Concept to risk management ( In context to Q9)

A Brief concept to Risk
assessment analysis…..
(where we stand ?)
In context to Q9….
We are living in full of risk….
Risk management not new…
Zero risk does not exist anywhere…

Presented by
Subhakanta Dhal .
Mail id-sdhal82@gmail.com

1

Examples of Everyday Risk
POSSIBLE RISK/ EVENT/ SCENARIO
STRATEGIC

FINANCIAL

OPERATIONAL

Including: Governance, Stakeholder
Relationships, Reputation, Environment

Including Capital Management, Budgeting,
Revenue and Expenditure, Reporting

CLINICAL (HEALTHCARE)

Including Human Resources, OH&S,
Procurement, Legislative, Asset Management

Changes in services provided

Incorrect valuation of capital assets

Medication errors

Power failure

Loss of customers to private sector
companies

Declining market value of assets

Services/ goods not provided within
budget

Capital assets not maintained/ deterioration

Patient aggression

Tender evaluation requirements not defined

Change in public demand for services/
products

Equipment obsolescence

Sentinel events

Overpayment for goods and services

Change in public demand for services/
products

Customer revenue/ collections targets not met

Incorrect diagnosis

Failure to comply with procurement
legislation/ processes

Loss of customers to other state
organisation

Unauthorised and irregular expenditure

Infection control procedures not followed

Conflicts of interest in tender award process

Political change

Wasteful or unproductive expenditure

Failure to report incidents

Failure/ closure of service provider

Poor market knowledge

Changes in funding allocations

Patient records not
available/incomplete/incorrect

Unethical service provider actions

Change in interest rates

Over/ under spending budget allocations

Not upto mark of ethical standards

Goods/ services not meeting quality
requirements

Stakeholders not identified

Inaccurate revenue forecasting

Terrorist attack/ Bomb threat etc.

Non-delivery of goods and services by
supplier

3

Contents
Concept based
• Terminology
• Define- Risk & Type
• ICH and FDA : Expectation
• Identify - what is risk ?
• Measure – how to mitigate risk And how much extend ?
• Improve & Analysis –how to improve ? Specific method ?
• Control – can risk be controlled? If controlled then how ?
• Root cause analysis
• Opportunities & Benefits.
• Potential Applications.
• Future prospective

Case study
• FMEA
4

ICH Framework (Q8,Q9,Q1O)....
Product Life Cycle

Product
Design

Process
Design

Scale-up &
Transfer

Commercial
Manufacture

ICH Q8/Q8(R) - Pharmaceutical Development
PAT Guidance
ICH Q9 – Quality Risk Management

ICH Q10 – Pharmaceutical Quality Systems

Product

Product development concept..

In line with Quality Risk Management ?

Product development concept..
Initiate
Quality Risk Management Process

Formulation & Process design

Risk Assessment
Risk Identification

Risk Analysis

Process understanding

Risk Evaluation

Product release Concept
Regulatory strategy

Ris k Commun ic at ion

Process control Concept

unacceptable

Risk Control
Risk Reduction

Risk Acceptance

Output / Result of the
Risk Review

Review the submission

Review Events

R isk Ma nage ment t ools

Manufacturing Concept

Role of risk Product development concept..

Drug substance properties; prior knowledge
Proposed formulation and manufacturing process Research

Determination of
Cause – Effect relationships
(Risk Identification with subsequent Risk Analysis)

Phase 1

Risk-based classification
(Risk Evaluation)

Parameters to investigate (e.g. by DOE)
(Risk Reduction 1. proposal; 2. verified)

FORMULATION
DESIGN SPACE

Operation

Phase 2

Product and process
characteristics on the
final drug product

CONTROL
STRATEGY

PROCESS
DESIGN SPACE
BY UNIT OPERATION
Review events

Launch

Process understanding
Re-evaluation and confirmation

Formulation understanding
Developm.
Re-evaluation and confirmation

Development

Target Product Profile

Phase 3
EFPIA PAT TG, 2006

Risk Management approach to focus on critical attributes
Unit operation

Quality Attributes

Dispensing
Dissolution
Disintegration
Hardness
Assay
Content
Uniformity

Degradation
Stability
Appearance
Identification
Water
Microbiology

Granulation

Drying

Blending

Tableting
Significant
influence

Initial
assessment
Prior
knowledge

First & Second
review cycle
Formulation
and Process
understanding

Third
review cycle
Control
Strategy

EFPIA PAT TG, 2006

What Risks Must Be Managed?

Risk to safety of

patients, users, handlers

Business

Regulatory

Product liability
11

.

Terminology
Risk: The combination of the probability of occurrence of harm and the severity of that harm .
Risk Acceptance: The decision to accept risk .
Hazard: The potential source of harm.
Risk Analysis: The estimation of the risk associated with the identified hazards.
Risk Assessment: A systematic process of organizing information to support a risk decision to be
made within a risk management process. It consists of the identification of hazards and the analysis
and evaluation of risks associated with exposure to those hazards.
Risk Communication: The sharing of information about risk and risk management between the
decision maker and other stakeholders.

Risk Control: Actions implementing risk management decisions .
Risk Evaluation: The comparison of the estimated risk to given risk criteria using a quantitative or
qualitative scale to determine the significance of the risk.
Risk Identification: The systematic use of information to identify potential sources of harm (hazards)
referring to the risk question or problem description
12

Terminology
.

Risk Management: The systematic application of quality management policies, procedures, and
practices to the tasks of assessing, controlling, communicating and reviewing risk.
Risk Reduction: Actions taken to lessen the probability of occurrence of harm and the severity of
that harm.

Risk Review: Review or monitoring of output/results of the risk management process considering
(if appropriate) new knowledge and experience about the risk.
Severity: A measure of the possible consequences of a hazard.
Stakeholder: Any individual, group or organization that can affect, be affected by, or perceive
itself to be affected by a risk. Decision makers might also be stakeholders. For the purposes of this
guideline, the primary stakeholders are the patient, healthcare professional, regulatory authority,
and industry.
Decision Maker(s):Person(s) with the competence and authority to make appropriate and timely
quality risk management decisions.
Detectability:The ability to discover or determine the existence, presence, or fact of a hazard.

Harm: Damage to health, including the damage that can occur from loss of product quality or
availability.

13

ICH and FDA :Expectation
ICH Q9 Link back to patient risk
Opportunities to impact
risk using quality risk
management

Design
Process
Materials
Facilities

Manufacturing
Distribution
Patient

Risk Management across the Product lifecycle for drug (medicinal) products

Research
Preclinical
Phase

Clinical
Phases

End of
life cycle

Launch
Manufacturing
& Distribution

GLP

Safety

GCP(clinical)

Efficacy

GMP

GDP (Distribution )

Quality
ICH Q9

FDA Pharmaceutical GMP Initiative
A Challenge to Industry: (FDA announcement 27 Sep. 2004)
At the end of the cGMP Initiative the pharmaceutical community has arrived at a crossroad; one path goes towards the desired state and the other maintains the current state. The
path towards the desired state is unfamiliar to many while the current state provides the
comfort of predictability. The Agency hopes the pharmaceutical community will choose to
move towards the desired state.

Why was ICH Q9 ( Quality risk management ) needed?
•The evaluation of the risk to quality should be based on scientific knowledge and
ultimately link to the protection of the patient.
•A systematic process for the assessment, control, communication and review of risks to
the quality of the drug product across the product.
•The level of effort, formality and documentation of the quality risk management
process should be commensurate with the level of risk.
•To facilitate moving to the “Desired State”.
•To facilitate communication and transparency.
16

Regulators evaluate category of risk, based on:
• Product, process and facility .
• Controls to assess & mitigate risk .
• Quality system implementation .
Regulators determine ‘risk category’ and modify level of oversight accordingly for:
• Post-approval change review .
• GMP inspections .
Result:
• Removal of barriers to continuous improvement .
• Efficient use of resources by industry & regulators .

17

ICH and FDA :Expectation…

Increasing
external
requirements
for best practice,
transparency and
compliance
• Public / Community
• Governments
• Regulators
• Patients
• Investors / Creditors

The Hurdles

Growing
complexity
and scope of risks

?
Increasing
efforts and costs
for sustainability

• Globalisation
“Multinational”
• Multi-factor approaches
• Regulatory expectations
• Acceptance of
risk and uncertainty

• Documentation
• Projects
• Systems
• Interfaces

Initiate
Risk Assessment

• Brainstorming
Elementary Cause and Effect
Assignments
– Fishbone (Ishikawa)
diagram
– Failure mode/effect table
• Fault tree analysis
• Process map
• Flow charts

Risk Identification

•
Risk Analysis
Risk Evaluation
Risk Communication

Risk Control
Risk Reduction

Risk Acceptance

Risk Management Tools

unacceptable

•

Output / Result of the

•

Risk Review

Process sensors
•
SOP
Data flow optimization
•

Review Events

•

FMEA
• FMECA
Risk ranking

Define risk…
RISK = f (severity, probability)
Risk has three components:
•What could go wrong?
•What is the probability of failing to achieve a particular outcome?
•What is the impact of failing to achieve a particular outcome?

Types of risk...
1. Positive risk and negative risk

2. Pure risk and business risk
3. Residual risk
4. Secondary risk
5. Known risk and unknown risk
6. Etc.....

20

Parameters for “calculating” risks

A picture of the life cycle
= Risk Priority Number

Probability

x Detectability

x Severity

Refers to

Refers to

Refers to

past

today

future

time

Define risk…
Impact of risk ?
 Individual: Risk is a cognitive and emotional response to expected loss.
 Society: Risk is a societal expression of expected harm tempered by expected benefits.
 Organizations: Risk is a combination of the probability of occurrence and severity of

selected harms.

 Technical: Risk is usually based on the expected value of the conditional probability of the
event occurring times the consequence of the event given that it has occurred.

Quality Risk Management is Not...
•Hiding risks
•Writing half the truth (e.g. in an investigation report) .
•A means of removing industry’s obligation to comply with regulatory requirements .

If we do Risk Management properly, we should be able to:
• demonstrate that we understand what is important about our business;
• have a documented, approved rationale for our decisions;
• be proud to share these with regulatory agencies because they demonstrate our
knowledge and logical thought processes.

22

Indentify Risk…

Quality

Degree to which a set
of inherent properties
of a product, system or process
fulfills requirements

Risk

combination of the
probability of occurrence of harm and
the severity of that harm

Management

QRM

Systematic process for the assessment,
control, communication and review
of risks to the quality of the
drug (medicinal) product
across the product lifecycle

Indentify Risk… (Manage quality risks!....)

Consequences

What if
disaster happens?
Prior use of QRM may
lower the consequences

Nowadays
QRM

Using QRM

Quality management as function of time

Indentify Risk…Who is responsible ?
Responsibilities
Teams include experts from the appropriate areas
• Quality unit,
•business development
• engineering

• regulatory affairs
• production operations
• sales and marketing
• legal, statistics and clinical

Decision maker
•Take responsibility for coordinating quality risk management across various functions and departments.
• Assure that a quality risk management process is defined, deployed and reviewed and that adequate resources are available.

Initiating a Quality Risk Management Process
•Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk;
•Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the
risk assessment;
•Identify a leader and necessary resources;
•Specify a timeline, deliverables and appropriate level of decision making for the risk management process.

25

Measure Risk…
Measure Risk

stage
Risk assessment
Risk identification
Risk analysis
Risk evaluation

Risk Assessment -It consists of the identification of potential hazards and the analysis and evaluation of risks
(harm) associated with those hazards.

Sources of information..
• Manufacturer’s technical, operation and maintenance manuals
• Equipment history cards
• Breakdown data- types, frequency, criticality , downtime etc.
• Quality Problems
• Safety incidents – near misses, accidents
• Qualifications status
.............................. Etc

26

Measure Risk…
Risk identification
Identify possible sources of risk (problems , breakdowns etc.) by asking two basic often
helpful questions:

•What can go wrong?
• What are the possible consequences?

What can go wrong.. FBD example
• Filter bag is damaged.
• Bottom air inlet mesh damaged ,
• Air leaking through base joint.
• Blower stops in between .
• Required temperature not reached .
• Vent joints/pipes developed leaks .
• Blower motor jammed.
• (Mechanical, electrical, instrument & other problems)

.......
27

Measure Risk…
Risk analysis
The estimation of the risk associated with the identified hazards.
•Basically Two factors..
• Severity (S) ----consequences & Level of impact(s)
• Occurrence (O) --- Probability of occurrence
• Risk Score = Severity x Occurrence
• Risk = S x O

Severity & probability ratings..
Qualitative or Quantitative ratings are used to judge the extent of severity and probability of
occurrence of the risk.

• Qualitative Severity – Minor , Moderate, Critical etc.
•Probability – high, medium, Low etc.
• Quantitative Rating scales 1-3, 1-5, 1-10 etc.
N.B-Guidelines need to be established for assigning appropriate rating.
28

Measure Risk…
sample copy Risk Assessment work sheet
Potential risk

Failure Mode

(what can go wrong ) (What can go wrong)

Severity

Probability

(1-10)

(10 is

very
List each failure mode 10 is Worst probable)

Risk Score

(High scores) Action plan Owner

Due
Date

(need
attention)

1.Solution
a)

b)

c)

29

Measure Risk…
Risk Evaluation
•Risk scores are used to decide whether the risk is significant and requires
further actions to reduce the level of risk (or otherwise accept and live with it)

• This is done either by analyzing individual risk scores or by preparing “ Risk
Evaluation Matrix”.
• Appropriate control actions are initiated to reduce or handle the risk
(mitigation).

30

Improve & Analysis….
Basic management facilitation method.
(flow chart, check sheets, process mapping ,etc)

 Failure Mode Effects Analysis (FMEA)
 Failure Mode, Effects and Criticality Analysis (FMECA)
 Fault Tree Analysis (FTA)
 Hazard Analysis and Critical Control Points (HACCP)

 Hazard Operability Analysis (HAZOP)
 Preliminary Hazard Analysis (PHA)
 Risk Ranking and Filtering
 Supporting Statistical Tools

31

Failure Mode Effects Analysis (FMEA)

32

Failure Mode Effects Analysis (FMEA)
•FMEA generates a living document that can be used to anticipate and prevent failures
from occurring.

FMEA is a systematic method to:
1. Recognize, evaluate, and prioritize potential failures and their effects .
2. Identify actions which could eliminate or reduce the chance of potential failure
occurring .
3. Document and share the process .

FMEA addresses :
•Potential failures of product , process, system or machinery to meet requirements
(failure mode) .
•Potential consequences (failure effect) .
• Potential causes of the failure mode (failure cause) .
• Application of current controls .
• Level of risk.
• Risk reduction (additional controls)

33

Failure Mode Effects Analysis (FMEA)…..
•Types of FMEA
System – Potential failure modes between the functions of the system caused by system deficiencies.

Design – Failure modes caused by system deficiencies.
Process – Failure modes caused by process design.
Service – Failure modes caused by system or process deficiencies.

34

Failure Mode Effects Analysis (FMEA)…
Definition
Failure :A proper function or performance (of product, process, equipment etc.) to meet a
standard; not performing as required or expected.
Failure Mode :The manner of failure . The way in which the product or process could fail to
perform its intended function.
Failure Effects : the consequences of failure. The outcome of the occurrence of the failure
mode on the system, product, or process. Failure effects define the impact on the customer. Ranking is
translated into “Severity” score .

Failure Causes :Potential causes or reasons the failure mode could occur .
•Likelihood of the cause creating the failure mode is translated into an “Occurrence” score
Current Controls .

•Mechanisms currently in place that will detect or prevent the failure mode from occurring .
Ability to detect the failure before it reaches the customer is translated in “Delectability” score.

35

When to Use FMEA
1)When a process, product or service is being designed or redesigned.
2) When an existing process, product or service is being applied in a new way.
3) Before developing control plans for a new or modified process.
4) When analyzing failures of an existing process, product or service.
5) Periodically throughout the life of the process, product or service.

Concept…A Team Tool
• A team approach is necessary.
• Team should be led by the Process Owner who is the responsible manufacturing engineer or technical
person, or other similar individual familiar with FMEA.
The following should be considered for team members:
– formulation development team
– Operators
– Process team
– Analytical team
– Materials Suppliers
– Suppliers
– Customers

36

Occurrence Rating Scale
Rating
10

Description

Potential Failure Rate

Very High: Failure is
almost inevitable.
High: Failures occur almost
as often as not.

More than one occurrence per day or a probability of more than three occurrences
in 10 events.
One occurrence every three to four days or a probability of three occurrences in 10
events .

8

High: Repeated failures.

One occurrence per week or a probability of 5 occurrences in 100 events .

7

High: Failures occur often.

One occurrence every month or one occurrence in 100 events .

6

Moderately High: Frequent
failures.
Moderate: Occasional
failures.
Moderately Low:
Infrequent failures.
Low: Relatively few
failures.
Low: Failures are few and
far between.

One occurrence every three months or three occurrences in 1,000 events .

Remote: Failure is unlikely.

One occurrence in greater than five years or less than two occurrences in one billion
events .

9

5
4
3

2
1

One occurrence every six months to one year or five occurrences in 10,000 events .
One occurrence per year or six occurrences in 100,000 events .
One occurrence every one to three years or six occurrences in ten million events .

One occurrence every three to five years or 2 occurrences in one billion events .

37

Severity Rating Scale
Rating

Description

10
9

Dangerously high
Extremely high

8
7
6

Very high
High
Moderate

5

Low

4

Very Low

3

Minor

2

Very Minor

1

None

Definition (Severity of Effect)
Failure could injure the customer or an employee.
Failure would create noncompliance with federal regulations.
Failure renders the unit inoperable or unfit for use.
Failure causes a high degree of customer dissatisfaction.
Failure results in a subsystem or partial malfunction of the product.
Failure creates enough of a performance loss to cause the customer to
complain.
Failure can be overcome with modifications to the customer’s process or
product, but there is minor performance loss.

Failure would create a minor nuisance to the customer, but the customer can
overcome it without performance loss.
Failure may not be readily apparent to the customer, but would have minor
effects on the customer’s process or product.
Failure would not be noticeable to the customer and would not affect the
customer’s process or product.

38

Detection Rating Scale
Rating

Description

Definition

10

Absolute Uncertainty

9

Very Remote

8

Remote

7

Very Low

6

Low

Product is 100% manually inspected using go/no-go or other mistake-proofing
gauges.

5

Moderate

Some Statistical Process Control (SPC) is used in process and product is final
inspected off-line.

4

Moderately High

3

High

2

Very High

1

Almost Certain

The product is not inspected or the defect caused by failure is not detectable.
Product is sampled, inspected, and released based on Acceptable Quality
Level (AQL) sampling plans.
Product is accepted based on no defectives in a sample.
Product is 100% manually inspected in the process.

SPC is used and there is immediate reaction to out-of-control conditions.
An effective SPC program high.
All product is 100% automatically inspected.
The defect is obvious or there is 100% automatic inspection with regular
calibration and preventive maintenance of the inspection equipment.

39


40

Failure Mode Effects Analysis (FMEA)… Procedure
1.

For each process input (start with high value inputs), determine the ways in which
the input can go wrong (failure mode)

2.

Severity (s) --For each failure mode, determine effects
 Select a severity level for each effect ( scaled range 1 to 10 , 10-very serious)
 Importance of the effect on customer requirements

3. Occurrence (o) ---Identify potential causes of each failure mode
 Select an occurrence level for each cause ( scaled range 1 to 10 , 10-high like wood)

4.

Detection (D)---List current controls for each cause.
 Select a detection level for each cause. ( scaled range 1 to 10 , 10-canot detect)
 The ability of the current control scheme to detect or prevent a given cause
5. Calculate the Risk Priority Number (RPN)= S x O x D

6. Develop recommended actions, assign responsible persons, and take actions
 Give priority to high RPNs
 MUST look at severities rated a 10
7. Assign the predicted severity, occurrence, and detection levels and compare RPNs
41

Failure Mode Effects Analysis (FMEA)…
Inputs

Outputs

Brainstorming
C&E Matrix

Process Map
Process History
Procedures
Knowledge

FMEA

List of actions to prevent
causes or detect failure
modes
History of actions taken

Experience

42


43


44

Failure Mode, Effects and Criticality Analysis (FMECA) Concept…
•Failure Mode And Effects Analysis (FMEA ) might be extended to incorporate an investigation of the degree of
severity of the consequences, their respective probabilities of occurrence, and their delectability, thereby becoming a
Failure Mode Effect and Criticality Analysis .
• Failure Modes = Incorrect behavior of a subsystem or component due to a physical or procedural malfunction.
• Effects = Incorrect behavior of the system caused by a failure.
• Criticality = The combined impact of the probability that a failure will occur & severity of its effect .
•Failure Modes effects and Ccriticality Aanalysis (FMECA) = a step-by-step approach for identifying all possible
failures in a design, a manufacturing or assembly process, or a product or service .
Significance
•The FMECA facilitates identification of potential design reliability problems
•Identify possible failure modes and their effects
•Determine severity of each failure effect
•FMECA helps
•removing causes of failures
•developing systems that can mitigate the effects of failures.

.to prioritize and focus on high-risk failures

45

Case study on Risk control

54

Case study on Risk control

55

Case study on sakura tablet
(formulation )

56

other methodes Improve & Analysis….


Fault Tree Analysis (FTA)


62

Process Mapping: Process mapping is a workflow diagram to bring a clearer understanding
of a process or series of parallel processes.
MethodFlowchart- A flowchart is a picture of the separate steps of a process in sequential order.
When?
• To document a process .
• When planning a risk .
• To communicate to others how a process is done.
• To develop understanding of how a process is done.

63

Basic management facilitation method…
Written Procedures: A written procedure is a step-by-step guide to direct the reader through a task .
When?
• process is lengthy and complex
• process is routine, but it's essential that everyone strictly follows rules.
• person wants to know what is going on when a product is being developed.
Benefits:
• Having written procedures prevent mistakes .
• Frees your creativity .

• Procedures saves time .
• Ensures consistency and improves quality .
Work Instruction: Work instructions defines how one or more activities in a procedure should be written in
detail, using technology or other resources .The purpose of a Work Instruction is to organize steps in a logical

format so that an employee can easily follow it independently .

64

Fault Tree Analysis (FTA)
What ?
• FTA represents the sequence and combination of possible events that may lead to a failure mode. Once causes are identified,
preventive action can be taken .A structured team analysis of the possible underlying causes of a known equipment failure.

 When ?
• Root cause analysis of a failure is needed .
 Why? - (outcomes)
•A better understanding of the root causes of a failure.
•A better set of action plans to eliminate those root causes .

How to build a Fault Tree
1) Identify a top failure.
2) Brainstorm basic contributors to failure.
3) Link contributors to the top failure
•Determine which combination of contributors is needed to cause the top failure.

(Ask: How many of the inputs are needed to cause the top failure? )
•Link the contributors to the top failure with the correct gate. (And/Or)
Ask: Can we determine contributors for this lower failure ?
Yes - repeat cycle making each contributor a top failure, assign gates, etc...
No - we are finished - We may also end our fault tree when we reach all indeterminable, basics, or causes which require further
research etc...
65

What ?

 When ?


research etc...
66

 Basic symbols: Basic Flow
FAULT

OR

AND

 Fault in a box indicates
that it is a result of previous faults

 Connects preceding fault
with a subsequent fault
that could cause a failure

 Connects two or more faults
that must occur simultaneously
to cause the preceding fault

Fault Tree Analysis (FTA)..
 Basic symbols: End Points & Connector

Root cause

 Root cause (= basic fault)

(e.g. part failure, software error, human error)

 Fault to be further analyzed
with more time or information if needed

 Transfer-in and transfer-out events

Fault Tree Analysis (FTA)..
 Additional SymbolsExclusive OR Gate:

Fault occurs
if only one of the input faults occurs
 Priority AND Gate:
Fault occurs
if all inputs occur in a certain order

m

 Voting OR Gate:
Fault occurs if “m” or more out of “n” input faults
occurs


 Investigation of laboratory failures

outlier

Production

Out of specification
result

or

Lab error

others

or

systematic

random

Calibration

or

Interfaces

other

Experiences
•Better as a retrospective tool
•Visually focused: aid for showing linkages
Limitations
•Only as good as input .
•Time and resource consuming (needs FMEA as a complement ).
•Need skilled leader to focus on what is really important
•Need significant amount of information
•Human errors may be difficult to predict
•Many potential fault trees for a system
-Some more useful than others
-Need to evaluate contribution

Hazard Analysis and Critical Control Points (HACCP)
•HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and safety & method of
identifying and controlling sources of variation at critical process steps that could lead to a hazardous condition.
•Similar to a control plan .

•Cannot be used effectively without manual or automated process control methods, including statistical process
control
Uses
•New manufacturing process or equipment .
•To identify and manage risks associated with physical, chemical and biological hazards (including microbiological
contamination).
Limitations
•Requires excellent process knowledge .
•FMEA should precede HAACP to identify critical hazards/failure modes (A HAACP could be an action to reduce risk in
a FMEA) .

•Requires use of more complex statistical tools to be effective (Characterization DOEs, SPC, Capability Matrices) .

72

STEPS ....
•conduct a hazard analysis and identify preventive measures for each step of the process;
•determine the critical control points;
•establish critical limits;
•establish a system to monitor the critical control points;
•establish the corrective action to be taken when monitoring indicates that the critical control points are not
in a state of control;
•establish system to verify that the HACCP system is working effectively;

•establish a record-keeping system.

Hazard

Tablet
Breakage

Critical Variable Target Acceptable Comments
Control to Control Value
Limits
Point
Tablet CompresForm
sion
Force

15kN

13 – 18kN

Thickness
and harness
of tablet

Monitoring Corrective Record
and Control
Action
Method
Automatic
Density
Measure

Eject
Tablet

On Line
Batch
Record
73

Hazard Operability Analysis (HAZOP)
•A theory that assumes that risk events are caused by deviations from the design or operating intentions.
•Identify potential deviations from normal use .

How to perform?
A systematic brainstorming technique for identifying hazards using so-called “guide-words” applied to relevant
parameters: No, More, Other Than, None.

Concept
•Focus team discussions by applying “deviations” to specific nodes .
•Deviations are generated by applying Guidewords to process parameters .
•Examine the process by discussing causes of each deviation
•Identify consequences
•Evaluate risk and safeguards
•Make recommendations, if necessary
•Include all parts of the process.

Potential Areas of Use(s)
1.

Manufacturing processes

2.

Equipment and facilities

3.

Evaluating process safety hazards

4.

Primarily as starter of a HACCP

5.

Operator error (“use error”)

74

other methodes Improve & Analysis….


Fault Tree Analysis (FTA)


75

Process Mapping: Process mapping is a workflow diagram to bring a clearer understanding
of a process or series of parallel processes.
MethodFlowchart- A flowchart is a picture of the separate steps of a process in sequential order.
When?
• To document a process .
• When planning a risk .
• To communicate to others how a process is done.
• To develop understanding of how a process is done.

76

Basic management facilitation method…
Written Procedures: A written procedure is a step-by-step guide to direct the reader through a task .
When?
• process is lengthy and complex
• process is routine, but it's essential that everyone strictly follows rules.
• person wants to know what is going on when a product is being developed.
Benefits:
• Having written procedures prevent mistakes .
• Frees your creativity .

• Procedures saves time .
• Ensures consistency and improves quality .
Work Instruction: Work instructions defines how one or more activities in a procedure should be written in
detail, using technology or other resources .The purpose of a Work Instruction is to organize steps in a logical

format so that an employee can easily follow it independently .

77

What ?

 When ?


research etc...
78

What ?

 When ?


research etc...
79

•HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and safety & method of
identifying and controlling sources of variation at critical process steps that could lead to a hazardous condition.
•Similar to a control plan .

•Cannot be used effectively without manual or automated process control methods, including statistical process
control
Uses
•New manufacturing process or equipment .
•To identify and manage risks associated with physical, chemical and biological hazards (including microbiological
contamination).
Limitations
•Requires excellent process knowledge .
•FMEA should precede HAACP to identify critical hazards/failure modes (A HAACP could be an action to reduce risk in
a FMEA) .

•Requires use of more complex statistical tools to be effective (Characterization DOEs, SPC, Capability Matrices) .

85

STEPS ....
•conduct a hazard analysis and identify preventive measures for each step of the process;
•determine the critical control points;
•establish critical limits;
•establish a system to monitor the critical control points;
•establish the corrective action to be taken when monitoring indicates that the critical control points are not
in a state of control;
•establish system to verify that the HACCP system is working effectively;

•establish a record-keeping system.

Hazard

Tablet
Breakage

Critical Variable Target Acceptable Comments
Control to Control Value
Limits
Point
Tablet CompresForm
sion
Force

15kN

13 – 18kN

Thickness
and harness
of tablet

Monitoring Corrective Record
and Control
Action
Method
Automatic
Density
Measure

Eject
Tablet

On Line
Batch
Record
86

•A theory that assumes that risk events are caused by deviations from the design or operating intentions.
•Identify potential deviations from normal use .

How to perform?
A systematic brainstorming technique for identifying hazards using so-called “guide-words” applied to relevant
parameters: No, More, Other Than, None.

Concept
•Focus team discussions by applying “deviations” to specific nodes .
•Deviations are generated by applying Guidewords to process parameters .
•Examine the process by discussing causes of each deviation
•Identify consequences
•Evaluate risk and safeguards
•Make recommendations, if necessary
•Include all parts of the process.

Potential Areas of Use(s)
1.

Manufacturing processes

2.

Equipment and facilities

3.

Evaluating process safety hazards

4.

Primarily as starter of a HACCP

5.

Operator error (“use error”)

87

Deviation
High
temperature in
blender

Causes
Steam heating
control
malfunction

Consequences
 Feed material #1
reaches
decomposition
temperature
 Violent reaction with
toxic gas generation

Safeguards
 Diverse high temp.
interlock on blender
 Blender vented

Recommend
 Test interlock
on quarterly
basis
 Add steam
heating control
to monthly PM

 Personnel exposure/
injury
 Equipment damage

Limitations of the model
•Applies to specific situations only .

•May need to use other models for quantifying risk .
•Not a structured approach .
•Not designed for quantifiable risk assessment .
•Complex output.

88

Preliminary Hazard Analysis (PHA)
Preliminary hazard analysis (PHA) is a semi-quantitative analysis that is performed to:
1. Identify all potential hazards and accidental events that may lead to an accident .
2. Rank the identiﬁed accidental events according to their severity .
3. Identify required hazard controls and follow-up actions .

The PHA shall consider:
1) The identification of the possibilities that the risk event happens.
2) The qualitative evaluation of the extent of possible injury or damage to health that could
result and
3) A relative ranking of the hazard using a combination of severity and likelihood of occurrence,
and
4) The identification of possible remedial measures.
89

Hazard

Investigation/
Controls

Sev

Freq

Imp
(SxF)

Potential Areas
• PHA might be useful when analyzing existing systems or prioritizing hazards
where circumstances prevent a more extensive technique from being used.
• It can be used for product, process and facility design as well as to evaluate the
types of hazards for the general product type, then the product class, and finally the
specific product.
90

Risk Ranking and Filtering
•Risk ranking and filtering is a tool for comparing and ranking risks.
•Risk ranking of complex systems typically requires evaluation of multiple diverse quantitative
and qualitative factors for each risk .
•The tool involves breaking down a basic risk question into as many components as needed to
capture factors involved in the risk.
•These factors are combined into a single relative risk score that can then be used for ranking
risks.
Usage : Risk Ranking and Filtering
• Is most suited to compare and manage a “portfolio” of complex risks .
•Is facilitated through careful breakdown of a risk into constituent risk scenarios.

91

Risk ranking and filtering
Risk Matrix (1)
Risk
Ranking

Probability

High

Medium

Low

Severity
Risk Class ONE

High

Risk Class TWO

Medium

Risk Class THREE

Low

Risk ranking and filtering
Detection

Risk Classification

High

Medium

Risk
Filtering

Low

Risk Matrix (2)
HIGH priority

MEDIUM priority
ONE

LOW priority
TWO

THREE

Supporting Statistical Tools
•Control Charts, for example:
a.

Acceptance Control Charts

b.

Control Charts with Arithmetic Average and Warning Limits

c.

Cumulative Sum Charts

d.

Weighted Moving Average.

•

Design of Experiments (DOE);

•

Histograms;

•

Pareto Charts;

•

Process Capability Analysis.

94

Control…….
Risk control
•The purpose of risk control is to reduce the risk to an acceptable level .
• Decision makers might use different processes, including benefit-cost analysis, for understanding the optimal
level of risk control.
•Risk control might focus on the following questions:
•Is the risk above an acceptable level?
•What can be done to reduce or eliminate risks?
•What is the appropriate balance among benefits, risks and resources?

•Are new risks introduced as a result of the identified risks being controlled?

Risk reduction
• Focuses on processes for mitigation or avoidance of quality risk when it exceeds a specified (acceptable) level .
• Risk reduction might include actions taken to mitigate the severity and probability of harm.
Objectives
•Reduce, control or eliminate the risk.
• Design away the risk
•Take action to reduce severity & probability, or improve detectability of hazard.

95

Control…….
Risk acceptance
• Decision to accept risk.
•Risk acceptance can be a formal decision to accept the residual risk or it can be a passive decision in
which residual risks are not specified.
•Risk communication
•sharing information regarding information of risk between decision maker and others.
•Risk Review

•A mechanism to review or monitor events should be implemented.
•After risk control in place, carry out new risk assessment to establish potential failures .
•Determine whether any new hazards may have been created. hazards may have been created.
•Review events that may impact the original decision .

96

Control…….
Root Cause Analysis (RCA )
OBJECIVE ..
•A structured investigation that aims to identify the true cause of a problem, and the actions necessary to eliminate it.
• structured process that uncovers the physical, human, and latent causes of any undesirable event in the workplace.
•Process to Discover

•what happened
• WHY IT HAPPENED
• How it can be prevented focus is on understanding , not blaming
•Analyses CAUSE & EFFECT Relationships
• Emphasis is on SOLUTIONS and System IMPROVEMENT
Types of cause
•Direct Cause: The cause that directly resulted in the event. (The first cause in the chain.)
• Contributing Cause: The cause(s) that contributed to an event but, by itself, would not have caused the event (The cause
after the direct cause.)
• Root Cause: The fundamental reason for an event, which if corrected, would prevent recurrence. (Last cause in the
chain.)

97

Control…….
Root Cause Analysis (RCA )
Methods
1. Cause Effect Diagram (fish bone)

2. Why Why Analysis

98

Opportunity for the Industry & Regulators
 Using the same guideline apply QRM to
 Industry (development, manufacture and distribution)
 Competent authorities (reviewer and inspectorate)

 Facilitates common approaches to quality risk management in our

every day jobs
 Supports science-based decision making

 Focus resources based on risks to patients
 Avoids restrictive and unnecessary requirements
 Facilitates communication and transparency

Opportunities & Benefits
 Encourages transparency
 Create baseline for more science-based decisions
 Facilitates communication
 Matrix team approach
 An aid to convince the stakeholders with trust
 Encourages a preventive approach
 Proactive control of risks and uncertainty
 Benefit of knowledge transfer by team approach
 Changes behavior
 Better understanding of risk-based decisions
 Acceptance of residual risks

Potential Applications
•Development;
•Facility, equipment and utilities;
•Materials management;
•Production;

•Laboratory control and stability testing;
•Packaging and labeling.
•Inspection and assessment activities.
•Regulatory Operations

•Etc.....

101

Next Steps?

 From great ideas to practice—how?
 Both industry and regulators want to know
 Which risks firsts?
 Which tools are best?
 How will I know “good” from “bad” risk management?
 Do we need dept./divisions of risk managers?

102

Concept to risk management ( In context to Q9)

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