Presentation on Failure Modes and Effects Analysis, in the pharmaceutical context. Covering: Introduction to risk assessment What are risks? Advantages and disadvantages of FMEA Applying FMEA to review a sterility testing isolator – case study

1. Application of FMEA to a Sterility
Testing Isolator: A Case Study
Dr. Tim Sandle
www.pharmamicreouresources.com

2. Introduction
 Introduction to risk assessment
 What are risks?
 Advantages and disadvantages of
FMEA
 Applying FMEA to review a sterility
testing isolator – case study

3. Risk Assessment

4. Risk Assessment
 Increasingly used tool in the pharmaceutical
sector.
 An expectation of regulatory authorities.
 Important because:
– A proactive tool;
– A reactive tool;
– To explore weaknesses and seek improvements;
– To construct rationales;
– Part of the qualification and validation of
processes.

5. Risk is ever present
 THERE IS NO SUCH THING AS
“ZERO” RISK
 Need to understand, “quantify” and manage risks in
pharmaceuticals and healthcare.
 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)?
 Risks relate to a situation where a recognized hazard may
result in harm.

6. Risk Assessment
 Different approaches for risk assessment
including:
– HACCP (Hazard Analysis Critical Control Points),
which has its origins in the food industry;
– Fault Tree Analysis (FTA) ;
– Modelling software (such as the Monte Carol
model);
– FMEA (Failure Mode and Effects Analysis), which
originated in the engineering sector.
– Several described in ICH Q9 and EU GMP Annex
20.

7. Risk Assessment
 Important
steps:
– Define problem;
– Select tool;
– Hazard identification;
– Risk assessment;
– Risk control;
– Risk review;
– Risk communication.

8. ICH Q9

9. Risk Assessment
 A more detailed approach involves:
– Gathering data through an audit and analysis;
– Constructing diagrams of work flows;
– Pin-pointing areas of greatest risk;
– Examining potential sources of contamination;
– Deciding on the most appropriate sample methods;
– Helping to establish alert and action levels;
– Taking into account changes to the work process /
seasonal activities;
– Using some type of scoring system so that the risk can be
ranked and the level of risk determined.

10. FMEA
What is it?

11. FMEA
 FMEA is “Failure mode and effects analysis”
 It is an analytical tool which was originated by the
US military and is widely used in the engineering
industry
 Very structured approach (ISO/TS 16949)
 FMEA is applied to many areas as a problem solving
tool
 This talk adopts one possible approach based on
the approach of the non-commercial FMEA
Information Centre:
http://www.fmeainfocentre.com/introductions.htm

12. FMEA
 FMEA looks for failure modes.
 A failure mode is a characterization of
the way a product or process fails.
 The term may be applied to
mechanical failure, structural failure,
electrical failure, biological risks and
systems failure.

13. FMEA
 Advantages:
– Improve product/process reliability and quality
– Increase customer satisfaction
– Early identification and elimination of potential
product/process failure modes
– Prioritize product/process deficiencies
– Capture engineering/organization knowledge
– Emphasizes problem prevention
– Documents risk and actions taken to reduce risk
– Provide focus for improved testing and development
– Minimizes late changes and associated cost
– Catalyst for teamwork and idea exchange between
functions

14. FMEA
 Disadvantages:
– It is subjective;
– It has a long-drawn-out approach;
– The focus is on failure / non-conformance
types and not on the chain of events
(cause / effect);
– It tends only to focus on major issues;
– Not ideal for environmental monitoring –
HACCP is better.

15. FMEA
 FMEA
 Dangers:
– Looks at ‘detection’ as a risk mitigation,
which influences the determined score
 Need to be careful with microbiological data
since our methods have poor detectability
 With microbiological risks, focus on severity
and likelihood
– Application of a ‘score’ is subjective.

16. FMEA
Determining
failure mode
Assessing
severity
Assigning
probability
number
Assigning
detection
number
Calculating risk
priority
number

17. FMEA
 FMEA steps:
– Setting the scope;
– Defining the problem;
– Setting scales for factors of severity,
occurrence and detection (see later);
– Process mapping;
– Defining failure modes;
– Listing the potential effects of each failure
mode;
– Assigning severity ratings to each process
step;

18. FMEA
 Steps continued:
– Listing potential causes of each failure mode;
– Assigning and occurrence rating for each
failure mode;
– Examining current controls;
– Examining mechanisms for detection;
– Calculating the risk;
– Examining outcomes and proposing actions to
minimise risks.
 Ideally it should be team based.

19. FMEA case study
Sterility Testing Isolator

20. Isolator Study
 Despite a superiority to cleanrooms, all Isolators
are at risk from contamination
 The approach of regulators, such as the FDA, is:
 “Barrier Isolators cannot prevent contamination
caused by GMP deficiencies such as poor aseptic
procedures and inadequate training of…operators”
(The Gold Sheet, Vol. 32, No.10)

21. Isolator Study
 Description:
– From a pharmaceutical manufacturer based in the
south-east of England.
– The Isolator was one half-suit Isolator, two
transfer Isolators and a steriliser unit.
– Positive pressure, flexible film Isolators with
stainless steel frames and wood bases designed
for aseptic processes (in this case: sterility testing
to Ph. Eur. 2.6.1).
– Air is using HEPA filters and material is transferred
into and out of the main Isolator using transfer
Isolators connected using Rapid Transfer Ports
(RPT).
– Sanitised by hydrogen peroxide vapour.
– The internal environment is classed as Grade A /
ISO 5

22. Isolator Study
 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.

23. Isolator Study
 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

24. Isolator Study
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.
A good detection system is one that can
detect a failure before it occurs.

25. Isolator Study
 A scale from 1 to 5. It followed that
the likelihood of high severity would
be rated 5; high occurrence rated 5;
but a good detection system would be
rated 1.
 See over….

26. Isolator Study
Severity 5 Specification limits exceeded. Probable rejection of
test or shutdown of system.
3 Observed trend takes place, but no critical
excursions. Requires investigation.
1 No excursion has taken place. No upward trends
and no investigation is required.
Occurrence 5 Expected to occur 50% time.
3 Expected to occur ≥10 - ≤50% time.
1 Expected to occur ≤10%.
Detection 5 No way to detect the failure mode.
3 Can be partially detected but detection could be
improved.
1 Good detection systems in place.

27. Isolator Study
 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

28. Isolator Study
 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
The numerical value '3' from:
Severity (3) x Occurrence (3) x Detection (3)
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.

29. Application of FMEA
Some examples

30. Examples
 3 examples
– Potential for sanitisation cycle failure
– Pressure leaks to gloves
– Connection of transfer Isolator to main Isolator and
transfer-in / out of material

31. Isolator Example 1
Potential for
sanitisation
cycle failure
#1
Process step Failure
Mode
Significance
of failure
Severity
of
conseque
nce
(score)
Performing
sanitisation
cycles on
transfer or main
Isolator
An
Isolator is
not
correctly
sanitised
Contaminated
items enter
main Isolator
or main
Isolator itself is
contaminated
4

32. Isolator Example 1
Potential for
sanitisation
cycle failure
#2
Measures to
detect failure
Occurrenc
e
(score)
Detection
systems
Detection
(score)
Evaporation rate
/ pre- and post-
lot testing of
acid /
sanitisation
cycles developed
using BIs
1 Steriliser
parameters
checked after
sanitisation
and before
use / acid
potency
checked for
each lot /
post-
sanitisation
environmental
monitoring
performed for
main Isolator
1

33. Isolator Example 1
Potential for
sanitisation
cycle failure
#3
FMEA score:
4 x 1 x 1 = 4

34. Isolator Example 2
Pressure
leaks to
gloves
#1
Process step Failure
Mode
Significance
of failure
Severity
of
consequ
ence
(score)
Use of gloves
to transfer
material or to
perform sterility
test (sterile
gloves may be
worn
underneath
Isolator gloves)
Contaminati
on from
technician
into Isolator
or weak
area of
positive
pressure to
allow
contaminati
on in
Contaminati
on present
in Isolator /
compromise
of aseptic
technique
4

35. Isolator Example 2
Pressure
leaks to
gloves
#2
Measures to
detect failure
Occurre
nce
(score
)
Detection
systems
Detection
(score)
Environment
al monitoring
(post-use
finger
plates) /
pressure
charts
2 Environme
ntal
monitoring
is
performed
post-test
on gloves /
gloves are
wiped with
disinfectan
t / gloves
are visually
examined
weekly and
changed as
appropriat
e
3

36. Isolator Example 2
Pressure
leaks to
gloves
#3
FMEA score:
4 x 2 x 3 = 24

37. Isolator Example 2
 However, on
review….
FMEA score:
4 x 2 x 1 = 8

38. Isolator Example 3
The transfer of material in and out of the Isolator is, arguably, the biggest risk:
Non-sterile area between doors
*
*Area of biggest risk

39. Transfer isolator

40. Isolator Example 3
Connection of
transfer Isolator
to main Isolator
and transfer-in
/ out of
material #1
Process step Failure Mode Significance
of failure
Severity
of
conseque
nce
(score)
Connection of
transfer
Isolator to
main Isolator
and moving
material in and
out
Contaminat
ion on
outside of
both
Isolators
may enter
the main
Isolator /
failure to
maintain
positive
pressure
Contamina
tion enters
the
Isolator or
positive
pressure is
not
maintained
4

41. Isolator Example 3
Connection of
transfer Isolator
to main Isolator
and transfer-in
/ out of
material #2
Measures to
detect failure
Occurrence
(score)
Detection
systems
Detection
(score)
Environmenta
l monitoring /
pressure
monitoring
1 DPTE seal
system / use
of
disinfectant
for
connection
1

42. Isolator Example 3
Connection of
transfer Isolator
to main Isolator
and transfer-in
/ out of
material #3
FMEA score:
4 x 1 x 1 = 4

43. Isolator study
 Revisit the ranking
 Define residual risk
 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 < 27)
– Recommended actions, responsibilities and due dates
(including approval, if appropriate)
– Person in charge for follow-up of FMEA

44. Isolator Study
 Summary of the entire study:
Isolator FMEA risk assessment
0
5
10
15
20
25
30
R
oom
C
ycle
Frequency
IntegrotyC
onnectionS
anitisation
P
hysical
G
loves
Category
FMEAscore
Cut off score

45. Further examples
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, 8(2): 43-49

46. FMEA
 A risk assessment technique – FMEA
can be readily applied to a key
operation
 This technique did not originate in the
pharmaceutical industry.
 This indicates how the synergy of
different approaches can be achieved.

47. FMEA
 Regular reviews must take place;
 FMEA is not suitable for everything e.g.
HACCP may be more suitable for suitable for
aseptic filling.
 It is not able to discover complex failure
modes involving multiple failures or
subsystems, or to discover expected failure
intervals of particular failure modes.

48. Thank you
Dr. Tim Sandle
www.pharmamicroresources.com
Any questions?