Risk Management

❶ Introduction

Risk of burn

Fire Burn

Risk analysis: The estimation of the risk

associated with the identified hazards.

Hazard: Harm:
Risk: The combination of the
The potential probability of occurrence of harm Damage to health, including the
source of harm and the severity of that harm damage that can occur from loss
of product quality or availability.

Risk reduction: Actions taken to lessen the

probability of occurrence of harm and the
severity of that harm
 FDA (USA): GMP
of the 21st century

Q9

Annex 20
to GMP
Concept of sterility: Practical application of
Absolute value! sterility: Probability of
No viable viable microorganisms
microorganisms! lower than 10-6.

Concept of quality: Practical application of

Absolute value! quality:
Pharmaceutical
according to Risk evaluation.
authorization. Acceptable risk level.
Patient protection Risk communication.
 - Knowledge of the subject.
- Hazard identification.
- Risk evaluation.
- Continual improvement.
- Provide confidence in our work.

Pharmaceutical
Quality
System
(PQS)

- Make decisions based on facts.

- Evaluation of real risk,
- Control (“management”) of risk.
 ...
...
Approach
Approach
based
basedon
on
risk
risk
analysis…
analysis…

- Analyze the situation in depth to see if there are

“weak points”.
- Act accordingly (show control of them)
=> “reassure” inspectors / auditors.
It is supposed, “just in case” (e.g., while validating)
that it is better to increase the amount of essays,
as this is a way to diminish the risk.

But this is only true

If there is a relation
Essays
between essays and risk!

Risk
 The“hazards”
The “hazards”of
of holidays
holidays

Practical
Practical
example
example Price Hotel

Holidays

Place Travel
 The“hazards”
The “hazards”of
of holidays
holidays

Factors producing the effect Factor 1 Factor 2

Causes and sub causes

Effect
Causes and sub causes

Factors producing the effect Factor 3 Factor 4

Price Place
Ishikawa Amount Aesthetics
Security
(fishbone) Inclusions Interest
diagram Amusement
Quality of the
Selection process
holidays
Duration Service
Comfort
Comfort
Interest

Travel Hotel
 The“hazards”
The “hazards”of
of holidays
holidays

Improvement

Level
Component Subcomponent Result
1 (low) 2 (medium) 3 (high)
Price Amount 20-40 $ 41-60 $ > 60 $
Inclusions breakfast B + lunch All meals
Place Aesthetics poor good Excellent
Security bad acceptable Good
Interest Low medium High
Amusement Boring normal Much fun
Travel Length Very long medium Short
Comfort bad acceptable Good
Interest Very limited medium Very high
Hotel Service bad acceptable Good
Cleanliness dirty clean Very clean
Comfort bad acceptable Good
 The“hazards”
The “hazards”of
of holidays
holidays

Determination of risk:
1st Evaluation
Probability x Severity

SEVERITY
Evaluation < 40 € 40 – 80 € > 80 €
Low Medium Hgh

Luxury High Class 1 risk

PROBABILITY

Medium Medium Class 2 risk

Budget Low Class 3 risk

 The“hazards”
The “hazards”of
of holidays
holidays

Determination of risk:
2nd Filtration
Capacity of detection

CAPCITY OF DECTECION
One is conscious of the One might not be One is not conscious of
Filtration of risk hazard conscious of the hazard the hazard
High Medium Low

Class 1 High priority

RISK CLASS

Class 2 Intermediate priority

Class 3 Low priority

 The“hazards”
The “hazards”of
of holidays
holidays

Resultado

Cuantía

Precio

Inclusiones

Estética

Tranquilidad

Lugar

A
Interés

Diversión

Duración

Viaje
Comodidad

Resultado

Duración

C
Cuantía

Servicio
Precio

Alojamiento
Inclusiones

Confort

Estética

Tranquilidad

Lugar

B A
Interés

Diversión

Duración
Filtering
Viaje
Comodidad

Resultado

Duración

E
Cuantía

Servicio
Precio

Alojamiento

Inclusiones

Confort

Estética

Tranquilidad

Lugar

C B
Interés

Diversión

Duración

Viaje
Comodidad

D
Resultado
Duración

Cuantía
Servicio

Precio
Alojamiento

Inclusiones
Confort

Estética

Tranquilidad

Lugar

D
Interés

Diversión

Duración

Viaje
Comodidad

Level Ranking
Resultado
Duración

Cuantía
Servicio

Precio
Alojamiento

Inclusiones
Confort

Estética

Tranquilidad

Lugar

E
Interés

Diversión

Duración

Viaje
Comodidad

Duración

Servicio

Alojamiento

Confort
 ❷ How to perform risk analysis

1º Appoint a task force

2º Define the objectives

Stages of risk
3º Gather information analysis
4º Prepare a flow diagram

5º Determine the procedure

6e Perform the analysis

7º Check the analysis

8º Draw conclusions

9º Write the report

10º Follow up

14
 ❷ How to perform risk analysis
Tools[ICH
Tools [ICH Q9: 5]
Q9: 5]

Amount of information / Level of formality

(+) (-)
Specific (formal) tools Basic (informal) tools

• Diagrams (flow, • Check lists

dispersion, Pareto, • Complaints
Ishikawa) • Reports
• Histograms • Graphs
• etc. • etc.

PHA/PRA FMEA/FMECA HACCP HAZOP ETA RRF

(Preliminary Hazard (Failure Mode & Effects (Hazard FTA (Hazard and (Event (Risk
Analysis / Failure Mode, Analysis and (Fault Tree Tree
Analysis / Preliminary Operability ranking and
Risk Analysis)
Effects & Criticality Critical Control Analysis) Analysis) filtering)
studies)
Analysis) Points)

Elementary general General method Design of Control of Comparison of

method « passe par tout » Process Investigation of
facilities accidents different
(joker) control deviations hazards
 ❷ How to perform risk analysis

“Check lists”

Diagram of Pareto
Complaints

Basic / informal tools Control charts

Provide useful information
for the risk management
Diagram of dispersion

Histogram
Reports
Diagram of causes and effects
(Diagram of Ishikawa)

16
 ❷ How to perform risk analysis

Severity x Probability

Hazard Risk Harm

The combination of the probability of

occurrence of harm and the severity of that harm

+
Probability
isk
R
-

Severity
 ❷ How to perform risk analysis

Facility of detection

When there is an effective system of

!control on the process risk diminishes Deviation will be detected:
If process fails we will
be aware of it

Deviation might be detected:

If process fails we might
detect it

(+ )
Deviation almost impossible
to detect: If process fails
Risk
we will not be aware of it (-)
 ❷ How to perform risk analysis

PHA (Preliminary Hazard Analysis) –

In development
PRA (Preliminary Risk Analysis)

FMEA (Failure
mode effects analysis) –
Personnel
FMECA (Failures mode, effects
Process and criticality analysis)
Well
situation established

HACCP (Hazard Analysis and

Operations
Critical Control Points)

Comparison of different situations RRF (Risk ranking and filtering)

 ❸ PHA / PRA

PHA (Preliminary hazard analysis) -

PRA (Preliminary risk analysis)

Characteristics
Taking into account the
existing knowledge or
experience future
problems (and their
probability) can be
identified.
Utilisation
For equipment, systems and
processes. It analyses existing
systems or the firsts steps of a
new project. It is often the
used for the first studies,
before going to other
methods.
 ❸ PHA / PRA

Determined by brainstorming

Preliminary Hazard Analysis (PHA)

Are corrective measures Corrective actions
HAZARD CAUSE EFFECT
necessary? implemented
 Yes
 No
 No
 Yes

Preliminary Risk Analysis (PRA)

Risk evaluation
Hazard Prevention measures Probability Severity Risk
(P) (S) (P x S)

21
 ❸ PHA / PRA

Projectof
Project ofnew
newinstallation
installation
PHAby
PHA bybrainstorming
brainstorming

Practical
Practical
example
example

• Containers
• HVAC
outer
• Compressed air
Contamination • Personnel
Inner (cross) • Equipment
• Materials
 ❸ PHA / PRA

Practical
Practicalexample:
example:Contamination
Contamination hazard
hazardininaanew
newinstallation
installation––part
partI I

Necessary
Hazard Cause Effect Comments / Actions implemented
actions?
Contamination Entry of dirty Diffusion of  Yes/  No Any container is cleaned
( outer) containers contamination
Inappropriate Entry of  Yes/  No Air filtered through HEPA filters
filtration contamination
Penetration of Entry of  Yes/  No Isolation of production areas
outside air contamination
 Yes/  No Positive pressure in the clean rooms
Compressed air Entry of  Yes/  No Oil-free compressor
contamination  Yes/  No
Air filtration
Personnel Entry of  Yes/  No Change of clothing
contamination
Changing rooms adequately designed
Training
Equipment Entry of  Yes/  No Area-dedicated (used exclusively in a
contamination definite area)
Materials Entry of  Yes/  No Any material is controlled and when
contamination necessary cleaned/purified/sterilized

23
 ❸ PHA / PRA

Practical
Practicalexample:
example:Contamination
Contamination hazard
hazardininaanew
newinstallation
installation––part
partIIII

Necessary
Hazard Cause Effect Comments / Actions implemented
actions?
Cross- Inadequate air- Particle  Yes /  No Clean room classification according to
contamination filtration diffusion GMP
In critical cases air is not recycled
Flow of air from Particle  Yes /  No Establishment of pressure gradients
one room to diffusion
Construction of intermediate air-locks
another
Use of closed systems
Equipment Mixture of  Yes /  No Dedicated equipment and objects
products
Cleaning areas well designed
Training
Adequate SOPs
Personnel Particle  Yes /  No Separation of areas
diffusion
Adequate flows
Training

24