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