The document discusses risk management tools and techniques for environmental monitoring in pharmaceutical manufacturing. It introduces quality risk management and defines risk. It then discusses three case studies: 1) Using Hazard Analysis and Critical Control Points (HACCP) to select environmental monitoring locations by identifying hazards and critical control points. 2) Applying risk filtering to determine monitoring frequencies by evaluating risk factors and their severity and probability. 3) Using Failure Modes and Effects Analysis (FMEA) to assess risks from a sterility testing isolator by identifying potential failure modes and their effects.

1. Dr. Tim Sandle
Pharmaceutical Microbiology Resources:
www.pharmamicroresources.com

2. Introduction
 Introduction to quality risk management
 Definitions of risk
 What is the aim of environmental monitoring?
 Risk management tools and techniques for
environmental monitoring
 Application of HACCP for selecting environmental
monitoring locations
 Use of risk filtering to determine frequencies of
monitoring
 Applying FMEA to assess risks from process equipment
– a sterility testing isolator.

3. Risk
 In general, risks describe any potential dangers.
 We are confronted with risks in our day to day life.
 Risks cannot be avoided.
 There is no such thing as 'zero risk.’
 Risk assessment is not an exact science.
 Risks relate to a situation, event or scenario in which a
recognised hazard may result in harm.

4. How to define risk?
 Risk is defined as the combination of the probability of
occurrence of harm and the severity of that harm i.e.
 What might go wrong?
 What is the likelihood (probability) it will go wrong?
 What are the consequences (severity)?

5. What is risk assessment about?
 Is the risk acceptable and what controls are available to
mitigate the risk?
 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?

6. Risk assessment
 Risk assessment involves identifying risk scenarios
either prospectively or retrospectively.
 Prospective = determining what can go wrong in the
system and all the associated consequences and
likelihoods. Can also be used for process improvements.
 Retrospective = what has gone wrong .
 Risk assessment can be used to assess the process,
product or environmental risk and to aid in
formulating the appropriate actions to prevent the
incident from re-occurring.
 This requires risk analysis.

7. Basics of risk assessment
 Risks relate to a situation where a recognized hazard
may result in harm.
 A hazard is any circumstance in the production, control
and distribution of a pharmaceutical product, which can
cause an adverse health effect.
 Formal risk approaches normally share four basic
concepts:
 Risk assessment,
 Risk control,
 Risk review,
 Risk communication.

9. Microbiological risks
 Microbiological contamination in the product, which
might cause patient harm.
 From:
 Equipment
 Air e.g. Cleanrooms:
 Air filtration
 Air direction
 Air movement (pressures)
 People
 Water
 Central issue is contamination transfer.

10. Relationship of risk
Level of bioburden
Opportunity for
bioburden transfer:
Airborne
Direct transfer
Likelihood of
transfer

11. EM: risk assessment and root
causes
 The process involves:
 Risk assessment
 Identification of hazards
 Severity, probability and
detection
 To stop things from going
wrong
 To investigate when things
have gone wrong
 To find ‘root causes’
 To propose CAPA

12. Biocontamination control
 Understanding risk and environmental control leads
to a biocontamination control strategy:
 Developing plans to minimize microbial contamination
for pharmaceutical operations
 Understanding manufacturing, quality and
contamination control are interconnected
 This stratgey is all about risk identification and risk
minimisation
 Then risk mitigation
 Then targeted environmental monitoring

14. Three case studies
 Application of HACCP for selecting environmental
monitoring locations
 Use of risk filtering to determine frequencies of
monitoring
 Applying FMEA to assess risks from process
equipment – a sterility testing isolator.

15. Hazard Analysis
and Critical Control Points

16. HACCP
 “A systematic, proactive, and preventive method for assuring
product quality, reliability, and safety.”
Potential Areas of Use(s)
 To identify and manage risks associated with physical,
chemical and biological hazards (including
microbiological contamination)
 Useful when process understanding is sufficiently
comprehensive to support identification of critical control
points (critical parameters / variables)
 Facilitates monitoring of critical points in the
manufacturing process

17. HACCP
How to perform?
1. Conduct hazard analysis: identify preventive measures
for
each step of the process
2. Determine critical control points (CCP’s)
3. Establish target levels and critical limit(s)
4. Establish system to monitor the CCP’s
5. Establish corrective actions to be taken, if CCP is out of
control
6. Establish verification procedures, that HACCP works
effectively
7. Establish documentation of all procedures and keep
records

18. HACCP
Risk Review
Risk Assessment = H azard A nalysis
Target levels &
critical limit(s)
unacceptable
Risk Control: C ritical C ontrol P oints
Determine critical
control points (CCP’s)
System to monitor
the CCP’s
Identify
preventive measures
Verification that
process works effectively
Corrective actions,
if CCP is out of control
Initiate
HACCP
Output / Results:
process described by HACCP
R
i
s
k
M
a
n
a
g
e
m
e
n
t
t
o
o
l
:
H
A
C
C
P
R
i
s
k
C
o
m
m
u
n
i
c
a
t
i
o
n
T
e
a
m
f
o
c
u
s
e
d
I
n
t
e
r
n
a
l
c
o
n
s
u
l
t
a
t
i
o
n
S
t
a
k
e
h
o
l
d
e
r
i
n
v
o
l
v
e
m
e
n
t

19. HACCP
 Benefit
 Teamwork in cross functional groups
 Use very similar principles in Qualification & Validation
 Critical control points (CCPs) are similar to
critical process parameters
 Limitations of the model
 Has to be combined with another tool (e.g. FMEA, statistical
tools)
 Not good for complex processes
 Assumes you know the processes
 Most CCPs should be addressed for risk control activities
 May need to use other models for quantifying risk

20. HACCP uses
 A route map (where the facility is drawn and the route
indicated).
 Identification of hazards (which can be divided into
biological, physical, equipment, transport and
chemical). This will allow an assessment of existing
control measures.
 Process flow.
 Assessment of environmental monitoring. This will
determine if the activity is safe to proceed.

21. Approaching HACCP
 Prior to performing the individual risk assessments,
the scope and the process should be evaluated.
 Obtain a process flow diagram / area map. Where
required the process steps can be broken down into
process steps or sub steps to help focus the effort.
 Walkthrough the area, detailing the process steps /
activities based on personnel flow, material flow,
storage, waste disposal and product transfer.
 A Historical Review of data (12 months) or previous
risk assessments, which should be considered.

22. Approaching HACCP
 Define every available contamination hazard from
each process step / activity.
 The hazard can be assessed and rated based on the
likelihood of occurrence and severity.
 To determine if the hazard is high medium or low.
 The risk rating will determine if a critical control point
is required and the level of monitoring which is
required.

23. Approaching HACCP – CCP’s

24. Approaching HACCP
 For each critical control point:
 Define what level of risk warrants monitoring i.e. if only
high and medium risks require monitoring.
 Where monitoring is required based on the risk rating,
 The monitoring type should be selected e.g. Settle plate,
contact plate etc.
 The monitoring type will depend on the hazard.
 All critical control points will require critical limits
assigned to them.
 Define monitoring frequencies.

25. HACCP example: sampling
locations
 ISO 14644 grid approach for particles should not be
followed
 Microbiological sampling sites are best selected with
consideration of human activity during manufacturing
operations.
 From careful observation and mapping of the clean room
 The most likely route of contamination (ingress into
product):
 Airborne
 Operators – direct transfer
 Materials – direct transfer

27. Problem statement
 Issue :
 How to set the frequencies for viable monitoring for a
non-sterile manufacturing area?

28. A risk based method
 Using risk ranking and risk filtering
 Consideration of 10 risk factors
 Assessing the level of risk for each risk factor for:
 Severity and Probability
 Considering methods of:
 Detection

29. Risk process
 The risk assessment process involves:
 What are risk factors for microbiological contamination
in cleanrooms (risk identification)?
 What is the likelihood (probability) that contamination
will occur?
 What are the consequences (severity) for the product
should contamination occur?

30. Risk process
 The process allowed:
 An evaluation of multiple factors for each risk:
 Identifying factors (risk identification) relating to cleanroom
design and processing which could pose a microbiological risk to
the environment and to the product
 Breaking down a basic risk question into as many
components as needed to capture factors involved in the
risk.
 The factors were combined into a single relative risk
score. The score can be compared, prioritized and
ranked.

31. Risk process
 Risk factors were divided into two categories:
 Severity
 The impact upon the product or the environment
 Categories:
 LOW (unlikely to cause product contamination)
 MEDIUM (low possibility of product contamination)
 HIGH (high probability of product contamination)
 Probability
 The likelihood that an environment will have a high recovery of
microbial counts
 Categories:
 LOW (contamination events are rare)
 MEDIUM (contamination events are infrequent)
 HIGH (contamination events are frequent)

32. Step 1: Frequencies of monitoring
 Frequencies of monitoring:
 Review historical data:
 For trends
 Action level excursions
 Review resources
 Consideration of costs

33. Step 2: Assigning monitoring
frequencies
Criticality Viable
Factor
Frequency of
Monitoring
CV1 Weekly monitoring
CV2 Fortnightly monitoring
CV3 Monthly monitoring
CV4 Three-monthly
monitoring

34. Step 3: Scoring range for risk
factors
 Each factor was scored (0
to 4) for severity and / or
probability
 A score range was set up
for severity and probability
Probability
Low 0 - 5
Medium 6 - 11
High 12 - 16

35. Relationship between Severity
and Probability
Low
0-5
Medium
6-11
High
12-16
Severity
Probability
High
11-15
Low
0
-5
Medium
5-10
Risk Class ONE
Risk Class TWO
Risk Class THREE
Risk
Ranking
I
Risk Matrix (1)

36. Step 4: Identify risk factors
 The factors selected were considered carefully, using
professional judgement:
 What, in relation to room design and processing, poses a
microbiological risk to the environment and to the
product?

37. Risk factors
 A number of risk factors can be
selected
 Temperature
 Ambient
 Cold
 Warm
 Wet or dry areas
 Water sources or drains in room
 Open or closed processing
 Duration of activity
 Number of personnel present
 Cleaning frequencies
 Distance from final formulation
 Fixed or mobile equipment
 Environmental monitoring
history

38. Risk factors
 Risk Factor 1: Room
Temperature
Freezer 0
Cold (typically
2-8oC)
1
Ambient
(typically 18-
25oC)
4
Warm (typically
with periods of
30oC, e.g.
autoclave
preparation
area)
3

39. Risk factors
 Detection methods need
to be reviewed
Factor
Group
Sub-factors Description and reason Weighting /
score
DETECTION Room environmental
monitoring
Room environmental
monitoring, examined
over time for trends,.
Low detection
In-process sample test
and room environmental
monitoring
In-process samples,
provide a direct
assessment of the quality
of the material.
In addition, the room
environmental
monitoring as indicated
above.
Medium
detection
In-process sample test,
room environmental
monitoring and a
monitored water (WFI)
outlet
In addition to the room
environmental
monitoring and in-process
tests, the presence of a
Water-for-Injection (WFI)
outlet affords an
additional detection
method. WFI is assessed
as part of a fortnightly
rota.
High detection

40. Example 1
 Clean room: P100
 Grade D / ISO class 9
 A room used for
preparing equipment
prior to autoclaving
 The room is reviewed and scored
 It is at ambient (severity = 3)
 It is a dry area (probability = 1)
 It has no floor drain (probability = 0)
 It is not used directly for processing
(severity = 0)
 The room is used for long periods of
time (severity / probability = 3)
 It is cleaned at a lower frequency
(probability = 3)
 The room is more than three steps
removed from final formulation
(severity = 1)
 The room has a low occupancy
(probability = 1)
 The equipment is fixed (severity = 1)
 The environmental monitoring
history is good (probability = 1)

41. Example 2 – risk class
Low
0-5
Medium
6-11
High
12-16
Severity
Probability
High
10-14
Low
0
-4
Medium
5-9
Risk Class ONE
Risk Class TWO
Risk Class THREE
Risk
Ranking
I
Risk Matrix (1)
P100

42. Example 3 - detection
THREE
TWO
ONE
Detection
Risk
Classification
High
Low
Medium
HIGH priority
MEDIUM priority
LOW priority
Risk
Filtering
Risk Matrix (2)
EM EM
+IP
EM, IP +
water
P100

43. Example 4 - frequency
Risk
Filtering
Risk Matrix (3)
CV4
CV4
CV4
THREE
CV3
CV3
CV3
TWO
CV2
CV2
CV1
ONE
Detection
Risk
Classification
High
Low
Medium
Room P100

44. Outcomes
 Lowest frequency of monitoring:
 Freezers
 Store rooms
 Cold storage areas
 Offices
 Medium frequency of
monitoring:
 Wash-up areas
 Airlocks
 Changing rooms
 Areas one step removed from
final processing.
 Slightly higher frequency:
 Corridors
 Store rooms
 Autoclave rooms
 Cleaning areas
 Highest frequency of
monitoring:
 Ultra-filtration areas
 Final formulation of product
 Open processing areas
 Filtration rooms
 Poor environmental
monitoring history

45. Review
 Review annually
 Has the room use changed?
 Have the room parameters changed?
 Has the room been redesigned
 Has the environmental monitoring trend altered?

46. Failure Modes and Effects Analysis

47. FMEA
 Evaluation of potential failure modes for processes
 The likely effect on outcomes and/or product performance
 Once failure modes are established,
risk reduction can be used to
eliminate, reduce or control the potential failures
 FMEA relies on process understanding
 Summarize the important modes of failure, factors causing
these failures and the likely effects of these failures
How to perform?
Break down large complex processes into manageable steps

48. FMEA
Potential Areas of Use(s)
 Prioritize risks
 Monitor the effectiveness of risk control activities
 Equipment and facilities
 Analyze a manufacturing process
to identify high-risk steps or critical parameters

49. FMEA
How to perform?
1. Establish a team
2. Identify the known and potential failure modes:
Develop lists of known problems and brainstorm other
potentials…
e.g.
 Product not meeting specification
 Process not meeting yield requirements
 Malfunctioning equipment
 Software problems
Newly identified failure modes should be added at any
time

50. FMEA
How to perform?
3. Characterise the severity, probability and detectability
 An equal number of levels is sometimes helpful
 Some preference to 3, 4, 5, 6 or 10 levels
 But: an even number of levels avoids the mid point
 Use different scales
 Linear: 1, 2, 3, 4
 Exponential: 1, 2, 4, 8
 Logarithmic: 1, 10, 100, 1000
 Self made: 1, 3, 7, 10
Multiplying different scales will differentiate the outcome

51. FMEA
How to perform?
4. Define actions
5. Revisit the ranking
6. Define residual risk
7. Perform a short summary
 Scope
 Data from the assessment & control
(e.g. No. of identified failure modes)
 Level of accepted risk without actions i.e. residual risk
(e.g. Risk priority Number < 50)
 Recommended actions, responsibilities and due dates
(including approval, if appropriate)
 Person in charge for follow-up of FMEA

52. FMEA: severity
• 10 Extreme
• Predicted to cause severe impact to quality (Product out of
specifications, no Expert Statement possible)
• 7 High
• Predicted to cause significant impact on quality (Failure to meet
specifications, no Stability data, Expert Statement possible)
• 3 Moderate
• Predicted to cause minor impact on quality (Failure to meet
specifications, Stability data available)
• 1 Low
• Predicted to have no/minor impact on quality of the product
(Quality within specifications)

53. FMEA: probability
• 8 Regular failures
• Expected to happen regularly
• 4 Repeated failures
• Expected to happen in a low frequency
• 2 Occasional failures
• Expected to happen infrequently
• 1 Unlikely failures
• Unlikely to happen

54. FMEA: detection
• 4 Normally not detected
• Failure very likely to be overlooked, hence not detected
(no technical solution, no manual control)
• 3 Likely not detected
• Failure may be overseen
(manual control, spot checks)
• 2 Regularly detected
• Failure will normally be detected
(manual control, routine work with statistical control)
• 1 Always detected
• Failure can and will be detected in all cases
(monitoring, technical solution available)

55. FMEA: case study #1
 Sterility testing isolator
 Identifying the main risks:
 Leaks;
 Gloves / operator manipulations;
 Filters;
 Other airborne contamination;
 Transfer of material into and out of the Isolator;
 The Isolator room;
 Decontamination cycle;
 Cleaning / environmental monitoring issues.

56. FMEA: case study #2
 Designing the FMEA scheme
 FMEA schemes vary in their approach, scoring and
categorisation.
 All approaches share in common a numerical approach.
The approach adopted was to assign a score (from 1 to 5)
to each of the following categories:
i) Severity
ii) Occurrence (or probability)
iii) Detection

57. FMEA: case study #3
i) Severity is the consequence of a failure, should it occur;
ii) Occurrence is the likelihood of the failure happening
(based on past experience);
iii) Detection is based on the monitoring systems in place
and on how likely a failure can be detected. Sometimes, a
good detection system is described as one that can detect a
failure before it occurs.

58. FMEA: case study #4

59. FMEA: case study #5
 Using these criteria a final FMEA score is produced
(sometimes called a Risk Priority Number):
x
125
 The total of 125 is derived from: severity score x
occurrence score x detect score, or:
5 x 5 x 5 = 125

60. FMEA: case study #6
 A score of 27 was the cut-off value: where action was
required.
 Based on 27 being the score derived when the mid-score is
applied to all three categories (i.e. the numerical value '3'
from severity (3) x occurrence (3) x detect (3)) and the
supposition that if the mid-rating (or a higher number)
was scored for all three categories then as a minimum the
system should be examined in greater detail.

61. FMEA: case study #7
 An example:
 Connection of transfer
Isolator to main Isolator
and transfer-in / out of
material

62. FMEA: case study #8

63. FMEA: case study #9
Connection of transfer
Isolator to main
Isolator and transfer-
in / out of material

64. FMEA: case study #10
FMEA score:
4 x 1 x 1 = 4

65. Summary
 Risk assessment
 Risk management
 Importance of assessment
 What is the aim of
environmental monitoring?
 Types of risk assessment tools
and case studies:
 HACCP
 Risk ranking
 FMEA
 Thank you for your attention
 References:
 Sandle, T: ‘The use of a risk assessment
in the pharmaceutical industry – the
application of FMEA to a sterility testing
isolator: a case study’, European Journal
of Parenteral and Pharmaceutical
Sciences, 2003; 8(2): 43-49
 Sandle, T. Environmental Monitoring
Risk Assessment’, Journal of GXP
Compliance, Volume 10, Number 2, 2006,
pp54-73
 Sandle, T. (2012). Application of Quality
Risk Management To Set Viable
Environmental Monitoring Frequencies
in Biotechnology Processing and
Support Areas, PDA Journal of
Pharmaceutical Science and Technology,
Vol. 66, No. 6, November–December
2012: 560 - 579