methodology to perform a Sterile
Boundary Assessment
• Questions
Background
• Provide a mechanism to evaluate the
design, components and process steps
that could impact sterility in an aseptic
manufacturing process and maintain
quality standards.
• A methodology was developed to conduct
a Sterile Boundary Assessment (SBA).
• The following presentation describes the
tools used.
Sterile Boundary Assessment
• A risk based approach that assesses
whether the risk of microbial ingress
into a sterilized system, within the
sterile boundary, is acceptable by
assessing system design, sequence
of operations and manufacturing
process.
Sterile Boundary
Is a predetermined
perimeter that is
safe guarded by a
device or element
where microbial
ingress might
occur during the
manufacturing
process.
Methodology
Summary of Findings
Review of the Process
State Diagrams (Color Coded)
Device Sequence Chart
Schematic Chart
P&ID Walkdown
Equipment & Process Assessment
Summary of Findings
Major Changes in Design or Process
Major Maintenance History
Risk Assessment
FMEA
Determination of Failure Modes
Sterile Boundary Devices Confirmation
Risk Assessment
P&ID Review or P&ID Walkdown
• For new or modified systems a P&ID review during Design Review phase is the best time for SBA evaluation.
• For existing systems, obtain latest revision of the P&ID and applicable supporting drawings.
• Identify and highlight portions of the P&ID that encompass the sterile boundary of the sterile operation.
• Walkdown the highlighted portions of the P&ID and document any discrepancies.
• While walking down the P&ID, also inspect the installation of any devices that could prevent the system from being sterilized or maintained as sterile. Document these items.
Example of Highlighted P&ID
Walkdown
Schematic Chart
• This is a P&ID version focusing on piping,
devices and items related to sterile
boundaries.
• The schematic focusses most on the portions
of the system within the sterile boundary.
• The schematics are intended to be a one
page drawing that contains all relevant
information of the system for the evaluation.
Example of a Schematic Chart
Device Sequence Chart (DSC)
• Is a table that shows the state condition (eg. open, close, modulating, etc.) of devices for the individual process steps within an overall process operations.
• To create this chart, first list in the vertical part of the chart all relevant devices involved in the process steps included for the sterile boundary. Examples of devices are valves, pumps, regulators, etc.
• In the horizontal part of the chart, list all process steps relevant to the assessment of the sterile process.
• The creation of process steps is a combined effort between automation, process engineer and operators.
• Any manual operations must be added in the steps.
• It is important to define the scope of the evaluation. This could be from end of SIP up to Product Transfer.
Example of a Device Sequence
Chart
Step
Des
crip
tion:
Idle
Sta
te
Man
ual I
nter
vent
ion/
Prom
pt S
tart
Pre
ssur
e Te
st
Verif
y Pr
essu
re C
harg
e
Conc
lude
Air
Supp
ly
Tim
e De
lay
to S
ettle
Reco
rd In
itial
Pre
ssur
e
Mon
itor P
ress
ure
and
Tem
pera
ture
Reco
rd F
inal
Pre
ssur
e
Vent
Ves
sel
Stea
m to
Tan
k
Incr
ease
Pre
ssur
e
Dela
y To
Tem
p
Heat
Del
ay
Build
Pre
ssur
e 2
Conf
irm T
emp
Stea
m H
old
Bloc
k Tr
aps
Stop
Ste
am
Redu
ce P
ress
ure
Time (s): 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
Step Number: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Phase Flag:
State Device Type Device Name Device Description
Cycle Analog TE-A Tank Temperature 1 1 1 95 123 122
Cycle Analog TE-B Tank Outlet Temperature 1 95 123 122
Cycle Analog TE-C Vent Line Temperature 95 123 122
Cycle Analog TE-D Vent Filter Temperature 95 123 122
Cycle Discrete PIT-A Tank Pressure 1 1 1 1 1 1 10 18 18 15
Cycle Discrete FV-A Tank outlet valve 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Cycle Discrete FV-D Transfer Line Out 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete FV-E Drain Block 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0
Cycle Discrete FV-F Trap Drain 0 0 0 0 0 0 0 0 0 1 1 0 1 0 0 0 0 0 0
Cycle Discrete FV-G CIPS to Vent 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete FV-H Vent l ine trap 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0
Cycle Discrete FV-I Filter Low Point Drain 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0
Cycle Discrete FV-J Air Supply 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete FV-K Vent l ine 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0
Cycle Discrete Steam Steam Supply 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0
Cycle Discrete FV-R Main to Vessel 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1
Cycle Discrete FV-S Inlet Line 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1
Cycle Discrete Process Product Pressure 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete CIP CIP Supply 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete STEAMHI STEAMHI 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1
Cycle Discrete AIRHI AIRHI 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Maintain Closed Discrete WATERHI WATERHI 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete PASSIVEHI PASSIVEHI 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0
Cycle Discrete PROCESSHI PROCESSHI 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete STEAMLO STEAMLO 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1
Cycle Discrete AIRLO AIRLO 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Maintain Closed Discrete WATERLO WATERLO 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete PASSIVELO PASSIVELO 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0
Cycle Discrete PROCESSLO PROCESSLO 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete CIP OUTLET CIP TOV 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cycle Discrete SPRAYS Flow to sprays 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0
Cycle Analog TOV AIR Passive air at tank bottom 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0
Cycle Discrete PSI TO VENT PSI TO VENT 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 1 1
Cycle Analog AGI Agitator 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Step Number: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Process Device Sequence
Sterile Tank
1.0
3-Oct-16
Revision:
Revision Date:
State
FinalProduct(s)
State Diagrams (aka Color Coded
Diagrams)• Is a representation of a specific process step. It uses
colors to highlight devices and process lines in the schematic diagram to represent a service or a condition at the process step that is under evaluation.
• State Diagrams indicate the state condition of the devices and flow paths for a given process step.
• Most common conditions represented on a State Diagram are:– Open/Closed valves
– Service Lines (Steam, Nitrogen, Air, Product)
– Conditions (pressurized, vacuum)
– Manual operations (hose connections, manual valves)
State Diagrams (aka Color Coded
Diagrams)
• Provides:– Design
• Allows design team to see if all lines are being cleaned and sterilized
• Shows the transitions between steps and what is cleaned or sterilized in each step
– Training
• Provides operations, quality, tech service, or engineering a
picture for each step of the cleaning or sterilization process
• Attachment for SOP or Batch Ticket to verify step conditions
or manual steps during the cleaning or sterilization
– Troubleshooting
• Allows a person to track each step in the field to insure each
device is in the expected position per the design
State Diagrams (aka Color Coded
Diagrams)
• Creating State Diagrams– Conditions of the devices are obtained from the
device sequence charts.
– Devices are highlighted with a specified color to represent the condition at a given process step.
– Process lines are colored indicating the service at a given process step.
– A colored diagram is generated per process step. Some process steps are 100 +.
– Manual highlighting can take a significant amount of time (depending on how complicated is the system and the amount of steps).
State Diagrams (aka Color Coded
Diagrams)
• Outsourcing capabilities:
– Seiberling was contracted to create a
computer program that generates a State
Diagram for each sequence step from the
DSC.
• The program linked each device status from the
DSC table to the Visio schematic.
• A new State Diagram was then automatically
generated for each process step.
State Diagram with Sterile
Boundary Key
State Diagram Sequence
Review of the Process
• Review each step of the process.
– Pay attention on device state changes (open/close)
• Evaluate areas where microbial breach could occur.
• Pay attention to changes in the sterile boundary perimeter.
• Understand the condition of the system (vaccum/pressure/flow).
Summary of Findings
• Provide a detail summary of the finding
indicating the process step, condition of
the system and devices involved.
Finding Process
Step
Possible Risk Recommendation
1 Valve sequencing on closing
creates a pressurized piping
between valves 10, 20 and 30
5 This could be a safety concern
as the piping is energized and
there is no pressure indicator for
an operator to see its condition.
Revise
sequencing to
relieve pressure
and close in
sequence.
Example Summary
Provide Detail Analysis
Step 5: Pressurized Piping
Close path valve sequencing
creates a pressurized pipe
section.
There could be a possibility
of injury if a person opens V
20 and expose Tank contents
to the mechanical space.
Recommendation is to review
the valve sequencing to
release valve pressure and
avoid exposure to
mechanical space.
Risk Assessment
• Is an evaluation to assure that the system,
equipment and process, is operating as
intended.
• Identify and implement suitable controls to
manage and reduce the risk of microbial
ingress.
Risk Assessment Pre-Work
• Define the Scope
– Device Level or Component Level
• Device type (i.e. ball valve, diaphragm valve, etc.)
• Device components (i.e. seals, O-rings, gaskets)
– Steps to cover
• From SIP to product unload
• From SIP to Product Transfer
• Provide Assumptions
– SIP provides sterilization.
– System is clean.
– Sterile filters are integral.
– Automation and sequence is appropriate
• Identify when the system is at risk
• Identify devices that pose potential risk
Sterile Boundary Confirmation
• Sterile Boundary Review– Understand the system state (Pressure, vacuum,
etc.)• Clarifies nature of risk
– Establish Dynamic and Static components.• Greatest risk are from dynamic components.
– Automatic valve – dynamic component
– Sight glass – static component
• Determine Credible Failure Modes– Maintenance History
– Changes
– Equipment Risk Assessment
Assessment Considerations
• One step at a time
– Review failure modes
• Can this failure happen and would it affect sterility?
• Document detection controls
– What is currently in place to detect this failure
if it happened?
– What is the chance of this failure being
detected before the material leaves the site?
Example of FMEA
RISK = PROBABILITY * DETECTION * SEVERITY
Device FailurePrevention Controls
Probability (P)
Detection (D)
P*D Severity Risk
Dia
ph
ragm
V
alve
Fail Open None 2 1 A 1 L
Leak at Flange
PM 3 1 B 4 M
Leak Through
None 5 4 E 4 H
5 C C D E E4 B C C D E3 B B C C D2 A B B C C1 A A B B C
1 2 3 4 5
E L M H H HD L M M H HC L L M M HB L L L M MA L L L L M
1 2 3 4 5
Dete
cti
on
(D
)
Probability (P) P *
DSeverity
Major Maintenance History and
Design or Process Changes
• Maintenance History and Changes
– Internal engineering activity.
• Report major activities that could cause SB
device changes.
• Review maintenance history to identify
previous failures
Summary of Findings
• Deliverables from the Assessment:
– All SB devices
– All sterile devices inside the SB
– All static, sterile devices
• Document the failed state of all SB devices
• Analysis of results
– Acceptable
– Unacceptable
Questions