Qua-Dmt-G-001 Guideline For Root Cause Analysis Investigations

EFFECTIVE DATE: 04-OCT-2012 GMT-0400
DOCUMENT PRINTED ON 05-JUN-2015
STANDARD OPERATING PROCEDURE PAGE NO. 1 of 60
SOP NO. SOP TITLE Version

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003
SITE SYSTEM
Singapore QMS Sub-System 3 – Deviation Management
Prepared by : Choi Byung Kook

Sub-System Owner Approval : Belinda Chen {See Appended Electronic Signature Page}
Quality Approval : Chin Hui Yee {See Appended Electronic Signature Page}
1.0 PURPOSE
The purpose of this procedure is to provide guidelines on the appropriate techniques to use for effective
root cause analysis, impact assessments and corrective and preventative action development, with
respect to all unexpected events that may be encountered during the course of manufacturing, testing,
storing and supporting pharmaceutical API, finished goods and intermediates.
This procedure is not intended to replace or modify existing function and site event, deviation and
atypical procedures nor provide alternative recording and tracking methods to the forms and checklists
detailed in the formal SOP's.
2.0 SCOPE
This guideline can be applied to all levels of investigation from laboratory and shop floor incidents and
process interruptions, through laboratory and production deviations and atypical investigations and
documentation to Internal Quality Audit Observations.
It is mandatory that at least one formal root cause analysis technique will be used for Atypical
Investigations.
3.0 REFERENCES
QUA-DMT-S-001 – Event Management/ Deviation and Atypical Procedure
QUA-DMT-S-002 – Laboratory Investigations
QUA-DMT-S-003 – Investigation For Analytical Laboratory Instruments.
QUA-DMT-S-004 – Significant Investigations
GDL 1.50 MMD Quality Risk Management
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4.0 DEFINITIONS
None
5.0 RESPONSIBILITIES
See Section 6.2
6.0 PROCEDURE
6.1 Real Time Problem Solving/ A3 Problem Solving
6.1.1 Real Time Problem Solving/ A3 Problem Solving Introduction
The A3 or RTPS methodology is a standardized methodology developed as part of the Toyota

Production System (an in turn developed from the Deming Improvement Cycle). The A3 name
derives from the paper size (approximately 11" x 17") that is used to present the progress and
key information about a process improvement initiative, with the reports written and drawn
(illustrations are encouraged) on one piece of A3 size paper.
The A3 problem solving tool used at MMD Singapore is not primarily designed for the
investigation of "deviations" in a GMP context but is focused on general process improvement. It
is mentioned in this guideline as one area of process improvement is responses to unplanned
events, some of which in a pharmaceutical environment may be or later be discovered to be
"deviations". Therefore it is probable that the first steps of documenting and investigating a
manufacturing problem may involve the use of the A3 or RTPS methodology.
The concepts contained in the A3 philosophy and process does represent best practice and is
aligned with the intent of the current regulatory guidance for manufacturing and laboratory
investigations, in that:
 Problems should not be dealt with superficially, but addressed with sound root cause
analysis.
 That problems should be characterized by direct observation and the collection of date.
 That the investigators must have a clear understanding of the process being investigated.
 That effective root cause analysis is done to find the true root cause.
 That effective countermeasures are developed based on the clear understanding of the
process to be improved and the relationships with other processes and activities and that
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the "improver" of the process has a clear and communicable vision of the improved version
of the process
The overall RTPS/ A3 methodology contains many of the elements that we are familiar with for
the investigation of "GMP deviations". However, there are a number of critical omissions which
means that the A3/ RTPS investigation, reporting and correction/ improvement system does not
on it's own meet the GMP requirements for GMP Investigations and therefore for events,
deviations and Atypicals as defined by SOP QUA-DMT-S-001 the A3 acts as only a data
collection and investigation facilitation tool and all formal data, information and investigation
analysis and reporting are captured, collated, reviewed, approved and filed as per the
requirements of QUA-DMT-S-001. See table 1 below.
Table 1 – comparison of the steps and flow of the A3 Problem Solving and GMP Deviation
Management Approaches.
A3 Process GMP Process
Identify Problem Identify Problem
Observe the problem Observe the problem
Record the problem on the A3 sheet Record Problem in batch Sheet
Assess Immediate Impact
Apply immediate corrective actions if required.
Raise Event/ Atypical and record relevant data
Notify Quality (if not a lab deviation)
Log in formal GMP tracking and trending system
Assign Investigation Resources Assign Investigation Resources
Understand the Current State Generate problem specification as part of the formal
investigation
Re-assess Immediate Impact
Apply immediate corrective actions if required.
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Perform Root Cause Analysis Perform Root Cause Analysis
Re-assess Immediate Impact and act if necessary
Propose Countermeasures Identify Preventative and further corrective measures
Re-assess Immediate Impact and act if necessary
Write up and seek approval and closure of investigation

in formal GMP system
Implementation Plan Track CAPA Closure
Check results/ effectiveness of counter Check for repeat atypicals.

measures
Future Improvement plans
6.1.2 When Should The A3 Process Be Used?
The A3 process can be used a the starting point for any investigation and provides an excellent
tool for the collection of initial data and observations in the field.
6.1.3 How To Complete An RTPS or A3 Problem Solving Exercise.
6.1.3.1 If the A3 Sheet/ Process is used as a starting point for deviations for any
production, testing or other GMP related activities, then all existing SOP's for
deviation management apply. This means that the A3 Sheet must carry as a
minimum the following data:
 Date
 Time
 Location
 Product/ Process
 Lot number
 Nature of the defect
 Whether a note was made in the batch record.
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 Whether and event or atypical was raised.
The original A3 Sheet can remain with the investigator until the completion of the
investigation and then may be filed by investigation lead for future training purposes.
This is not a Quality Record as all data and information will be present in any formal
event, deviation and atypical investigation report.
Note the following sections of this guideline referring to the roles and responsibilities of
investigation stakeholders, the tools for investigation and the tools and rules for Impact
Assessment, Corrective and Preventative measures are common for GMP investigations
and Non-GMP investigations.
6.2 Roles and Responsibilities For Investigations
6.2.1 Collective Expectations For Best Practice Investigations
It is important to be clear on the general expectations before looking at the specific roles,
responsibilities and accountabilities.
 It is expected that sound science methods and logic are used for all investigations and that
the data collected are accurate and verifiable.
 It is expected that investigations are undertaken with an open mind to ensure that there all
relevant facts are considered.
 It is expected that as most deviations will involve people as observers or contributors that
the fact finding starts with the recording of information from the people present at the time
the incident occurs and that this observational information may be collected and captured in
notes and formats that do not appear in the finished report.
 It is expected that the investigation team may return to gather more information by interview
or discussion as the investigation progresses.
 It is expected that facts and data (dates, times, temperatures etc.) will be verifiable.
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 It is an expectation that all stakeholders understand that the goal of an investigation is to

find the true root cause and effective corrective and preventative measures.
 It is an expectation that all stakeholders understand that the true measure of success is the
number of iterative investigation cycles required to get to the true root cause (ideally one)
and the effectiveness of the preventative actions with respect to reoccurrence.
 It is not an expectation that the quality of an investigation be judged by:
 It's length. Demonstrating good logic and efficiency in establishing the root cause
and effective corrective actions is the goal of the process. The fewer the words
required to do this the better.
 The scale of the assessed impact to the business. A complete, unbiased and
exhaustive impact assessment is a core GMP requirement.
6.2.2 Roles and Responsibilities/ Accountabilities
The following roles are defined in this section of the guideline and the responsibilities and
accountabilities are defined in the following sections:
 Discoverer
 Assignor
 Lead investigator Responsibilities
 Contributing Investigators
 Investigation Process Facilitator
 Investigator's Line Management
 Functional Reviewers
 Quality Assurance Reviewers
6.2.2.1 Lead investigator Responsibilities
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 It is the responsibility of the lead investigator to formally and visibly use logical
analysis techniques such as Kepner Tregoe (Analytical Problem Solving) and/ or “5
whys” analysis to drive to the root cause of all atypicals.
 It is the responsibility of the assigned investigators and assessors to use logical

analytical thought processes to investigate events and recurrent problems that may
not impact product quality but do substantially impact on the business (due date
misses etc.) to allow the development and implementation of effective and lasting
preventative actions.
 It is the responsibility of the lead investigator to be familiar with, and competent in,
the technologies, processes and/ or procedures involved in the investigation or to
involve the appropriate expertise and/or acquire the appropriate knowledge.
 It is the responsibility of the lead investigator to ensure that appropriate corrective

actions are taken to address the immediate or short term impacts of the deviation/
atypical, if prior to the completion of the investigation.
 It is the responsibility of the lead investigator to identify/ develop preventative actions

that address the specific root cause(s) of the problem(s) and not the symptoms or
unrelated problems as part of the investigation close out.
 It is the responsibility of the lead investigator to agree and develop the plan for the
execution of corrective and preventative action to ensure their execution in the
allowed time frame.
The technical accuracy and the thoroughness of the investigation process are the
primary responsibilities and accountabilities of the lead investigator. These
responsibilities and accountabilities cannot be delegated.
6.2.2.2 Contributing Investigators
 It is the responsibility of the contributing investigators to contribute to and be familiar

with logical analysis techniques such as Kepner Tregoe (Analytical Problem Solving)
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and or “5 whys” analysis to drive to the root causes of the problems under
investigation.
 It is the responsibility of the contributing investigators to use logical analytical thought

processes to investigate level 1, 2 and 3 deviations/ atypicals that do not require full
root cause analysis.
 It is the responsibility of the contributing investigators to familiar with and competent

in the technologies, process and/ or procedures involved in the investigation or to
involve the appropriate expertise or acquire the appropriate knowledge.
 It is the responsibility of the contributing investigators to provide input into the

development of appropriate corrective actions based on their functional and technical
expertise.
 It is the responsibility of the contributing investigators to provide input into the

identification/ development of preventative actions that address the specific root
cause, root causes of the problem and not symptoms or unrelated problems as part
of the investigation close out, based on their functional and technical expertise.
 It is the responsibility of the contributing investigators assist in the development of

preventative measures and to agree and assist in the development of the plan for the
execution of corrective and preventative action to ensure their execution in their
functional area within the allowed time frame.
The technical accuracy and the thoroughness of the information and analysis
provided to the lead investigator are the primary responsibilities and
accountabilities of the contributing investigators. These responsibilities and
accountabilities cannot be delegated.
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6.2.2.3 Investigator's Line Management
The line managers of investigation staff are accountable for ensuring that the
investigators adopt the most appropriate formal root cause analysis tools for the
investigation to which they are assigned. In addition, they are accountable for
reviewing the work of their staff on the context of the expectations for root cause
analysis, impact assessment and corrective and preventative action
development, planning and implementation and for coaching and development
for the highest quality of investigational and process improvement skills.
6.2.2.4 Functional Reviewers
 It is the responsibility of the functional reviewers to ensure that any factual

and or investigational process errors are highlighted to, and addressed by,
the lead investigator prior to approving the investigation for closure.
 It is the responsibility of the functional reviewers to ensure that the

appropriate rigor of investigational method has been used by the investigator/
or investigation team and that any deficiencies in the investigation
methodology are addressed prior to functional approval. The functional
reviewer should provide guidance and direction as required to assist the
investigation team prior to the completion of the report.
 It is the responsibility of the functional reviewer to ensure that the

investigation team is directly or via stakeholder line managers, held
accountable for discharging their responsibilities.
6.2.2.5 Quality Assurance Reviewers
 It is the responsibility of the Quality Assurance Reviewers to be familiar with

and conversant in the methodologies of root cause analysis to allow objective
evaluation of the rigor of the investigation.
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 It is the responsibility of the Quality Assurance Reviewers to be familiar with

and conversant in the methodologies of root cause analysis to allow objective
evaluation of the logical arguments, positions and conclusions derived for and
documented in the report.
 It is not the responsibility of the Quality Assurance Reviewers to have direct

expertise in the equipment, system or process that is the subject of the
investigation.
 It is the responsibility of the Quality Assurance reviewer to ensure that the

Corrective and Preventative Actions are appropriate and clearly linked to the
root cause of the problem being investigated.
6.3 Why perform a root cause Analysis.
6.3.1 Introduction
Root cause analysis is an essential tool in the process of preventing repeat process and activity
deviations from expected process outcomes. When a GMP manufacturing process or system
delivers an unexpected negative outcome or is not executed correctly then there may be a risk
that the safety, efficacy, purity, quality or identity of the product maybe impacted. It is a
regulatory and a company expectation that these deviations for the expected process or
process outcome are recorded and evaluated. For those deviations determined to have a
potential impact on the safety, efficacy, purity, quality or identity of the product the following is
required:
 They must be formally investigated;

 The root causes must be identified;
 Effective preventative measures established to prevent re-occurrence;
 The full impact of the root causes analyzed to ensure the complete impact of the atypical is
known and documented;
 Appropriate corrective and remedial actions are taken to address the identified impact.
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While the above is a GMP regulatory expectation and a condition of us being authorized to
produce pharmaceutical products, the business, safety, health and environmental benefits of
good quality reproducible formal root cause analysis are clear. By understanding the true root
causes of the deviation we can identify corrective actions that will truly remediate the process
output or product where that is possible. More importantly, we can identify effective actions that
prevent to process deviation from occurring again and permanently improve the quality of life for
all stakeholders and eliminate needless waste from our daily activities.
Thorough and formal root cause analysis requires discipline and focus, but it ensures that we do
not address only the symptoms of the problem and miss the underlying issue.
Thorough and formal root cause analysis also ensures that we do not jump to conclusions as to
the underlying issues and forces us to use facts and not experience, preference and bias to
develop preventative actions.
6.3.2 When a formal Root Cause Analysis Is Required.
A formal peer reviewed and quality reviewed Root Cause Investigation is not required for every
deviation from expected outcomes. A formal Root Cause Analysis is expected for every event
formally designated as an atypical and the Event, Deviation and Atypical Investigation
procedure (QUA-DMT-S-001) provides specific expectations with respect to GMP and
regulatory expectations.
However, the use of the logical thought processes required for a Root Cause Analysis and use
of techniques such as fish bone diagrams, Real Time Problem Solving and 5 whys can help
structure and speed up simpler investigations or non GMP investigations into Safety, Health and
Environment deviations and flow interruption and process waste. In short, effectively and quickly
identifying the root cause and correct preventative measures for any unexpected event will only
increase customer and Stakeholder satisfaction with respect to products, services and working
environment.
6.3.3 Introduction to The Common Root Cause Analysis Techniques
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The root cause analysis technique that we will use are based on 3 techniques:
 Kepner Tregoe (KT) Root Cause Analysis (RCA).

 Fish Bone or Ishakawa diagrams.
 5 whys.
(Note that it is a best practice to incorporate 5 whys and Fish Bone techniques into a KT
analyses to ensure that the process being investigated is clear and all potential root
causes are considered (Fish Bone) and/ or that human choice and motivation is analyzed
(5 whys)).
Two other specialized derivations of the fish bone and 5 why's tools are used to help guide the
investigation of human error and to assist rapid problem solving in a production, engineering
and laboratory "shop floor environment". These are:
 Human Error type classifications which incorporates guidance on Rasmussen/ Amalberti

behaviour migration.
 Real Time Problem Solving, also known as RTPS and A3 Problem Solving.
Our reporting structure for Root Cause Analysis is based on a Kepner Tregoe Root Cause
Analysis as this is the basis of our more complex technically focused Root Cause Analysis
approach.
There is one fundamental objective for a root cause analysis that we must not lose sight of and
one fundamental error that we must avoid:
Objective
Eliminate the problem and prevent reoccurrence the first time around.
To do this we must avoid the fundamental error of:
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Assuming that we know the root cause just by looking at the point of failure. If we jump to
conclusions, and if we believe that we know the answer we will start fitting the facts to our
theory, when we should be fitting our theory to the facts.
6.4 Kepner Tregoe Root Cause Analysis
6.4.1 Overview of Kepner Tregoe Root Cause Analysis
A formal root cause analysis follows 6 fixed steps to ensure that the true root cause is
determined and effective preventative measures are implemented.
1) PROBLEM STATEMENT
2) PROBLEM SPECIFICATION
3) POTENTIAL ROOT CAUSES/ POSSIBLE ROOT CAUSES (Fishbone diagram and 5
whys)
4) CONFIRMATION OF ROOT CAUSE
5) CONCLUSION AND IMPACT ASSESSMENT
6) CORRECTIVE AND PREVENTATIVE ACTIONS
Note that the development of Impact Assessments And Corrective and Preventative
Actions are common to all investigation techniques and are called dealt with separately
in section 6.10 and 6.11
It is also important to remember that the development of the problem specification is iterative
and that the specification will develop and become more complete as the investigation
progresses. In the case of atypical investigations this means that impact assessments regarding
product, work in progress materials and the suitability of equipment and processes/ methods for
manufacturing and testing will need to be re-visited periodically to ensure the emerging
understanding of the event under investigation does not change past assessment.
Figure 1 provides an overview of the investigational steps and the points at which it is
recommended that any preceding impact assessments are reassessed.
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KT Root Cause
Analysis selected
Figure 1 – Over view of the
investigational steps
Assemble
Problem
Observations
Used With Atypicals
To Ensure Timely Action
With Respect To Product,
Document Problem
Processes and People
Yes Problem Statement

No
Accurate?
Does the interim

No
impact assessment
Assemble
Problem
Yes Specification
Notify
Operations and
Quality Document Problem
stakeholders Specification
of change in
Yes
Document revised Problem Specification No
impact assessment Complete?
and
Actions in an
Interim report
Assemble
Potential Root
Act on the Causes
revised Impact
Assessment
Analysis Of Problem
Document the Specification Versus
completion and Potential Root Causes
outcome of the action
arising from the
change in Yes
interim impact Possible To No
Decide On Root
No
Is Confirmation
Yes Did Test Confirm
Test Required Root Cause?
No
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Go to final impact assessment
Document the root cause
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The best and most effective problem solving events are run to a plan and are facilitated. This
ensures that sequential problem solving is avoided. A typical plan would proceed as follows:
 Assemble the team (if Appropriate)

 Define the problem statement
 Assemble the first pass at the problem specification and identify obvious gaps and plan to fill
specific gaps.
 Do second pass of the problem specification then move to the potential root causes.
 Do preliminary review of potential root causes against known facts in problem specification
and identify gaps in problem specification.
 Go back and collect data to fill gaps in the problem specification.
 Complete problem specification and complete root cause analysis by reviewing the potential
root causes against the final problem specification.
 Develop experiment or logic to prove/ confirm the root cause.
 Assemble stakeholders and experts to design the corrective and preventative actions.
 Spend an equal amount of time and effort on the corrective and preventative actions as on
the investigation and write up. Ultimately, the success of the investigation team is judged by
the relevance, quality and effectiveness of the preventative and corrective actions and as
well as on the clarity of the report.
6.4.2 Element 1 - The Problem Statement
There should be a clear understanding and definition of the problem to be solved if time is not to
be wasted in order for the investigation to be successful.
PROBLEM STATEMENT examples:
Briefly describe only the problem - Do not describe symptoms.
E.g.
“The low BHA assay of VYTORIN tablets at release”
NOT “QC’s rejection of VYTORIN tablets”
Beware of trying to solve more than one problem at once - more than one RCA maybe required.
E.g.
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"Customer Complaints For Broken Tablets", this could include:

The investigations of specific tablet breakage on a deduster.
Damage of tablets in the bottle package during shipping.
6.4.3 Element 2 – The Problem Specification
For an effective root cause analysis there must be an accurate and complete problem
specification. Demonstrable facts and data should be included. There is no limit to the numbers
of entries in each section and the number of “is” and “is not” entries do not need to match.
The following table (table 2) lists the questions that should be asked to allow a complete
specification of the problem. Some examples of statements are provided as a guide.
Note on documentation: Hand written A3/ A4 KT investigation templates can be used to

develop the problem specification (see appendix 1). These can be attached to the
atypical report manually or scanned.
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Table 2 – Problem specification table with some example facts for a problem.
IS IS NOT
What the problem is? What the problem is not?
e.g. e.g.
 Suppressed dissolution of Ezetimibe….  Suppressed dissolution of Simvastatin.
 Low Ezetimbe assays………
Where the problem is occurring? Where the problem is not occurring?
e.g. e.g.
 10/10 and 10/20 tablets  10/40 and 10/80 tablets……..
 From each HPLC……..
When the problem is occurring? When the problem is not occurring (but
could)?
e.g.
 Intermittently e.g.
 Since November 2005  Continuously
 Grouped incidents  At fixed intervals
 At all compression forces  Individual events
 Meggle lactose  Before November 2005………
 With different lots of excipients
 For all lab techs
 All results for as system suitability….
To what extent the problem is occurring To what extent the problem is not occurring
e.g. e.g.
 Mostly out side of lower SPC 3 sigma  Above upper 3 sigma limits.
limits  Failures of specification.
 Clear shifts (9 batches consecutively  A trend of reducing dissolution values
below the mean for the process)…  Individual batches showing the
result…….
What changed Since the last "correct" What has not changed since the last
event/ activity: "correct" event/ activity:
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e.g. e.g.
 Change control implemented for sensor  All staff are the same as for previous PM
PM/ Calibration Changes. event
Specific Examples Of Information That Should Be Considered For Collection And Review as
Part of the investigation process:
 Details Of the process

 Outcome Of process and procedure reviews
 Details Of operator interviews (The input of people present at the time of the incidents/
problems is essential to all investigations)
 References to photographs and graphical/ pictorial information
 Batch record review, current and historical
 Changes to process or system between last conforming and current non conforming
performance
 Process history
 Related previous atypicals/deviations
 Other systems or batches potentially affected
It is important to remember the following points when constructing a problem definition.

 KT problem solving is an iterative process and the first attempt at constructing the problem
definition table will be incomplete and you will need to return and populate the table with
more data as you find it.
 You will almost certainly need to return to the problem specification and or gather more data
after the first attempt at constructing the list of possible root causes high lights that some
types of facts are missing. This is acceptable.
 Only demonstrable and verifiable facts can be entered into the table. If data cannot be
verified, or an assumption is put into the table then the root cause analysis process may not
give the right answer and there is a high probability that you will reach the wrong conclusion.
6.4.4 Element 3 – Causes/ Possible Causes
The identification of the possible causes and the evaluation of the causes must take place in
two separate exercises as two different processes are required.
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6.4.4.1 Step 1 - The identification of possible causes
This process step requires a brainstorming approach of all possibilities:

 All potential causes should be recorded without evaluation, even if the belief
is that the evidence at hand eliminates the possibility.
 The recording of all potential causes regardless of relevance goes some way
to ensuring that no possibility is missed and that the biggest risk of failure,
jumping to conclusions, is avoided.
 During these sessions process expertise must be available and the correct
knowledgeable people involved in the brain storming.
 The identification of potential causes for process based problems can be
greatly aided by the use of techniques such as fish bone (or cause and effect
or Ishakawa) diagrams. Again during the use of these techniques it is critical
that no filtering goes on and process expertise is available.
 The identification of potential causes for human and process problems can be
greatly aided by the use of the 5 why’s questioning technique. For process
problems this does require the presence of a knowledgeable expert to ensure
that the cause and effect relationships are correct.
 In addition for where the 5 whys leads to a true human error situation (i.e. the
right action not taken at the right time although all indicators were available) it
may be necessary to consider psychological factors related to human
behaviour.
 Techniques such as Fishbone (or cause and effect or Ishakawa) diagrams.
Again during the use of these techniques it is critical that no filtering goes on
and process expertise is available.
6.4.4.2 Step 2 - The evaluation of potential causes
This process step requires a methodical and systematic approach to logically

evaluating the potential causes against the known facts of the Problem
Specification. The allowed results of the evaluation of the root causes against
each fact in the problem specifications are:
 Explains the fact
 Does not explain the fact
 Explains the fact only if……
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This last option is important to remember as many problems that we will

encounter will be complex and not simple single variable cause and effect
events.
6.4.5 Element 4 – Confirmation of Causes/ Possible Causes
Good and effective Root Cause Analysis requires that the identified root cause be proven to be
correct. This ensures that flaws in the investigation process (such as jumping to a conclusion
early in the exercise) are discovered before the corrective and preventative measures are
determined.
There are effectively 2 ways that this proof can be obtained:
 The preferred option is by direct experimentation and measurement. However this may not
always be possible depending on the complexity of the system that failed, the duration
between failure events or the cost of experimentation.
 Logical analysis where the rationale for the cause and effect correlations are described in
the report. Using this approach however requires that consideration must be given to on-
going monitoring of one or more Key Performance Indicator for the system under
investigation for a duration that would ensure the potential for repeat events of the problem
investigated would surface.
6.5 5 Whys Root Cause Analysis
6.5.1 Overview of The 5 Whys Root Cause Analysis Technique
The 5 Whys technique is a simple but powerful tool to help find the root cause of a problem and
it is particularly useful for systematic and people related problems. The tool does not require
detailed statistics, but is considered to be powerful enough to be included in Six Sigma
methodology.
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The technique works by repeatedly asking the question "Why" and using the question to peel
away the layers of symptoms that get in the way of seeing the true root cause of a problem. The
power of the technique comes from the simplicity and the intuitive flow of one question it's
answer forming the basis of the next question. Branches in cause and effect can be
accommodated which allows the relationships between the different root cause elements in
complex problems to be evaluated against one another.
Although the technique is called "5 Whys" it may take more or less than 5 questions before you
find the root cause of the problem. However the traditional concept is that you can get to the
root cause of any problem with the right series of 5 questions and answers.
6.5.2 When Should A 5 Whys Analysis Be Used?
As already stated a 5 Whys analysis should be selected for investigating problems which
involve human and human operated systems and human machine/ process interactions. It can
form part of a Kepner Tregoe Root Cause Analysis to help with the identification of potential root
causes resulting from process/ equipment and human interactions. It can also be used without
on its own for incident investigations where a KT is not applicable (i.e. the root cause elements
are visible, but the relationships are not clear.)
One very important thing to remember is that 5 whys frequently fail to reach the true root cause
because the process when the a why question generates an answer that indicates that a person
failed to act in the correct manner for the situation. In the examples shown in section 4.5.4 you
will see called out points where there was more than one answer to a question and where the
answer given is actually a simplification of the true human error. The examples actually illustrate
the concepts of "migration".
6.5.3 How To Complete A 5 Whys Analysis
6.5.3.1 Step 1 – The Problem Statement
Write down the specific problem (see section 3 – item number 2 Element 1 -
The Problem Statement). Like KT analysis an accurate problem statement is
critical to arriving at the true root cause as it formalizes the problem and it also
helps the investigation team focus on the same problem.
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6.5.3.2 Step 2 - Ask Why?
Ask Why the problem happens and write the answer down below the problem.
6.5.3.3 Step 3 – Is Your Answer The Root Cause?
If the answer you arrive at doesn't identify the root cause of the problem written
down in step 1, ask Why again and write that answer down. If you find a branch
(i.e more than one potential answer is identified) write both and apply the
technique to both / all branches).
6.5.3.4 Step 4 – If The Answer Is Not The Root Cause?
If the answer is not the root cause loop back to step 3 until the problem's root
cause is identified. This may take more or less times than five Whys.
6.5.4 5 Whys Examples
Below are two examples. The serious example looks suspiciously similar to the way that some
procedures and practices evolve in the work environment, where one system is used for a
purpose other than the original intention and that purpose then drives unintended actions and
behaviours that have a negative impact on the business.
Serious Example - Problem Statement: Customers are unhappy because they are being
shipped products that don't meet their specifications.
6.5.4.1 Why are customers being shipped bad products?

Because manufacturing built the products to a specification that is different from
what the customer and the sales person agreed to.
6.5.4.2 Why did manufacturing build the products to a different specification than that of
sales?
Because the sales person expedites work on the shop floor by calling the head of
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manufacturing directly to begin work. An error happened when the specifications

were being communicated or written down.
Note: there is an opportunity for a branch here as there is a human error in

transferring and transcribing the data. This could be called out as a
separate problem if this process was going to continue. However the other
branch in this 5 whys described below, illustrates that the main issues
were not with errors in transcription and data transfer.
6.5.4.3 Why does the sales person call the head of manufacturing directly to start work
instead of following the procedure established in the company?
Because the "start work" form requires the sales director's approval before work
can begin and slows the manufacturing process (or stops it when the director is
out of the office).
6.5.4.4 Why does the form contain an approval for the sales director?
Because the sales director needs to be continually updated on sales for
discussions with the CEO.
The answers in 4.6.4.4 looks straight forward, however buried in these simple
statements is a much more significant problem, which requires some special approaches
to ensure effective corrective and preventative actions are developed and implemented.
Section 4.7 provides guidance on how to proceed when one or more answers to a why
question are characterisable as "Human Error".
Humorous example - Problem Statement: You are on your way home from work and
your car stops in the middle of the road.
6.5.4.5 Why did your car stop?

Because it ran out of gas.
6.5.4.6 Why did it run out of gas?

Because I didn't buy any gas on my way to work.
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6.5.4.7 Why didn't you buy any gas this morning?

Because I didn't have any money.
6.5.4.8 Why didn't you have any money?

Because I lost it all last night in a poker game.
6.5.4.9 Why did you lose your money in last night's poker game?
Because I'm not very good at "bluffing" when I don't have a good hand.
6.6 Human Error Focused 5 Whys Investigation Process
6.6.1 Overview of The Human Error Focused 5 Whys Investigation Process
The objective of this process is not to apportion blame or find the guilty, it is to understand what
contributed to the "human error".
For these types of investigations the term error is used to describe an unintended outcome from
a process that involves human actions/ activities or decision making or a failure to use a
process or use the correct process.
For this type of investigation to work correctly it is essential that everyone involved feels
comfortable that the purpose is to identify improvement opportunities.
It is also essential that everyone involved in the process or decision is included directly in the
investigation process.
6.6.2 When Should The Human Error Focused 5 Whys Investigation Process Be Used?
This process should be used when it is clear that the correct and incorrect outcome for a
process, decision or action is primarily dependent on a human conscious or unconscious
choice.
An example, taken from section 6.5 and used as the basis for the illustration below:
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 Why does the sales person call the head of manufacturing directly to start work
instead of following the procedure established in the company?
 Clearly there is a procedure and it is not being followed, why?
 Well there could be many reasons, in section 6.5.4 the sales man makes a choice.
 Because the "start work" form requires the sales director's approval before work can
begin and slows the manufacturing process (or stops it when the director is out of the
office).
 However, there could have been an number of different answers, for example:
 The salesman did not know of the procedure and was following an example learned
from his predecessor in the job.
The majority of work in the area of human error breaks down errors in to 6 types:
 Learning Gap
 Memory Gap
 Inconsistency
 Application
 Omission
 Decisions (also known as violations)
The example answer where the Salesman knew about the form and signature would be an
example of a decision error, a deliberate violation. The example answer where the salesman
did not know the proper procedure would be a Learning Gap.
6.6.3 How To Complete Human Error Focused 5 Whys Investigation
6.6.3.1 Step 1 describe the error

For example:
Shaking was not carried out every 5 minutes as required by the method.
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6.6.3.2 Step 2 – Characterize the Nature Of The Error

Characterize the error in the one of the following 6 categories.
 Learning Gap
 Memory Gap
 Inconsistency
 Application
 Omission
 Decisions (also known as violations)
The age, length of service, training status, complexity of task and operating conditions at
the time are all relevant factors and should be noted as the facts are assembled.
6.6.3.3 Step 3 – Characterize the External Factors Influencing Internal Nature Of The
Error
 Were there actual or perceived increased production demands?

 Was there actual or perceived reduced manpower?
 Was there actual or perceived poor machine performance?
 Was there actual or perceived poor method performance?
 Was there actual or perceived poor ergonomic performance/ Task design?
 Was there actual or perceived poor materials performance?
 Were there actual or perceived changes in staffing?
 Were there actual or perceived changes in the work processes in other
areas?
 Were there actual or perceived changes to the machine?
 Were there actual or perceived changes to the product?
6.6.3.4 Step 4 – Characterize the Internal Factors Influencing Internal Nature Of The
Error
A - Did the individual perceived personal benefit from the migration?
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 Perception that peers support/ expect migrated behaviour.

 Perception that supervisors/ management support/ expect migrated
behaviour.
 Perception that migration aids the team and therefore the individual.
B - Did the individual perceive a low personal risk from the migration?
 Perception that there are no negative consequences to company/ dept.
 Perception that there are no negative consequences from peers.
 Perception that there are no negative consequences from supervisors and
managers.
6.6.3.5 Step 5 – During the analysis Did You Find That Another Individual Made An
Error?
Characterize the error in terms of the 6 classes of Human error and restart the
process for this new branch.
6.6.3.6 Documentation Process
A number of branches will be present as multiple factors will affect an individual's

decision making. Suggest a comprehensive 5 whys layout in excel as the
recording toll.
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6.7 The Fishbone Diagram Technique
6.7.1 Overview of The Fishbone Diagram Technique

The Fishbone diagram technique (also know as the cause and effect diagram and the Ishakawa
diagram techniques) is another powerful tool to use in the search for the root cause of a
problem. Like the 5 Whys technique the tool does not require detailed statistics, but again like
the 5 Whys technique is considered to be powerful enough to include in Six Sigma
methodology. The tool works extremely well in combination with both Kepner Tregoe and 5
Whys techniques and in particular when there is a team involved. The pictorial/ graphical
method of representing the potential causes and effects related to a problem, helps team
members capture and visualize a complex combination of relationships in a simple and efficient
manner. The technique itself is dependent on brainstorming and therefore the process/ system/
people knowledge of the investigation team members is a critical factor in the success of this
technique.
The technique is also particular useful on its own when there is little quantitative data available
and can help generate ideas as to where to look for or how to generate quantitative data to
support the root cause analysis. Using the fishbone diagram can also keep the investigation
team focused on the problem and the investigation process, and avoid the temptation to jump to
conclusions.
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Cause Cause
Detail/ Why Detail/ Why
Problem Statement
Detail/ Why Detail/ Why
Cause Cause
6.7.2 When Should A Fishbone Analysis Be Used?
As stated above the Fishbone diagram tool is works extremely well in combination with both
Kepner Tregoe and 5 Whys techniques and in particular when there is a team involved and little
quantitative data.
In a Kepner Tregoe Root Cause Analysis the Fishbone Diagram technique can be used to
develop the potential Root Causes required in Element 3 (Causes/ Possible Causes). The
Fishbone can be used to identify the potential causes and then be supplemented with the 5
Whys technique to drive down from the potential cause to the contributing factors.
6.7.3 How To Perform A Fishbone Cause and Effect Diagram Focus Analysis
6.7.3.1 Step 1 – The Problem Statement
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Write down the specific problem as a question. Like KT and 5 Whys analyses, an
accurate problem statement is critical to arriving at the true root cause as it
formalizes the problem and it also helps the investigation team focus on the
same problem. Expressing the problem as a 'why' type question will help the
team brainstorm as each root cause idea should answer the question either
singly or in combination with another contributing factor.
The agreed problem statement is placed in a box at the 'head' of the fishbone.
6.7.3.2 Step 2 – Construct The Skeleton
The rest of the fishbone then consists of the spine (one line drawn across the
page) which attaches the problem statement to the bones that branch out from
the spine. These branches are labeled with different root cause categories. The
Root Cause categories that are selected and the number depend on the nature
of the problem being investigated. There are some standard choices that are
suggested in the literature.
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One suggestion is the 6 M’s for manufacturing care of the iSixSigma Magazine
web site (http://www.isixsigma.com).
 Machines (or Equipment)
 Methods (or Instructions/ procedures)
 Materials (or Raw Materials)
 Measurements (or Processes)
 Mother Nature (or Environment)
 Manpower (or People)
Or the 4 P’s for Systems and Services from the same source.
 Policies
 Procedures
 People
 Plant/Technology
6.7.3.3 Step 3 – Add Branch Detail By Brainstorming and Asking Why?
With the skeleton constructed the team should take a branch at a time and
brainstorm to find contributing potential causes and list these down as fine detail
off of the main branches.
For each cause identified, continue to ask 'why does that happen?' as with the 5
Whys technique, until you get to the end answer and attach that information as
another bone off of detail branch. This will drive the process to identify the true
root causes of a problem.
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Cause
Detail
Why Why Why Why Why

? ? ? ? ?
Problem
Statement
6.7.3.4 Step 3 – Validate
With the branches completed with detail and whys, some validation and/ or
prioritization of the potential causes is required to see which match the facts and
have the biggest effect. This may require asking additional staff to review the
diagram and validate the potential root causes in the detail.
6.8 Impact Assessments
6.8.1 Overview of Impact Assessments
A critical element in all investigations is the assessment of the impact of the event under
investigation based on the data available and knowledge of the risks and sensitivities of the
product and the regulatory and Company requirements and guidance's. Impact assessments
guide both our long term preventative measures as well as short term immediate actions.
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As any investigation is an evolving process with more knowledge and understanding being
added over time, Impact Assessments must also be periodically refreshed and updated in the
light of this new information. Given the constant requirement to respond quickly to patient safety
and compliance risks and for the clear documentation of rationale for action/ inaction a formal
process of triggering and documenting impact assessments is required.
However, impact assessments must be considered not only from a risk to the patient
perspective (Product Compliance to the filed specifications and expectations for product purity,
safety, efficacy and identity), Process Compliance to file process parameters, Equipment
Compliance to qualification, reproducibility and performance requirements and final People
Compliance to cGMP and specific job performance requirements.
In addition, the potential impacts in each of these four categories of risk over different time
periods, specifically, the past, the present the near future and the shelf life of the product.
The following section provides a detailed guidance on the responses required for different
possible risks under the four classifications of impacts.
6.8.2 When To Perform Impact Assessments
An impact assessment must be performed by staff competent and knowledgeable of the

processes, the product, the equipment and the applicable regulatory compliance requirements.
Impact assessments should be performed and documented as a minimum at the time of

discovery and at the time of the completion of the investigation into the unexpected incident.
However, during the course of an investigation there will be several opportunities for additional
information to become available that may change the previous impact assessment, for example
see the flow chart below:
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Figure 2 - Impact Assemble

Assessment and Problem
Re-assessment Path Observations
Document Problem
Used With Atypicals Statement
To Ensure Timely Action
With Respect To Product,
Processes and People
Perform Impact
Assessment
Document Impact
Assessment
Assemble Problem
Specification
Notify Operations and
Quality stakeholders Document Problem
of change in Specification
impact assessment
No
Impact Assessment
Document revised impact Still Accurate?
assessment
and actions in an Interim report Yes
Assemble Potential
Root Causes
Act on the revised

Analysis Of Problem
Impact Assessment
Specification Versus
Potential Root
Causes
Document the completion and No

outcome of the action arising from Impact Assessment
the change in interim Impact Still Accurate?
Assessment
Yes
Conclude Root
Cause
No
Impact Assessment
Still Accurate?
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6.8.3 Performing An Impact Assessments, Risk Levels and Response Assessment Tool
Tables 3 and 6 provide a basic tool kit for objective determination of impact with respect to four
broad types of risk:
A - Process Compliance Impact

B - Product Perfromance Impact
C - Equipment Compliance Impact
D - People Compliance Impact
Each of the 4 risk types can be assigned one of 6 severity levels:

5 - Catastrophic
4 – Very Serious
3 - Serious
2 - Important
1 - Negligible
0 – No potential impact
However, there is another dimension to consider the scope of the incident in terms of the time of
discovery, the location of the incident in terms of product and impact of the incident on future
performance. risk to future outcomes need to be considered. As a result some additional
qualifying questions must be asked, these are:
 Does this severity level apply to "The Batches under investigation"?
 Does this severity level apply to "Related batches of a different product?
 Does this severity level apply to " Past production
 Does this severity level apply to " Next Production
 Does this severity level apply to " Over Product shelf Life" "
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Finally, we need to consider the probability of an event, from 100% certain to 0% possibility
(using scores such as 100%, 75%, 50%, 25% or 0%).
When all 4 elements have been considered, by placing a probability score in each of the scope
boxes at each level of severity, it is possible to then use the "Risk Level Key" table (found at the
bottom left sides of tables 3 to 6) to translate the score, scope and severity into a risk ranking of
High, Medium or Low.
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Table 3 - Impact Assessments, Risk Levels and Response Assessment Tool (Risk Type A)
Area of Impact (Consider probability from 100% certain to 0% possibility, score 100%, 75%, 50%, 25% or 0%) Review against risk map. Write
risk level in box (high, medium, low, N/A see guide at bottom of the table)
Location of Risk and Severity
Risk Type Severity of The Batches Related Past Next Over

outcome under batches of production Production Product
investigation. a different shelf Life
product
A. Process Compliance Impact
Any potential permanent impact to patient health as a result of non- 5-

compliance to the filed processes and process parameters of: Catastrophic
Any potential temporary impact to patient health as a result of non- 4 – Very

compliance to the filed processes and process parameters for: Serious
Any potential impact to compliance to the filed critical processes and 3 – Serious
N/A
critical process parameters for:
Any potential impact to compliance to the filed and validated 2 – Important

N/A
processes and filed and validated process parameters for?
Any potential impact to the capability and robustness of the 1 – Negligible

N/A N/A
production and release processes for:
Probability of an undesirable outcome
Severity 100% 75% 50% 25% 0%
5 - Catastrophic High High High High N/A
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4 – Very Serious High High Medium Medium N/A
3 – Serious High Medium Medium Medium N/A
2 – Important Medium Medium Medium Low N/A
1 – Negligible Medium Low Low Low N/A
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Table 4 - Impact Assessments, Risk Levels and Response Assessment Tool (Risk Types B)

product
B. Product Perfromance Impact
Any potential permanent impacts to patient health due to the risks 5-

related to the identity, safety, quality (performance) or purity of: Catastrophic
Any potential temporary impacts to patient health due to the risks 4 – Very
related to the identity, safety, quality (performance) or purity of: Serious
Any potential impact on the conformance to filed specifications and 3 – Serious
N/A
expectations of product safety, quality (performance) or purity for:
Any batches potentially of outside of the regulatory expectations but 2 – Important

N/A N/A
not product safety, quality (performance) or purity specifications for:
Any batches potentially of outside of the release testing process 1 – Negligible
N/A N/A
control limits for:
Severity 100% 75% 50% 25% 0%
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Table 5 - Impact Assessments, Risk Levels and Response Assessment Tool (Risk Type C)

product
C. Equipment Compliance Impact
Any potential permanent impact to patient & operator safety from 5-

N/A
non-compliance equipment operating and use standards during: Catastrophic
Any potential impact to external licenses/ regulations for equipment 4 – Very

N/A
operation due to non-compliance of the equipment to operating and Serious
use standards during:
3 – Serious N/A
Any potential that the equipment was not under a validated or 2 – Important
qualified state or was operating inside of its qualified envelope at N/A
the time of production of:
Any potential that the robustness/ sensitivity of the equipment was 1 – Negligible
N/A N/A
unsuitable for reliable production of :
Severity 100% 75% 50% 25% 0%
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Table 6 - Impact Assessments, Risk Levels and Response Assessment Tool (Risk Type D)

product
D. People Compliance Impact
Any potential permanent impact to patient and operator safety due to 5-

N/A N/A
non-compliance to GMP during the production of: Catastrophic
Any potential temporary impact to patient and operator safety due to 4 – Very
N/A N/A
non-compliance to GMP during the production of: Serious
3 – Serious N/A N/A
Any potential that the person was not/ is not competent to perform 2 – Important
N/A N/A
the task or action at the time of production of:
Any potential that the person was not/ is not qualified/ trained to 1 – Negligible
N/A
perform the task or action at the time of production of:
Severity 100% 75% 50% 25% 0%
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Then using the high, medium low risk ranking scores, the scope and the Risk Type, appropriate
actions and timings can be determined by using table 7;
Table 7 – Corrective Action Required For Risk Scope and Risk Ranking
Risk Assessment
Scope Question High Medium Low
The Batches under Immediate quarantine Immediate quarantine Immediate quarantine

investigation. of batch under of batch under of batch under
investigation investigation investigation
Related batches of a Immediate quarantine Immediate quarantine Immediate quarantine
different product of potentially impacted of potentially impacted of potentially impacted
batches batches batches
Past production Immediate quarantine Immediate quarantine Initiate Local Fact
of impacted lots in of impacted lots in Finding following SOP
Merck Control, Initiate Merck Control, Initiate QUA –DMT-S-004
Fact Finding and Rapid Fact Finding following (potential Class 3 recall
Alert Process following SOP QUA –DMT-S-004 and FDA Field Alert)
SOP QUA –DMT-S-004 (potential Class 2 recall
(potential Class 1 recall and FDA Field Alert)
and FDA Field Alert)
Next Production Halt All Related Halt All Related Develop risk mitigation
Production Activities Production Activities in parallel with
until Risk is mitigated until Risk is mitigated production under
additional supervision
or recovery plan.
Over Product shelf Life Immediate quarantine Initiate Fact Finding Initiate Fact Finding
of impacted lots in following SOP QUA – SOP QUA –DMT-S-004
Merck Control, Initiate DMT-S-004 (potential (potential Class 3 recall
Fact Finding following Class 2 recall and FDA and FDA Field Alert)
SOP QUA –DMT-S-004 Field Alert)
(potential Class 1
recall) FDA Field Alert
6.9 Element 5 - Conclusion
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Summarising and formally closing the root cause analysis is critical. It allows the lead investigator to
review the root cause analysis process and understand what went well and what learning opportunities
can be gained from the investigation. Another critical element of the conclusion is to collect together
and properly document the impacts on the product, process people, data, equipment, material etc. that
arise from the Root Cause Analysis process and findings.
The conclusion therefore must condense the investigation and the findings into a summary that will
allow people not directly involved in the investigation to:
 Understand the events and issues
 Feel confident in the accuracy and completeness of the investigation
 Feel confident in the accuracy and thoroughness of the impact assessment.
 Feel confident in the relevance and appropriateness of the corrective and preventative actions.
6.10 CAPA Guidance and Principles
6.10.1 Corrective Actions
 Corrective actions are reactions to a problem that has already occurred and focused on the
steps to be taken to address the immediate risks identified in the impact assessments
performed through out the investigation cycle.
 As such they are likely to evolve as the investigation progresses however they must always be
formally documented and filed with the investigation report.
 Table 7 provides guidance on the types of corrective actions applicable for the types of impact
assessments that are likely to arise from incident investigations.
 Corrective actions should be documented with the relevant impact assessment and the
responsible parties and completion date or due dates recorded.
6.10.2 Preventative Actions
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 Preventative actions are those actions required to ensure that the underlying root cause of an
incident does not reoccur or the loss repeat. As such they are only possible to determine at the
end of the investigation process when the root cause is known.
 Because they must be based on a deep understanding of both the failure and the process/
product, equipment, person or systems that failed, Preventative Actions require time to develop
and a most effective if developed in a team of knowledgeable stake holders.
 Significant preventative actions require not only time to identify the possible options, but to
qualify them as feasible and to plan their implementation.
 All stakeholders should be engaged in this development and implementation planning process.
 All actions must have an identified assignee and a suggested implementation date.
 It is recognised that the implementation date may change based on resources and priority
changes that occur after the completion of the investigation.
 It is also recognised that the nature of a corrective or preventative action may change as more
data about the technical nature of an action becomes available.
 Cross function Preventative Actions require the approval of all stakeholders and it is the lead
investigators responsibility to obtain this.
 Approving Management are accountable for ensuring that the CAPA principles and guidance's
are observed and adhered and that actions are supportable in the time frame given.
6.10.3 CAPA Development Process
6.10.3.1 Identification
 The identification of the (potential) problem and nonconformity. It is important to

understand the true nature of the problem not the symptoms and clearly describe the
facts.
 The source of problem and nonconformity may come from various sources including
internal audit, external audit, customer complaint, atypical, deviation, events, and etc.
6.10.3.2 Evaluation
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 Conduct a risk assessment to evaluate the magnitude of the problem and potential
impact as described in the section 6.8 Impact Assessments. Types of risk and
severity levels of the problem should be considered during the evaluation.
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Table 8 - Preventative Action Guidance Tools
Severity/ High Frequency (Low Medium Frequency Low Frequency (High

detectability) (Moderate detectability)
Probability of event detectability)
occurring(or Very likely Improbable
detectability) Probable
(i.e. occurs three (i.e. occurs less than
times in 6 month) (i.e. in between Very once a year)
likely and improbable)
High Severity Risk Level 5 Risk Level 4 Risk Level 3

(i.e. failure to meet High Risk High Risk Medium Risk
filed specification and
process, product Significant system System failure No System failure
adulteration/ failure concerns concerns concerns
contamination) Product quality/ Product quality/ Product quality/
regulatory impact regulatory impact regulatory impact
Medium Severity Risk Level 4 Risk Level 3 Risk Level 2
(i.e. outside of High Risk Medium Risk Low Risk
validated process
parameter/ Significant system System failure No system failure
equipment, failure to failure concerns concerns concerns
follow critical Potential product Potential product Potential product
procedure) quality/ regulatory quality/ regulatory quality/ regulatory
impact impact impact
Low Severity Risk Level 3 Risk Level 2 Risk Level 1

(i.e. failure to follow Medium Risk Low Risk Low Risk
internal procedure,
equipment failure do Significant System System failure No system failure
not have product failure concerns concerns concerns
quality impact) No product quality/ No product quality/ No product quality/
regulatory impact regulatory impact regulatory impact
 If it meets the High Severity and High Frequency threshold, production should be
stopped and only can be resumed with the corrective action(s). The risk level 3 and
above would require PA(s). If it is in the Risk Level 2, then there is an evaluation to
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determine whether CAPA is required or not. However, PA for the Risk Level 2 is not
mandatory. If it is in the Low Risk threshold (Risk Level 1), no CAPA is required.
 When evaluating a CAPA, the risk types (process, product, equipment, and people
compliance impact) should be considered.
6.10.3.3 Generation of CAPA
 The person who is assigned the CAPA needs to be part of identifying the CAPA, its
timeline and must ensure its full intent.
 If the Lead Investigator is not the SME for the process/system, then CAPA
development needs to be led by the latter.
 The extent of preventative actions to be taken must be based on risk assessment,

taking into consideration of the following factors:
 The significance to the purity, identity, quality, safety and efficacy of the product
of the underlying root cause and symptoms of a failure, should it re-occur.
 The risk of reoccurrence of the root cause failure (not the symptoms).
 The probability of a single action or correction effectively reducing the probability

of a repeat to negligible levels.
 Preventative actions should be prioritised on the basis for the standard risk
management approach of:
1 - Remove the risk
2 – Substitute the high risk element for a lower one.
3 – Apply engineering controls
4 – Proceduralise and train on preventative human systems.
 When entering the description of the CAPA do not use generic terminology (for
example, "complete as per the above", "update procedure as per investigation", or
"modify equipment as outlined"). Apply the SMART principles when describing the
CAPA – Specific, Measurable, Applicable, Realistic and Tied to Business. Write the
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description so that future reviewers are able to determine the exact intent of the
CAPA. Keep in mind that you are writing for someone else and not yourself.
 CAPAs must be developed with the objective to avoid a repeat of the issue so the
following should be adhered to :
 CAPAs involving SOP updates are to be minimized. It is acceptable where the
system/approach is being changed to make it more robust or if it is to undergo a
major design modification to make it more understandable etc However, updates
to add minor clarifications or details are not, particularly where 99.9% of the time
the task is being done correctly so the SOP detail is not the issue. Updating the
SOP as a CAPA should be justified by the area management (i.e QMS system
owner and Quality Owner).
 Re-training as a CA should be conducted in a timely manner (i.e. before the

closure of the investigation). Re-training as a PA is to be limited unless as a
secondary CAPA. This is particularly the case where a person is completing the
job correctly 99.9% of the time so knowledge is not the issue. However,
atypicals/deviations should be used as learning opportunities (i.e. as part of
PST).
 Preventive Action is aligned to the root cause and it should be clear that there is
a clear link between the problem and root cause and the CAPA.
 When developing a CAPA, it is important to ensure the root cause of problem is

addressed and evaluation and actions will not result in any other adverse effects.
 Preventative actions for issues unrelated to the true root cause should not be
included in the formally tracked CAPA list for an incident unless a failure to do so
could lead to deviation requiring a Risk Level 3 or above investigation.
Contributing factors not related to the true root cause do not require the formally
tracked CAPA.
 Where CAPAs will require significant resources to implement (e.g. a project),

these need to be escalated to management level and agreed as they will have be
balanced versus other priorities based on risk.
 It must be noted that it is not an acceptable Preventative Action to commit to

evaluate options for improvement. However, It is recognised that the most
common failure for root cause analysis is the lack of data relating to the moment
of failure, or the lack of definition or granularity in the available data to adequately
characterise a problem. Therefore for some complex investigations, gathering
more data is required before a true root cause can be determined. As a result it is
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60
acceptable to write a preventative action that commits to the collection of

additional data from a production or testing environment with a clear time frame
and with the stated objective of the collection of expanded data to support the
identification of the true root cause of the problem(s).
 When possible, 'gang' updates to SOPs and training.
6.10.3.4 Implementation
 Given that CAPAs have been chosen for higher risk issues, the target should be to
close as soon as possible so that the risk of repeats is reduced.
 If a CAPA can be implemented within the approval time of the investigation, it should
be done so.
 CAPA timelines have to be appropriate. For a major issue where the incident has
resulted in a higher risk issue that would result in a Major audit observation or
Regulatory non-compliance, the CAPA must be closed within 60 days. As a guide,
CAPA closure should not exceed 90 days unless justified. If CAPA can not be closed
immediately and significant risks exist, interim risk mitigation plan should be
considered.
 When we make a commitment to close a CAPA, we need to deliver on this

commitment. To manage this each group will formally review their CAPAs on a
routine basis to ensure they are closed ahead of the commitment.
o Managers are responsible for ensuring these reviews happen.
o CAPA owners need to target closure times ahead of the committed dates.
o CAPA owners must aim to extend a timeline at least one week in advance of the
original commitment date (in the exceptional case that an extension is required).
o Periodic forum (i.e. monthly stewardship meeting or bi-weekly compliance
meeting) will review the status of closure and extensions to ensure they are only
done when appropriate.
o More than two times of CAPA extension should be escalated to Sr. Management.
 To avoid the vast majority of CAPAs being due for closure at the end of the month
the CAPA closure date should be the same date within the month of closure as the
atypical/deviation occurs. This is to help load level the CAPA closure dates.
o The only exception is when you want to set a shorter timeline to closure (which is
good to do).
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60
o For CAPAs, the due date is to be determined via "Investigation Closure Data +
fixed number of days" method such that they are spread.
 When CAPA is closed, CAPA closure note should be sent to area governance team.
CAPA closure note consists of Issue, CAPA Intent, and Closure.
 CAPA Closure Note example:
ISSUE (Briefly describe the problems/issues)
o Visual inspection failure for HSM post manual intervention and COP parts.
CAPA INTENT (Briefly described the intent of CAPA)
o As an interim action prior to the next HSM cleaning, the HSM technicians who
will complete the cleaning will be briefed on the learning from this atypical,
retrained on the visual inspection SOP and training package used to train the
lead techs and informed that this procedure must be applied for inspections
carried out during the cleaning process. The technicians involved will not
complete manual cleaning of the HSM until they have been retrained on the
cleaning procedure and assessed to be competent to complete the activity. While
the above preventive action is being implemented, final visual inspection (to
confirm equipment surfaces are clean and dry) will continued to be performed by
an independent Lead Technician or Shift Lead or Engineer prior to release of
equipment for production use.
CLOSURE (Briefly describe how the CAPA intent is addressed. Ask ourselves. Have all
of the goals and intents of this CAPA been met? Did the actions correct or prevent
the problem? Have all actions been completed? Will there be any potential adverse
impact as a result of actions taken?)
o The technicians involved in the atypical have been trained by either shift leads or
the operation lead on the visual inspection SOP and training package which was
used previously for training the lead technicians. The training was conducted in
the field explaining the locations of failures involved in the atypical and the
contributing factors leading to the failures. Importance of adhering to the visual
inspection requirements including the right tools and techniques have been
communicated.
6.10.3.5 Follow-Up and Effectiveness Review
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60
 When a repeated event occurs, there should be an analysis of why previous CAPA is
not effective to prevent reoccurrence and underlying process or system problem still
exist.
 Implementation of the CAPA and its effectiveness should be actively monitored until
it is concluded that the issue has been fully addressed. Periodic review on the
effectiveness of CAPA is required to ensure the actions taken were effective.
Periodic review (i.e Monthly Atypical/Deviation review meeting, Proactive Process
Analysis) should review the trend of repeated incidents and progress of actions
items.
7.0 SUMMARY OF CHANGES
Version No Summary of Changes from the previous version

003 Added GDL 8.02 MMD Quality Risk Management in the Reference section.
8.0 APPENDICES
APPENDIX 1 - KT Problem Specification Template

APPENDIX 2 Fish Bone Diagram Templates
APPENDIX 3 – Types of Human Error
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APPENDIX 1
KT Problem Specification Template
Problem Statement Kepner Tregoe – Example Worksheet
Dates Of Investigation Lead Investigator Facilitator
Co Investigators
Problem Specification – Part 1
IS IS NOT
What the problem is? What the problem is not?


IS IS NOT
Where the problem is occurring? Where the problem is not occurring?
When the problem is occurring? When the problem is not occurring (but could)?

IS IS NOT
To what extent the problem is occurring? To what extent the problem is not occurring (but could)?

60
APPENDIX 2
Fish Bone Diagram Templates
Machines (or Equipment) Materials (or Raw Materials) Measurements (or Processes)
Manpower (or People)

Methods (or Instructions/ procedures) Mother Nature (or Environment)

APPENDIX 2 - Fish Bone Diagram Templates
Policies Procedures
People Plant/Technology

Appendix 3 - Types of Human Error

Learning Gap
o Errors made by amateurs, new employee, new equipment, changed procedure.
o Questions
o How new is the person involved?
o How many times have they performed the task ?
o Were they properly trained in the execution of the task?
o Has there been a recent change in equipment, procedures, process or personnel?
o Memory Gap
o Seldom used process or long and complex sequence that is difficult to remember.
o How many steps are there in the process?
o When was the last time the person successfully completed the task?
o Are easy to follow instruction to hand when the task was executed? available?
o Does the person use any aids to help them remember the sequence of events and other critical and important points about the task?
o Inconsistency
o Processes and procedure not standardized, require individual adaptation of the methods.
o Instructions not documented, process sequence/ layout does not match training and instructions.
o Application
o Task requires switching of attention between too many activities so wrong techniques applied to a task.
o Who does what not clear. Job aids are wrong but it is not apparent to the person or person executing the task
o Edits are not highlighted in a document and do not get checked before release.
o Underestimation of potential error in task design.
o Omission
o Forgetfulness leading to informal error prone memory aids such as post it notes, scrap paper, emphasis signs. Second person check
missed or not done on time (from the second person perspective)
o First person did the second person check unknowingly . Task not started on time or in right sequence.
o Decisions (also known as violations)
o Decision made is not in line with approved procedures (and the procedure is known and available)
o Decision made is subjective and inconsistent with documented expectations and agreements.
o Situation is misjudged due to insufficient attention or time given to the decision making.
o Jumping to conclusions before one is familiar with the situation
DOCUMENT APPROVALS
Document ID: 0901435082adf727
Document Name: QUA-DMT-G-001 GUIDELINE FOR ROOT CAUSE ANALYSIS INVESTIGATIONS
Server Date Signed by Outcome

26-Sep-2012 23:42 GMT-0400 Chen,Siang Ling Belinda Approve
Reason for Signature Approval, Authorization
27-Sep-2012 03:45 GMT-0400 Chin,Hui Yee Approve

Reason for Signature Quality approval
Reason for Signature

Qua-Dmt-G-001 Guideline For Root Cause Analysis Investigations

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EFFECTIVE DATE: 04-OCT-2012 GMT-0400

DOCUMENT PRINTED ON 05-JUN-2015

STANDARD OPERATING PROCEDURE PAGE NO. 1 of 60

SOP NO. SOP TITLE Version

Prepared by : Choi Byung Kook

STANDARD OPERATING PROCEDURE PAGE NO. 2 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

6.1 Real Time Problem Solving/ A3 Problem Solving

6.1.1 Real Time Problem Solving/ A3 Problem Solving Introduction

The A3 or RTPS methodology is a standardized methodology developed as part of the Toyota

STANDARD OPERATING PROCEDURE PAGE NO. 3 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

Identify Problem Identify Problem

Observe the problem Observe the problem

Record the problem on the A3 sheet Record Problem in batch Sheet

Assess Immediate Impact

Apply immediate corrective actions if required.

Raise Event/ Atypical and record relevant data

Notify Quality (if not a lab deviation)

Log in formal GMP tracking and trending system

Assign Investigation Resources Assign Investigation Resources

Re-assess Immediate Impact

Apply immediate corrective actions if required.

STANDARD OPERATING PROCEDURE PAGE NO. 4 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

Perform Root Cause Analysis Perform Root Cause Analysis

Re-assess Immediate Impact and act if necessary

Propose Countermeasures Identify Preventative and further corrective measures

Re-assess Immediate Impact and act if necessary

Write up and seek approval and closure of investigation

Implementation Plan Track CAPA Closure

Check results/ effectiveness of counter Check for repeat atypicals.

Future Improvement plans

6.1.2 When Should The A3 Process Be Used?

6.1.3 How To Complete An RTPS or A3 Problem Solving Exercise.

STANDARD OPERATING PROCEDURE PAGE NO. 5 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

 Whether and event or atypical was raised.

6.2 Roles and Responsibilities For Investigations

6.2.1 Collective Expectations For Best Practice Investigations

STANDARD OPERATING PROCEDURE PAGE NO. 6 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

 It is an expectation that all stakeholders understand that the goal of an investigation is to

 It is not an expectation that the quality of an investigation be judged by:

6.2.2 Roles and Responsibilities/ Accountabilities

6.2.2.1 Lead investigator Responsibilities

STANDARD OPERATING PROCEDURE PAGE NO. 7 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

 It is the responsibility of the assigned investigators and assessors to use logical

 It is the responsibility of the lead investigator to ensure that appropriate corrective

 It is the responsibility of the lead investigator to identify/ develop preventative actions

6.2.2.2 Contributing Investigators

 It is the responsibility of the contributing investigators to contribute to and be familiar

STANDARD OPERATING PROCEDURE PAGE NO. 8 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

 It is the responsibility of the contributing investigators to use logical analytical thought

 It is the responsibility of the contributing investigators to familiar with and competent

 It is the responsibility of the contributing investigators to provide input into the

 It is the responsibility of the contributing investigators to provide input into the

 It is the responsibility of the contributing investigators assist in the development of

STANDARD OPERATING PROCEDURE PAGE NO. 9 of

QUA-DMT-G-001 Guideline For Root Cause Analysis Investigations 003

6.2.2.3 Investigator's Line Management