Human Error, Root Cause Analysis and Conducting Objective and Effective Investigations

Human Error, Root Cause Analysis and
Conducting Objective and Effective

Investigations
Presented by: Karen GinsburyFor
IFF Denmark
November 2012
PCI Pharmaceutical Consulting Israel Ltd 1
Workshop Objective
• To understand why operators make

mistakes and how to identify the real
problem rather than “human error –
retrain” corrective actions

What is an investigation?
• You are not investigating if when

looking for EVIDENCE you start out
BELIEVING you know what
happened
• EVIDENCE provides proof
• Proof is convincing objective evidence that
compels the mind to accept a truth or fact
MHRA – April 2011 – March 2012
• 303 inspections: 26 criticals; 644 majors
• Top 10:
EU GMPs Part 1
Finished Product
Chapter 1 - PQS
• Under Quality Assurance:
8
US GMP Trends – Risk
Management
Suicide or Murder?
“I’ll never find the killer syndrome”

Sudoku – “it’s impossible”
How many of you completed the puzzle
How many of you have done a Sudoku in
the past?
Here is a fiendish puzzle
See if you can finish it by the end of the
day. You can ask anyone else or do it in a
group AFTER you have spent 30 minutes
trying to do it yourself (NOT during the
class – take it home if necessary)
The Orange Juice Problem
and Lateral Thinking
How can you move one glass only and have
alternating filled / empty glasses?

Impossible? You tell me.
Logical / Rationale Thinking
• There are three boxes, one contains only
apples, one contains only oranges, and one
contains both apples and oranges. The boxes
have been incorrectly labeled such that no
label identifies the actual contents of the box
it labels. Opening just one box, and without
looking in the box, you take out one piece of
fruit. By looking at the fruit, how can you
immediately label all of the boxes correctly?
Course Objective – Take Home
• Understand how to:
– Effectively and objectively investigate:
Deviations, Non-conformities, Unexpected, Unwanted,
Undesirable, OOS, Out of trend
– events and document the investigation
• Concisely
• precisely
Toolkit
‫‪Identify‬‬
‫‪Expand‬‬
‫‪Problem‬‬ ‫הרחבת החשיבה לזיהוי הבעיה‬
‫‪Problem‬‬
‫‪Focus‬‬ ‫‪well‬‬ ‫התכנסות להגדרת הבעיה ואפיונה‬
‫‪defined‬‬
‫‪Expand‬‬
‫איסוף נתונים מהאירוע וחשיבה רחבה של‪:‬‬
‫‪Analyze‬‬ ‫מה יכולים להיות הגורמים?‬
‫‪causes‬‬
‫התכנסות ע"י פסילת גורמים בהתאם לעובדות‬

‫‪Focus‬‬
‫‪Root‬‬ ‫הגעה לבעיות השורש ובעיות תורמות‬
‫‪cause‬‬
‫‪identified‬‬ ‫חקירת בעייות השורש ו‪...‬‬
‫‪Expand‬‬
‫‪Generate‬‬
‫‪solutions‬‬ ‫מציאת פתרונות אפשריים‬
‫‪Solution‬‬
‫‪Focus‬‬
‫‪chosen‬‬ ‫בחירת הפיתרון המתאים ביותר‬
Cool; Neutral,
Information needed;
Looking for facts
Emotive; Gut
feelings; Intuition;
Hunches
Critic; Analyst;
Logical;
Negative
Objectivity
Sunshine; Optimist;
Logical; Positive
Six Thinking Hats

Creative; Growth;
Possibilities; Ideas
Cool; Agenda;
Process; Organizer;
Overview; Decision
Bioburden IPC for aseptic fill
product before filtration
• Too Numerous To Count / ml
• Specification: NMT 10 cfu / ml
• Alert level (historical data): NMT 4 cfu / ml
• Off the top of your head what do you think

is the cause

Karen’s questions
1. TNTC / ml = too numerous to count
a very different result to those normally obtained if the alert is 4 cfu /
ml
2. Any other samples TNTC for this or other products in the past
months: - answered in the investigation checklist BUT not analyzed
and no conclusions in report
3. (Has anything changed in the sampling plan? Is the same lot of
containers being used? What about different starting materials?)
4. Who took / tested the sample?
5. Was EM performed?
6. Where was the test performed? What was tested immediately
before this product? What disinfectant is used for the BSC? Do the
cleaning records show that the BSC was indeed disinfected? Who
did that? When were they last observed doing it?
7. What was the ID and where is the colony morphology of the plate
documented? Was there a single colony type? Is there a picture of
the plate? How was ID performed? Is the organism in the library etc.
etc. etc.
The Investigation
• Test Procedure
• Two 15ml portions were filtered and washed with PW and PWTL and filters
were transferred to TSA and SDA
• Another 1ml portion was filtered and washed with PW only and then the
filter transferred to TSA
• TSA incubated 30 – 35; 2 days. SDA 20 – 25; 5 days
• For exact sample testing see method ID43253 ver 02, attachment 2
This is the most important part – it is the analyst

interview…
Did the 15ml sample show an identical pattern to the
1ml plate? Same contamination – single strain or
more than one microbe? After the same incubation
time? Why is the procedure different for the 1ml
sample (PW only and not PWTL) and only TSA?

More Details
TSA plates: tested for GPT – well they would be valid

– they showed TNTC – so are only interested in
STERILITY – was this part of the control testing?
What does “vastly” mean… MUST give figures: how
many plates were received and how many used in
tests? Did the tests show zero counts or low counts
where zero is usually obtained?
Experienced Operator

More Details
• Historical results show no or very low
microbial bioburden counts for this product
• Contamination is Micrococcus Luteus
Historical results from when to when?
Was Micrococcus luteus the ONLY bacterium seen on the TNTC plate
Is there a photo of the plate
Is there a morphological description of the contamination documented?
Next piece of information says BET <0.005 EU/ml – so what: M. luteus
isn’t an endotoxin producer! Can give the information but draw the
appropriate conclusion…

A Few Minutes of GMPs
• The GMP regulations:
– EU and US on handling deviations
• Q10 – Pharmaceutical Quality System
and CAPA management

The GMP Regulations
European Directive
• 1.3 (vi) …any significant deviations are
fully recorded and investigated
• 5.15 Any deviation from instructions or
procedures should be avoided as far as
possible
• 5.39 Any significant deviation from the
expected yield should be recorded and
investigated
21 cfr 211.100
Written procedures; deviations
(b) Written procedures and process
control procedures shall be followed in
the execution of the various production
and process control functions…… Any
deviations from the written
procedures shall be recorded and
justified

Q10: CAPA
• A pharmaceutical company should have

a system for implementing corrective
actions and preventive actions resulting
from investigation of product quality
feedback and trends from process
performance and product quality
monitoring

Q10: CAPA
• A structured approach to the investigation

process should be used with the objective of
determining root cause
• The level of effort and formality of the
investigation should be commensurate with the
level of risk
• CAPA methodology should result in product
and process improvements and enhanced
product and process understanding
Application Across the Product
Lifecycle – do I need to investigate?

Investigations
• Always covered in inspections
• The display window of the firm
– Reporting culture
– Level of understanding
– Level of efforts invested
– Level of documentation skills
– A sole effort of QA?
– Do they lead to continuous improvement?
RED FLAGS
• Last year we had less deviations than
complaints….
• In a deviation categorized as MAJOR, QA
decided not to conduct an investigation
• Same effort invested in trivial and major
deviations
• Majority of “root cause” defined as human error
and retraining is chosen as the sole corrective
action
• Deviations are not closed in a timely manner
and the statistics looks bad
RED FLAGS
• Environmental monitoring deviations starts and ends
with ID of the microorganism
• Recurrent deviations with “copy paste”
investigations
• Immediate cause for deviations (e.g. electrical
blackout) is defined as root cause
• Conclusion are drawn based on R&D scientist’s
statement
”the product is known to be stable at this
temperature”
with no supporting scientific evidence
RED FLAGS
• Failure in systems (e.g., HVAC) not correlated
with production activities in the affected area
• Written documentation does not allow
understanding of what happened and lengthy
verbal explanations are required
• Shallow investigations if at all following
calibration failures
• Investigation only at the level of the impact on
the product
RED FLAGS
• Trends revealed in PQRs or
System/Equipment QR not investigated
• Internal e-mail correspondence presented
as an investigation
• Majority of CAPA activities as response to
failures; preventive actions based on
proactive activities such as risk
assessments or internal audits are rare
Circumstantial Evidence
“…is a very tricky thing “ answered Holmes
thoughtfully
“it may seem to point very straight to one
thing but if you shift your own point of
view a little, you may find it pointing in an
equally uncompromising manner to
something entirely different”
“Obvious” facts
“ there is nothing more deceptive than an
obvious fact,” he answered laughing
“ besides, we may chance to hit upon some
other obvious facts which may have been
by no means obvious to Mr Lestrade.”
“ I shall approach this case from the point of
view that what this young man says is
true, and see where that hypothesis leads
us.”
…and finally…look for the flaw
Challenge the evidence
• “you have read the evidence. You have

formed some conclusion? Do you not
see some loophole, some flaw? Do you
not think that he is innocent?
Capturing the Event
Description of the Deviation
• Four case studies will be distributed –
work with your colleagues and come up
with a list of questions regarding additional
information you need in order to
understand the nature of the deviation

#1:

#2

#3

#4

:‫עלינו לשאול את השאלות הבאות‬
Who? - ?‫מי‬
What? - ?‫מה‬
where? - ?‫איפה‬
when? - ?‫מתי‬
why? - ?‫למה‬
how? - ?‫כיצד‬
Courtesy of Maya Weber 2010

Possible Causes
• You are going to Brainstorm – but
because we are not good at doing that –
let’s warm up first

Problem statement:
There is a mouse in the cheese
• A large block of very good Swiss cheese on a
kitchen table a few feet away from an open
screen door. The weather outside is warm. A
man comes to the table for some wine and
cheese and sees a mouse in the cheese
• Comments, questions, hypotheses
regarding contributing causes and
most probable cause(s)
Please work on your own
write it down
and think laterally
there are NO WRONG ANSWERS at this stage
44
Comments, Hypotheses

Mouse in Cheese
• Here is a solution to the problem:
• Throw out the cheese with the mouse and
open up a new packet of cheese
• Have I solved the problem – Yes / No?
• Defend your answer
46
Mouse in Cheese – 6M’s
Fishbone
• Man Group #1
• Machines
• Materials Group #2
• Methods
• Measurement Group #3
• Miscellaneous / Mother Nature / Management
• Please work in groups – be a bit crazy
write it down – at least three for each
category - we need ideas
there are NO WRONG ANSWERS at this stage
A Tool
• Root Cause Analysis is a tool for

identifying prevention strategies. It is a
process that is part of the effort to build
a culture of doing things right,
continuous improvement and move
beyond the culture of blame

Root Cause Methodology
• NOT intended to identify a single cause

• Look for:
– Contributing cause(s)
– Most probable cause(s)
The Problem Solving Cycle
There are ALWAYS at least
several hypotheses for any
event I can think of at
least 7 different
explanations…now
Problem I am going to look
for facts
Solution Hypotheses
Cool; neutral,
information needed; Emotive; gut feelings;
Facts
looking for facts Analysis = intuition; hunches
DATA
50
Expand Thinking Using
– Process Flow chart : from test method and
SOPs
– Fishbone / Ishikawa: 6m’s – MANY possible
causes
• Relates cause and effect
• Sorts ideas
– Why- why diagram
51
Focusing Thinking
• Data collection and analysis tools
– Control charts
– Graphs
– Histogram
You have started to collect data –
– Pareto chart but is it sufficiently organized and
are you drawing OBJECTIVE
– Process capability conclusions?
– Run chart
– Survey
52
5 why’s
Mouse in Cheese
Why?
Mouse in House
Why?
Screen Door Open

Why?
Put Cat Out

Left Door Open
Solution
Screen with
Spring
53 Latch
• Alternative solutions:
– "Be sure to close screen door“
– "Put a note on door asking, 'Did you latch me?
• Comments please
54
Mouse in the Cheese
• Should the cheese be left on the table?
• Why was it left on the table?
• If it is left on the table shouldn’t it be
covered?
• Why wasn’t it covered?
• Did the mouse definitely come from
outside?
• Should there be a pest control program
Juran’s Universal Sequence for
Making Quality Improvements
• Study the symptoms of the defects and failures

• Theorize as to the causes of these symptoms
• Test the theories until the cause(s) is known
• Stimulate remedial action by the appropriate
department
Use Project Teams – A Project is a Problem

Scheduled for Solution = CAPA
Root Cause Analysis
• The goal of a Root Cause Analysis is to
find out
 what happened
 why did it happen
 What is the risk to product – through
understanding cause(s) of the event rather
than just symptoms
 what do you do to prevent it from
happening again.
Let’s take the case studies and
Hypothesize
• What could be the reasons for the event

Case #1

Case #2

Case #3

Case #4

Now select some most probable and
contributing causes for case study #1

Now do 5 why’s for the most
probable causes

Now suggest some corrective
actions

Completing the Cycle
A whole is that which has beginning, middle
and end, Aristotle, Rhetoric
To complete a deviation / change report:

– all relevant details documented
– complete investigation recorded
– final product disposition verified as implemented
– corrective actions / tests verified as successfully
performed
Deviation Documentation
• Let’s Write a Deviation Report as we think
it should look for one of the cases we
studied today

MHRA – UK Regulator
• Paul Hargreaves emphasised that the
MHRA, and other regulatory agencies,
expect companies to actively reduce the
frequency and severity of human error
• Regulatory agencies expect companies to
actively prevent errors from happening,
not to react after the event
• The root cause of a vast majority of
quality problems is not ‘human error’.
Such a conclusion is usually symptomatic
of a poor and inadequate investigation.
Most informed regulatory auditors will
refuse to accept ‘retraining’ as a
suitable corrective action
Error Reduction: Practical Tools and
Techniques
• Achieving a genuinely open and blame free

working environment
• Taking a positive approach to mistakes and
error
• Driving out complexity
• The importance of User Centred Design (UCD)
• The crucial importance of SYSTEM
SAFEGUARDS
• Avoid overly complex quality management
systems which can cause errors
Categorize and Accurately Report
Error
Learning Gap
• Don’t know what to do:
– Missing skill
– Missing knowledge
– Failure to understand the consequences
– Lack of risk communication
Memory Gap
• “know” but don’t remember at the time of
performing an action
or
• Unable to apply the skill at the time of
action
or
• Unable to apply the skill in a particular
situation
Omission Errors
• Failure to document a step in a procedure

– Generally arises because of poor documents
– user friendly documents encourage
accurate recording
• Skip a step in a procedure e.g. because of
an interruption or lack of concentration (or
perform same step twice)
• Use wrong reagent / wrong type of
water…
Inconsistent Performance
• “Know” and “Understand” but variability in method
/ standard leads to inconsistent results e.g.
– Poor instrument maintenance
– Unclean instruments / contaminated incubator
– Poor reagent control e.g. contaminated LAL reagent
– Unclear method leads to inconsistent performance
between different or even the same analyst
– Analyst’s mood / tired / angry / bored / stressed /
over-worked: too many tests per analyst…
Application
• “know” but apply technique wrongly or use
the information incorrectly:
– Transcription errors
– Touch tip to sample and then use for a new
sample
– Scratch face before opening reagent
– Failure to disinfect BSC
Decision Errors
• Wrong decision made
– In a particular situation
or
– Given a series of facts / information
• E.g. put plates back in incubator rather
than report breakage
• “analyst error” when results may be true
Actively REDUCE and REMOVE Risk Increasing Factors
• Can conduct audits to identify RIFs

– Structural (poor lighting, material and people flows
etc)
– Organisational (poor communication, leadership
and complex, hierarchical bureaucracies)
– Process related (poor documentation / process
design)
– Poor work place ergonomics
– Individual (fatigue, stress, competence, skill
related)
Actively remove RISK INCREASING
FACTORS(RIF)
• After an event – conduct an audit for RIFs
• Observe several analysts performing the
operation and ask “why?” “why?” “why?”
• Why did the plates drop:
– was the incubator overcrowded?
– Was there no trolley nearby?
– Was there no workspace available?
– Was the operator rushed / stressed?
Juran – inadvertent error
• Inadvertent errors come from workers’
inability to maintain attention
• The errors are unintentional, unwitting,
and unpredictable (they exhibit
randomness)
• The bulk of remedies lie in fool-proofing
the system
Juran – Technique Errors
• Technique errors arise because the worker lacks
some essential technique, skill, or knowledge
needed to prevent the error from happening
• They are typically unintentional, specific,
consistent, and unavoidable
• Remedies often require the discovery (using the
diagnostic techniques) of differences of technique
which represent the beneficial “knack” that
produces superior results
• and training others or changing the process to
embody the better method
Inadvertent and Technique
Errors
• Usually workers cannot find the reasons
for defects themselves, and therefore they
will keep on doing what they have been
doing
• They will keep on producing defects
• This will go on until they get the help
they need from management
And regarding operator error:
Juran on operator error: Management has the

responsibility to provide a:
1. Means for knowing what he is supposed to do
2. Means for knowing whether he is doing what he
is supposed to do
3. Means for changing what he is doing if it does
not conform with what he is supposed to do

In Conclusion
• Expand your thinking:
#1 question: three or more possible
explanations for every deviation event – write
down at least three each time and be sure to
include “I / my department messed up”
• Collect data and analyze to convert into
information
• Apply the information as knowledge to draw a
scientifically defendable conclusion
Thank You for your Attention
Any questions
Find us at
pcikaren@netvision.net.il

Some answers from earlier on…
BUT NOT ALL THE ANSWERS

KEEP AN OPEN MIND
Documenting the Deviation
• What was missing in the report:
– When (did it occur)
– Who (discovered it)
– How and When (did they discover it)
– Whom (did they notify)
– When (did they make the notification)
– What (immediate action was taken)
– What was the scale of the deviation e.g. whole
batch affected, portion of the batch segregated;
how far out of specification (give the spec)

Which are “Contributing” vs “Most Probable”?
For the cheese
• cheese left on the table – why? E.g. refrigerator broken / man

lazy CONTRIBUTING
• If it is left on the table shouldn’t it be covered? Why wasn’t it
covered? No cover available / man lazy CONTRIBUTING
• Did the mouse definitely come from outside?
Should there be a pest control program – depends – if the
mouse is the kid’s then that could be the most probable cause
– if not then contributing cause
• Screen door open? – most probable cause
Automatic latch / get rid of cat?
• What will happen if you get rid of cat??????
Be careful not to be too quick to chose a corrective action plan
without examining potential consequences and collecting more
data to support your hypothesis

Human Error, Root Cause Analysis and Conducting Objective and Effective Investigations

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Human Error, Root Cause Analysis and

Conducting Objective and Effective

• To understand why operators make

PCI Pharmaceutical Consulting Israel Ltd 2

• You are not investigating if when

PCI Pharmaceutical Consulting Israel Ltd 10

PCI Pharmaceutical Consulting Israel Ltd 12

‫התכנסות ע"י פסילת גורמים בהתאם לעובדות‬

Six Thinking Hats

• Off the top of your head what do you think

PCI Pharmaceutical Consulting Israel Ltd 17

This is the most important part – it is the analyst

PCI Pharmaceutical Consulting Israel Ltd 19

TSA plates: tested for GPT – well they would be valid

PCI Pharmaceutical Consulting Israel Ltd 21

PCI Pharmaceutical Consulting Israel Ltd 22

PCI Pharmaceutical Consulting Israel Ltd 23

PCI Pharmaceutical Consulting Israel Ltd 25

• A pharmaceutical company should have

PCI Pharmaceutical Consulting Israel Ltd 26

• A structured approach to the investigation

PCI Pharmaceutical Consulting Israel Ltd 28

• “you have read the evidence. You have

PCI Pharmaceutical Consulting Israel Ltd 37

PCI Pharmaceutical Consulting Israel Ltd 38

PCI Pharmaceutical Consulting Israel Ltd 39

PCI Pharmaceutical Consulting Israel Ltd 40

PCI Pharmaceutical Consulting Israel Ltd 41

Courtesy of Maya Weber 2010

PCI Pharmaceutical Consulting Israel Ltd 43

PCI Pharmaceutical Consulting Israel Ltd 45

• Root Cause Analysis is a tool for

PCI Pharmaceutical Consulting Israel Ltd 48

• NOT intended to identify a single cause

Screen Door Open

Put Cat Out

• Study the symptoms of the defects and failures

Use Project Teams – A Project is a Problem

• What could be the reasons for the event

PCI Pharmaceutical Consulting Israel Ltd 58

PCI Pharmaceutical Consulting Israel Ltd 59

PCI Pharmaceutical Consulting Israel Ltd 60

PCI Pharmaceutical Consulting Israel Ltd 61

PCI Pharmaceutical Consulting Israel Ltd 62

PCI Pharmaceutical Consulting Israel Ltd 63

PCI Pharmaceutical Consulting Israel Ltd 64

PCI Pharmaceutical Consulting Israel Ltd 65

To complete a deviation / change report:

PCI Pharmaceutical Consulting Israel Ltd 67

• Achieving a genuinely open and blame free

• Failure to document a step in a procedure

• Can conduct audits to identify RIFs

Juran on operator error: Management has the

PCI Pharmaceutical Consulting Israel Ltd 83

PCI Pharmaceutical Consulting Israel Ltd 85

BUT NOT ALL THE ANSWERS

PCI Pharmaceutical Consulting Israel Ltd 87

• cheese left on the table – why? E.g. refrigerator broken / man

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