Risk based approach to

qualification of equipment and

utilities
Tetra Pak Stainless Equipment
Agus Rascana

Tangerang, September 15th, 2015

Risk based approach

AR/2015-09-15
ISPE- Risk based approach to qualification
of equipment and utilities
Agenda :
► Buying Process in Pharmaceutical, Validation and
Q lifi ti P
Qualification Principles
i i l iin GMP – V Model
M d l
► Scope & Approach Requirements
► Rationale and Key
y Concept
p
► Direct and Indirect Impact
► Quality Assurance & Scope of Supply
► Project Quality Assurance Plan - Practice
► Samples
− Hygienic Risk Assessment
► Q&A
► Conclussion

Risk based approach

AR/2015-09-15
Buying Process, Validation
and Qualification Principles

Risk based approach

AR/2015-09-15
 Flowchart of Buying Process
Product
Capacity Rooms Layout, Personal DQ, Plant Layout,
Market Size & Material Flow, Plant Architecture, Cost of
Validation Layout, Utilities , HVAC, Budget Investment,
master Plan VMP, URS, Process VMP, URS

Preliminary Feasibility Engineering Basic Design Detailed

Study Study Conceptual /Engineering Engineering

VMP, URS

IMB, R
BPOM &
BPOM AMDAL, I
Headquarter BKPM
Approval Approvals Approvals
S
K

A
Bidding Detail:
VMP N
Compile All Designs Engineering Tender
New Product
& Cost Approval A
Formulation L
HVAC Y
Electrical
B Automation
DQ
S
Waste
Plant Design, I
Note : S
Automation and Detailed
Processing
: Consultant or supplier roles Plant P Automation Engineering Construction
Integration, Plant Integration & Approval
: Done
D b
by C
Customer
t B ildi
Building
Civil Architecture
Installation completed
IQ, OQ, PQ
Process Validation

Commercial BPOM Stability Test Stability

Approval for
Product production
Result Test

BPOM
Facility Approval
Improvement for use of
facility
Risk based approach
AR/2015-09-15
 Illustration of the validation and
qualification principles in GMP.

Risk based approach

Ref. ISPE AR/2015-09-15
ASTM Key Principals
RISK BASE APPROACH
► #1 Risk Based ► ASTM E2500-07 : Standard
► #2 Science Based
► #3 Critical Quality
Attribute (CQA)
► #4 Quality by Design
► ASTM International, known until
(QbD)
► #5 Good Engineering
Practices (GEP)
► #6 Subject Matter
Experts (SME)
► #7 Use of Vendor
Documents
Guide for The Specification,
Specification
Design and Verification Of
Pharmaceutical and
Biopharmaceutical Equipment,
Systems And Facilities
2001 as the American Society y
for Testing and Materials
(ASTM), is an international
standards organization that
develops
p and p publishes
voluntary consensus technical
standards for a wide range of
materials, products, systems,
and services.
Risk based approach
AR/2015-09-15
 Baseline Guide 5 vs. FSE Guide
Applied: Facilities, System, Equipments

Risk based approach

Ref. ISPE AR/2015-09-15
 ASTM- Risk Based Approach

ASTM Process

Supporting
activities

Risk based approach

Ref. ISPE AR/2015-09-15
Main Propose and Validation

Risk based approach

AR/2015-09-15
 The Risk - Based Verification Process

Risk based approach

Ref. ASTM AR/2015-09-15
Scope and Approach
Requirements

Risk based approach

AR/2015-09-15
Scope

► New commercial manufacturing and modification to

existing regulated manufacturing facilities
► Planning, specification, design, and delivery
(harmonized) with GAMP 5
► Addresses the verification (or qualification) portion
of the validation life cycle
y on which process
validation is built

Risk based approach

AR/2015-09-15
 Approach and Method Validation
Traditional & RBA Based on ASTM E 2500

► (Product) User Requirements not ► Process Requirements Documented,

Formally Documented Approved

► Protocols Developed from ► Risk Assessments Determine Critical

“Templates”
Templates IQ/OQ Protocols Aspects of Design

► “Preapproved” Commissioning not ► Engineering Testing (“Commissioning”)

Leveraged
g Verification

► Engineering And “Validation” ► All Documents with Technical Merit

Personnel Often Distinct Used as Evidence of Fitness or Use

► Emphasis on Documents Not ► Emphasis on Meeting Process

System Performance Requirements

Risk based approach

AR/2015-09-15
Summaries of requirement

► 1. Introduction ► 8. Good Engineering

► 2. Overview Of The P ti
Practice
Lifecycle ► 9 . Design Review
► 3. Requirements
q ► 10. Change
g Management
g
► 4. Specification & Design ► 11--‐15. Appendices
► 5. Verification, Acceptance ► 16. Appendix 6 Glossary
and Release and Acronyms
► 6. Continual Improvement ► 17. Appendix 7
► 7. Quality Risk References
Management ► Note : A
Automation
tomation dealt
with throughout each
chapter

Risk based approach

AR/2015-09-15
Rationale and
Key Concept

Risk based approach

AR/2015-09-15
FSE-Rationale for the New ISPE GUIDE
Facilities, System, Equipments

► Presents a structured lifecycle approach to the delivery of

f iliti
facilities, systems
t andd equipment
i t which
hi h supportt th
these
regulatory initiatives
► Designed to improve the way in which the industry delivers
regulated manufacturing
f capacity
► – Improve the ability to meet documented process
requirements
► – Control risks within the manufacturing process
► – Produce high quality products which consistently meet
product user requirements.
p q
► The GUIDE describes the Principles required when
► Applying a science and risk based program

Risk based approach

AR/2015-09-15
Our Aim and benefits

► Encourage the industry (including supplier) and

individual organizations to reassess the
terminology, practices, and roles and
responsibilities involved in delivering new
manufacturing capacity to focus on the criteria
required to establish “suitability for intended use.”

Risk based approach

AR/2015-09-15
Key Concepts

► Science Based Quality Risk Management

− Describes the importance of a QRM program
– Documented risk assessments focused on risk to patient
– Focus on identifying, assessing and controlling risk
► Product and Process Understanding
– Resulting from scientific investigation
– Enhanced continually during ongoing operations
– Begins with knowing the product CQAs and associated CPPs
► Focus on Achieving Fitness or Intended Use
− Verification activities focused on confirming that CAs of
equipment/
i t/ systems
t andd associated
i t d meett acceptance
t criteria
it i
− Verification inspections and tests are not limited to CAs

Risk based approach

AR/2015-09-15
 Key Concepts Science

► Flexible Approaches to Specification and Verification

− Several approaches to structure the documents, inspections, and
testing activities
− Demonstration of fit for intended use and sufficient to meet
regulatory
l t expectations
t ti
► Clarification of Roles and Responsibilities
− The roles of Quality Unit and ASME are described in the context of
the scope of activities covered by this Guide.
− Subject Matter Experts (SMEs) are defined as those individuals
with specific expertise in a particular area or field.
− The
Th Quality
Q lit Unit
U it has
h a key
k rolel within
ithi the
th quality
lit managementt
system governing facilities, systems, and equipment.
− In addition to acting as a Subject Matter Expert (SME) the Quality
Unit is responsible for overseeing quality and compliance

Risk based approach

AR/2015-09-15
Concerns from Some Industries

► Too big of a leap for us

► Too much time spent on implementing quality
systems with BG5 model
► I like the concepts but don’t see how I can fully
Implement this model
► My facility is all legacy systems

Risk based approach

AR/2015-09-15
Direct and Indirect
Impact

Risk based approach

AR/2015-09-15
 Commissioning and Qualification based on
ISPE Baseline Guide Vol.5
Commissioning and Qualification

Risk based approach

Ref. ISPE AR/2015-09-15
 Direct, Indirect Impact

URS VMP DQ COM IQ OQ PQ PV

Equipment
Parenteral Vessel (LVP and SVP) Yes Yes Yes Yes Yes Yes Yes Yes

Premix, Mixing, Storage vessel Yes Yes Yes Yes Yes Yes Yes Yes
(oral Solution)
PW, WFI Storage tank Yes Yes Yes Yes Yes Yes Yes Yes
Transfer pump for PW, WFI, Yes Yes Yes Yes Yes Yes Yes Yes
Products
Multi media filter, Yes Yes Yes Yes
Carbon active filter

Utility System
Fire Water System Yes Yes Yes Yes

Breathing Air System Yes Yes Yes Yes

Cold/Glycol water Yes Yes Yes Yes
USP water (PW, HPW, WFI) Yes Yes Yes Yes Yes Yes Yes Yes
HVAC Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes

Risk based approach

AR/2015-09-15
Typical VMP Contents

Risk based approach

AR/2015-09-15
Quality Assurance &
Scope of Supply

Risk based approach

AR/2015-09-15
 Productions solutions for Oral products

CIP Module
Vacuum Mixing
Module

PW Generator

PW tank
and Loop module
Holding Module

Risk based approach

AR/2015-09-15
Production solutions for Parenteral
products

PSG and
WFI Loop
LVP Module
LVP Filling
g
Machine

SVP Module

SVP Filling
CIP SIP Module Machine
Risk based approach
AR/2015-09-15
►Complete line solutions
►Integrated automation
►Traceability

Risk based approach

AR/2015-09-15
Quality Assurance
Plan

Risk based approach

AR/2015-09-15
Project Quality Assurance Plan
Design Review and Risk Assessments

► Review of Production Solution Functionality

− Production Functionality review
− Operation
O Functionality review
► Review of Technical Design
► Hygienic
yg Risk Assessment
► Health & Safety Risk Assessment

Risk based approach

AR/2015-09-15
Project Quality Assurance Plan
Implementation

► Supplier selection
► Procedure, Facility
► Certification, etc.
► Testing
► Third party inspections
► F t
Factory Acceptance
A t Test
T t – FAT - Dry
D
► Factory Acceptance Test – FAT – Wet
► Factory Acceptance Test – FAT – Product Test
► Waste handling
► Etc.

Risk based approach

AR/2015-09-15
Project Quality Assurance Plan
Installation Completion

► Pre-delivery Inspections
► Factory Acceptance Test (FAT)
► Box Opening Inspection
► Health & Safety Risk Validation
► Completed Installation Inspection

Risk based approach

AR/2015-09-15
Project Quality Assurance Plan
Commissioning

► Commissioning Test
► Performance Test

Risk based approach

AR/2015-09-15
Project Quality Assurance Plan
Performance Validation

► Performance Test

Risk based approach

AR/2015-09-15
Some Samples
It works

Risk based approach

AR/2015-09-15
 Flowchart of Buying Process
Product
Capacity Rooms Layout, Personal DQ, Plant Layout,
Market Size & Material Flow, Plant Architecture, Cost of
Validation Layout, Utilities , HVAC, Budget Investment,
master Plan VMP, URS, Process VMP, URS

Preliminary Feasibility Engineering Basic Design Detailed

Study Study Conceptual /Engineering Engineering

VMP, URS

IMB, R
BPOM &
BPOM AMDAL, I
Headquarter BKPM
Approval Approvals Approvals
S
K

A
Bidding Detail:
VMP N
Compile All Designs Engineering Tender
New Product
& Cost Approval A
Formulation L
HVAC Y
Electrical
B Automation
DQ
S
Waste
Plant Design, I
Note : S
Automation and Detailed
Processing
: Consultant or supplier roles Plant P Automation Engineering Construction
Integration, Plant Integration & Approval
: Done
D b
by C
Customer
t B ildi
Building
Civil Architecture
Installation completed
IQ, OQ, PQ
Process Validation

Commercial BPOM Stability Test Stability

Approval for
Product production
Result Test

BPOM
Facility Approval
Improvement for use of
facility
Risk based approach
AR/2015-09-15
 The Risk - Based Verification Process

Risk based approach

Ref. ASTM AR/2015-09-15
Production Functionality Review

► Objective
− Toevaluate the ability of the functional design documents to
meet production related requirements in contract and to
identify deviations (if any) and agree necessary actions.
► Requirements
− As per the Contract
− Exhibits:
− Design Requirements
− Technical Description and Drawing list
− Specification of Equipment and Services
− Commissioning
C i i i C Criteria
it i and
dPPerformance
f T
Targets
t

Risk based approach

AR/2015-09-15
Production Functionality Review

► Scope
− The works or agreed sections thereof as per documents
listed below.
− Process Technology Diagram
− Mass
M balance
b l
− Production Time Schedule or manufacturing,
characteristics
− Production Block Diagram
− Functional Diagram
− Automation System Configuration
− Machinery layout
− Single Line Diagram

Risk based approach

AR/2015-09-15
Next

► Next and detail

− See file P0031-033_QualityAssurancePlan.doc

Risk based approach

AR/2015-09-15
Tetra Pak Stainless
Equipment
Hygienic
Risk Assessment

Risk based approach

AR/2015-09-15
 Commissioning and Qualification based on
ISPE Baseline Guide Vol.5
Commissioning and Qualification

Bio Safety Level and Trend ????

Risk based approach
Ref. ISPE AR/2015-09-15
 Direct, Indirect Impact

URS VMP DQ COM IQ OQ PQ PV

Equipment
Parenteral Vessel (LVP and SVP) Yes Yes Yes Yes Yes Yes Yes Yes

Premix, Mixing, Storage vessel Yes Yes Yes Yes Yes Yes Yes Yes
(oral Solution)
PW, WFI Storage tank Yes Yes Yes Yes Yes Yes Yes Yes
Transfer pump for PW, WFI, Yes Yes Yes Yes Yes Yes Yes Yes
Products
Multi media filter, Yes Yes Yes Yes
Carbon active filter

Utility System
Fire Water System Yes Yes Yes Yes

Breathing Air System Yes Yes Yes Yes

Cold/Glycol water Yes Yes Yes Yes
USP water (PW, HPW, WFI) Yes Yes Yes Yes Yes Yes Yes Yes
HVAC Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes Y
Yes

Risk based approach

AR/2015-09-15
Typical VMP Contents

Risk based approach

AR/2015-09-15
Typical VMP Contents

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Purified Water is not meeting expected requirements: Contaminated
with others

Source Purified Water

GMP Risk Other Risk type
PW Supply yes no
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA
Component

Process/Unit operation
Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that purified water USP - PW Grade
supply can not come into the PW loop system alarm system 60-80%
action limit 80-100%
80 100%
Closed valve 99%

Verification
T Strategy
Test S IQ & OQ

continuous monitor
Risk based approach
AR/2015-09-15
Risk Assessment Hygienic
Source PW - RO

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Purified Water is not meeting expected requirements: Contaminated
with others

Source Purified Water

GMP Risk Other Risk type
PW Supply yes no
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that purified water USP - PW Grade
supply can not come into the PW loop system alarm system 60-80%
action limit 80-100%
80 100%
Closed valve 99%

Verification
IQ & OQ

continuous monitor
Risk based approach
AR/2015-09-15
Risk Assessment Hygienic
PW Distribution system

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Purified Water is not meeting expected requirements: Contaminated
with others

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - water supply yes no
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that purified water USP - PW Grade
supply can not come into the PW loop system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Flow rate of the Purified Water is not meeting expected requirements, more than 2
hours

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - speed of water Yes Yes
Mitigation Method 2

Justification Justification
Pressure indicator, table conversion of Potential of quality and TOC increase,
pressure, flow rate, and Re number bio film

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water Flow rate PW - above
supply running at Re < 17000 for 2 hours on the system: turbulence - Re number
1 Valve to WFI Distiller
1. above 17 000
2. Valve to the PS Generator alarm system 60-80%
3. Indicator to the POU washing System action limit 80-100%
Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
UV lamp is not function

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - UV lamp Yes Yes
Mitigation Method 3

Justification Justification
UV lamp has expired date, operation Potential of quality and TOC increase,
hours wave length is not acceptable bio film

Risk Level
Low

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - PW Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of PW system

Purified Water Loop system

GMP Risk Other Risk type
PW Loop -sterility Yes Yes
Mitigation Method 4

Justification Justification
Microorganism and Sterilization of the Potential of quality PW water impact,
system micro growth and sterilization
periodically

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - PW Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
periodic sterilization, every 4 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of PW system

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - vent filter PW tank Yes Yes
Mitigation Method 5

Justification Justification
Microorganism and Sterilization of the Potential of quality PW water impact,
system micro growth and vent filter

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - PW Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
periodic and inspection, sterilization, every 12 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of PW system

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - pump Yes Yes
Mitigation Method 6

Justification Justification
Microorganism and Sterilization of the Potential of quality PW water impact,
system micro growth and pump seal leakage

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - PW Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
periodic and inspection, sterilization, every 12 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of PW system

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - inverter No Yes
Mitigation Method 7

Justification Justification
Microorganism and Sterilization of the Potential of quality PW water impact,
system micro growth and pump pressure is
not running, inverter is not running

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - PW Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Operational of PW system

Purified Water Loop system

GMP Risk Other Risk type
PW Loop - Tank Volume No Yes
Mitigation Method 8

Justification Justification
Consumption and volume POU Potential of quality PW water impact,
micro growth and air will penetrate to
the PW system

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if Pressure is low and USP - PW Grade
tank volume is low: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
continuous monitor, impact on the flow rate or speed will drop see item:3
Risk based approach
AR/2015-09-15
Risk
Ri kAAssessmentt H
Hygienic
i i
WFI Generator

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Purified Water is not meeting expected requirements: Contaminated
with others

WFI Generator (Distiller)

GMP Risk Other Risk type
PW Supply Yes Yes
Mitigation Method 1

Justification Justification
Sampling Via TOC meter Potential of quality PW water impact,
micro growth and air will penetrate to
the PW system

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if Pressure is low and USP - PW Grade
tank volume is low: alarm system 60-80%
1 Valve to WFI Distiller
1. action limit 80-100%
80 100%
2. Valve to the PS Generator Closed valve 99%
3. Indicator to the POU washing System

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Quality of the Water For Injection is not meeting expected requirements:
Contaminated with others

WFI Generator (Distiller)

GMP Risk Other Risk type
WFI Quality Output Yes No
Mitigation Method 2

Justification Justification
Sampling Via TOC meter, before NA
entering the WFI loop

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automaticcaly stop, if purified water USP - WFI Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI tank is stop
1. action limit 80-100%
80 100%
2. WFI outlet from WFI Generator are be rejected Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kAAssessmentt H
Hygienic
i i
Pure Steam - PS Generator

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Purified Water is not meeting expected requirements: Contaminated
with others

Pure Steam Generator

GMP Risk Other Risk type
PW Supply Yes No
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that PW supply USP - PW Grade
can not come into the PS generator system alarm system 60-80%
action limit 80
80-100%
100%
Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Quality of the Pure Steam is not meeting expected requirements: Contaminated with
others

Pure Steam Generator

GMP Risk Other Risk type
PS Quality Output Yes No
Mitigation Method 2

Justification Justification
Sampling Via Conductivity NA
sensor/TOC meter, before entering the
Pure steam distribution system

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - WFI Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to WFI tank is stop
1. action limit 80
80-100%
100%
2. WFI outlet from WFI Generator are be rejected Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Quality of the Pure Steam is not meeting expected requirements: Contaminated with
others

Pure Steam Generator

GMP Risk Other Risk type
PS Quality Output - quality of pipe Yes No
Mitigation Method 3

Justification Justification
Sampling Via Conductivity NA
sensor/TOC meter, after distribution
system on the longest point of use

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if purified water USP - WFI Grade
supply running with low quality on the system: alarm system 60-80%
1 Valve to point of use (central)
1. action limit 80
80-100%
100%
2. Share all information to POU am,aily sterilization Closed valve 99%
process, via Scada

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kAAssessmentt HHygienic
i i
WFI Distribution System/Loop

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Water for injection is not meeting expected requirements:
Contaminated with others

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - water supply Yes No
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Quality of the Water for injection is not meeting expected requirements:
Contaminated with others

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - water supply Yes No
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Flow rate of the Water for injection is not meeting expected requirements, more than
2 hours

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - speed of water Yes Yes
Mitigation Method 2

Justification Justification
Pressure indicator, table conversion of Potential of quality and TOC increase,
pressure, flow rate, and Re number bio film

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if Water for injection Flow rate WFI - above
supply running at Re < 17000 for 2 hours on the system: turbulence - Re
1 POU valve
1. number above 17 000
3. Indicator to the POU washing System alarm system 60-80%
action limit 80-100%
Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
HE is not function

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - HE Yes Yes
Mitigation Method 3

Justification Justification
HE will has a function for keep Potential of quality and TOC increase,
temperature and sterilization bio film

Risk Level
Low

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, if Water for injection USP - WFI Grade
supply running more than 2 hours on the system: alarm system 60-80%
1 POU valve
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of WFI system

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop -sterility Yes Yes
Mitigation Method 4

Justification Justification
Microorganism and Sterilization of the Potential of quality WFI water impact,
system micro growth and sterilization
periodically

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
periodic sterilization, every 4 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of WFI system

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - vent filter WFI tank Yes Yes
Mitigation Method 5

Justification Justification
Microorganism and Sterilization of the Potential of quality WFI water impact,
system micro growth and vent filter

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
periodic and inspection, sterilization, every 12 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of WFI system

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - pump Yes Yes
Mitigation Method 6

Justification Justification
Microorganism and Sterilization of the Potential of quality WFI water impact,
system micro growth and pump seal leakage

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
periodic and inspection, sterilization, every 12 weeks
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of WFI system

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - inverter Yes Yes
Mitigation Method 7

Justification Justification
Microorganism and Sterilization of the Potential of quality WFI water impact,
system micro growth and pump pressure is
not running, inverter is not running

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
continuous monitor, impact on the flow rate or speed will drop see item:3
Risk based approach
AR/2015-09-15
 Risk verification
Operational of WFI system

Water for injection Loop system

GMP Risk Other Risk type
WFI Loop - Tank Volume Yes Yes
Mitigation Method 8

Justification Justification
Consumption and volume POU Potential of quality WFI water impact,
micro growth and air will penetrate to
the WFI system

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System Closed valve 99%

Verification
IQ & OQ
continuous monitor, impact on the flow rate or speed will drop see item:3
Risk based approach
AR/2015-09-15
 Risk verification
Operational of WFI system

Water for injection Loop system

GMP Risk Other Risk type
Cooling WFI - washing Yes Yes
Mitigation Method 9

Justification Justification
temperature to high, HE not working safety operator HOT water
properly, cooling not enough or flow
rate too high

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valve washing will not open
1. action limit 80
80-100%
100%
3. Indicator to the POU washing System temperature Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kAAssessmentt H
Hygienic
i i
Mixing system - Dumping

Risk based approach

AR/2015-09-15
 Risk verification
Quality of the Water for injection is not meeting expected requirements:
Contaminated with others

Dumping station
GMP Risk Other Risk type
WFI Loop - water supply Yes No
Mitigation Method 1

Justification Justification
Sampling Via TOC meter NA

Risk Level
Sampling Via TOC meter

Risk Control

Mitigation Method Residual risk level

The valve will be automatically stop, so that Water for USP - WFI Grade
injection supply can not come into the WFI loop system: alarm system 60-80%
1 POU valves from HMI
1. action limit 80
80-100%
100%
Closed valve 99%

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Quality of the Water for injection is not meeting expected requirements:
Contaminated with others

Dumping station
GMP Risk Other Risk type
WFI Loop - Quantity Yes No
Mitigation Method 2

Justification Justification
calibration of Flow meter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Wrong dumping

Dumping station
GMP Risk Other Risk type
Powder Dumping Yes No
Mitigation Method 3

Justification Justification
sequence and checked with bar code NA
or manual system

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Hepa filter and sterilization process

Dumping station
GMP Risk Other Risk type
Sterilization Yes No
Mitigation Method 4

Justification Justification
SOP Washing and sterilization NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Wrong sequence

Dumping station
GMP Risk Other Risk type
Process Sequence Yes No
Mitigation Method 5

Justification Justification
SOP process and HMI control NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
wrong weight, loot, wrong material dumping

Dumping station
GMP Risk Other Risk type
Weight material Yes No
Mitigation Method 6

Justification Justification
SOP process and HMI control NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kAAssessmentt H
Hygienic
i i
Mixing system – Mixing tank

Risk based approach

AR/2015-09-15
 Risk verification
mixing all ingredient

Mixing Tank
GMP Risk Other Risk type
Agitating and disolving Yes No
Mitigation Method 1

Justification Justification
Sampling NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

prolong agitating time, increase inverter/adjustment,
adjustment time

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
temperature control

Mixing Tank
GMP Risk Other Risk type
Heating Yes No
Mitigation Method 2

Justification Justification
temperature of product as requirement NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating, steam, if HMI control, card
temperature not reach process will continuously heat until control
desire temperature

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
temperature control

Mixing Tank
GMP Risk Other Risk type
Cooling Yes No
Mitigation Method 3

Justification Justification
temperature of product as requirement NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating, steam, if HMI control, card
temperature not reach process will continuously heat until control
desire temperature

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
temperature of product as requirement, sirculation and filtration

Mixing Tank
GMP Risk Other Risk type
Pyrogen revomal, additional Yes No
carbon, circulation

Mitigation Method 4
Justification Justification
Sampling NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

prolong agitating time, increase inverter/adjustment, HMI control, card
adjustment time control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Wrong sequence

Mixing Tank
GMP Risk Other Risk type
Process Sequence Yes No
Mitigation Method 5

Justification Justification
SOP process and HMI control NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
wrong weight, loot, wrong material dumping

Mixing Tank
GMP Risk Other Risk type
Weight material, carbon Yes No
Mitigation Method 6

Justification Justification
SOP process and HMI control NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

The valve will be automatically regulating HMI control, card
control

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
quality of filter

Mixing Tank
GMP Risk Other Risk type
Filtration Yes No
Mitigation Method 6

Justification Justification
integrity test of filter NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

intyerity tester

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kA
Assessmentt H
Hygienic
i i
Mixing system – Transfer To
Filling
Filli

Risk based approach

AR/2015-09-15
 Risk verification
compressed air quality

Transfer to Buffer tank

GMP Risk Other Risk type
Transfer ke Buffer tank Yes No
Mitigation Method 1

Justification Justification
Sterile filter and sterility NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

Sterility and record of filter, integrity test

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of filter

Transfer to Buffer tank

GMP Risk Other Risk type
Filtration Yes No
Mitigation Method 2

Justification Justification
Sterile filter and sterility NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

Sterility and record of filter, integrity test

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
balancing of pressure

Transfer to Buffer tank

GMP Risk Other Risk type
Transfer ke Buffer tank and buffer Yes No
to filling at the same time
Mitigation Method 3
Justification Justification
setting and balancing pressure NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

control automatic or manual base on the requirement

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Risk
Ri kA
Assessmentt H
Hygienic
i i
Mixing system – Buffer tank
andd Filli
Filling

Risk based approach

AR/2015-09-15
 Risk verification
Keep homogen

Buffer tank- storage and filling

GMP Risk Other Risk type
Agitating and keep homogen Yes No
Mitigation Method 1

Justification Justification
Sampling NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

prolong agitating time, increase inverter/adjustment, Low speed
adjustment time

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterile filter and sterility

Buffer tank- storage and filling

GMP Risk Other Risk type
Sterility of filter Yes No
Mitigation Method 2

Justification Justification
setting and balancing pressure NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

Sterility and record of filter, integrity test

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
balancing of pressure

Transfer to Buffer tank

GMP Risk Other Risk type
Transfer to Buffer tank and buffer Yes No
to filling at the same time
Mitigation Method 3
Justification Justification
setting and balancing pressure NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

control automatic or manual base on the requirement

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
setting and balancing pressure

Transfer from buffer to filling

GMP Risk Other Risk type
balancing of pressure Yes No
Mitigation Method 1

Justification Justification
Sampling NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

control automatic or manual base on the requirement

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of filter

Transfer from buffer to filling

GMP Risk Other Risk type
Filtration Yes No
Mitigation Method 2

Justification Justification
Sterile filter and sterility NA

Risk Level
High

Risk Control

Mitigation Method Residual risk level

Sterility and record of filter, integrity test

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
 Risk verification
Sterility of line , contamination or leakkage

Transfer from buffer to filling

GMP Risk Other Risk type
Transfer line/pipe Yes No
Mitigation Method 2

Justification Justification
Sterile filter and sterility, long waiting NA
time (more than 2 hours), re-
sterilizations

Risk Level
High

Risk Control

Mitigation Method Residual risk level

Pressure test over pressure during filling:
after sterilization dry on fill with dry sterile compressed air
pressurerized or N2

Verification
IQ & OQ
continuous monitor
Risk based approach
AR/2015-09-15
Q&A

Risk based approach

AR/2015-09-15
Q and A

Risk based approach

AR/2015-09-15
Conclusion

Risk based approach

AR/2015-09-15
CONCLUSION

► Risk assessment must be in URS and is a process

loop during beginning and end of project phase
► Risk of process must be documented and the
system is operating consistently and according to
the desired specifications.
► Risk assessment must be part of a tool for total
quality management and it is necessary for
process optimization, safety, efficiency and
assurance of quality
quality.
Such validation protocols also fulfill regulatory
requirements and provide good business sense.

Risk based approach

AR/2015-09-15
CONCLUSION

► Successful accomplishment of risk validation is

ensured by various testing phases.
Usually, a three-phase testing approach is
recommended over an extended period to prove
reliability and robustness of the system for
producing product at specified quality with a high
degree of assurance.

Risk based approach

AR/2015-09-15
Thank you

Risk based approach

AR/2015-09-15