Palestra: Quality of Investigations: Reliable Supply
Chain, Manufacturing Deviations and the Human Factor
Luciana Mansolelli
Group Compliance and Audit
Group Quality Assurance
Novartis Pharmaceuticals Corporation
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Some of the information contained in this presentation is confidential. Accordingly,
Novartis respectfully requests confidential treatment with respect to this
presentation and any related materials under the U.S Freedom of Information Act.
Further, if any person (including any governmental employee) should request the
opportunity to inspect, copy or otherwise obtain Novartis confidential information,
Novartis requests that it be immediately notified of any such request, furnished with
a copy of all written materials pertaining to such request (including the request
itself) and given advance notice of any intended release so that it may, if deemed
necessary or appropriate, pursue available remedies.
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Quality of Investigations
Objectives
 Process and requirements for handling deviations and Out of
Specification Test Results.
 Productive strategy meetings
• Driving logical thinking
• Operate in a team environment
• Drive toward agreements and conclusions.
 Soft data and hard data.
 Effective and efficient techniques for data collection
 Evaluation of data - techniques to analyze and challenge conclusions in
order to correctly identify the root cause(s).
 Human Error as a root cause.
 Appropriate corrective and/or preventive actions.
 Investigation report.
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Why is it important to improve the quality of
Investigations?
William Edwards Deming
 Patient Risk
 Compliance
• Health Authority Requirement
• Continual Quality Improvement
• Effectiveness
- Eliminate recurrence – (focus on deviation reduction)
• Identify root cause/most probable cause
• Identify adequate/appropriate Corrective and Preventive
Actions
 Efficiency
 Economics
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Quality of Investigations
Health Authority Requirements (examples)
 ANVISA RDC 17 of 16.04.2010 Chapter V
Art. 26. All complaints and other information related to products with
possible deviations in quality should be carefully investigated and
recorded in accordance with written procedures.
Sole paragraph. Preventive and corrective actions should be taken
when quality deviation is proved.
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Quality of Investigations
 21CFR - Part 211 (Section 211.192)
• “Any unexplained discrepancy (including a percentage of theoretical
yield exceeding the maximum or minimum percentages established
in master production and control records) or the failure of a batch or
any of its components to meets any of its specifications shall be
thoroughly investigated, whether or not the batch has already been
distributed. The investigation shall extend to other batches of the
same drug product and other drug products that may be associated
with the specific failure or discrepancy. A written record of the
investigation shall be made and shall include the conclusions and
follow-up.”
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Quality of Investigations
 21CFR - Part 820 - Quality System Regulation
Subpart I - Control of nonconforming product.
“Each manufacturer shall establish and maintain procedures to
control product that does not conform to specified requirements. The
procedures shall address the identification, documentation,
evaluation, segregation, and disposition of nonconforming product.
The evaluation of nonconformance shall include a determination of
the need for an investigation and notification of the persons or
organizations responsible for the nonconformance. The evaluation
and any investigation shall be documented.”
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Quality of Investigations
 Guidance for Industry: Investigating Out of
Specification (OOS) Test Results for Pharmaceutical
Production, 2006
• “FDA Regulations require that an investigation be conducted
whenever an OOS test result is obtained (211.192). ………Even
if the batch is rejected based on the OOS result, the
investigation is necessary to determine if a result is associated
with other batches of the same drug product or other products.
Batch rejection does not negate the need to perform an
investigation. The regulations require that a written record of the
investigation be made, including conclusions and follow-up
(211.192).”
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Quality of Investigations
 EU Guide to Good Manufacturing Practice for Medicinal
Products - Chapter 6 Section 6.5
• “Written procedures should be established and followed for
investigating critical deviations or the failure of a batch of intermediate
or API to meet specifications. The investigation should extend to other
batches that may have been associated with the specific failure or
deviation.”
 ISO 9001:2000 – Section 8.3 “Control of Nonconforming
Product”
• “The organization shall deal with nonconforming product by one or
more of the following ways
- by taking action to eliminate the detected nonconformity;
- by authorizing its use, release or acceptance under concession by a
relevant authority and, where applicable, by the customer;
- by taking action to preclude its original intended use or application.”
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Quality of Investigations
 ISO 13485:2003 Section 8.5.3 “Preventive Action”
• “The organization shall determine action to eliminate the causes of
potential nonconformities in order to prevent occurrence.
Preventive action shall be appropriate to the effects of the potential
problems.
• A documented procedure shall be established to define the
requirements for:
- by taking action to eliminate the detected nonconformity;
- by authorizing its use, release or acceptance under concession by a
relevant authority and, where applicable, by the customer;
- by taking action to preclude its original intended use or application.”
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Quality of Investigations
Question: How do the regulations differ?
They don’t………………
 The requirements, expectations are the same, only worded differently.
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Quality of Investigations
There is an expectation:
 Action
• To investigate deviations from procedures, process, etc.
 Demonstrate “due diligence”
• Dig “deep” enough
• Ensure an understanding as to why the “event” occurred and how to
prevent recurrence
• Identify the root cause or most probable cause
• Identify, implement and monitor effectiveness of corrective and preventive
actions
 Quality Oversight
 Notification to Quality in a timely manner
• When to notify, how to notify, what information to document
• Appropriate Site Management/Quality...... review and approval
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Quality of Investigations
Definitions
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Quality of Investigations
Definitions (1/3)
 Deviation: Unplanned departure from an approved instruction or




established standard or an unexpected observation.
Nonconformity: Non-fulfillment of a requirement.
Out-of-Expectation Results (OOE): A test result that falls outside
historical, expected or previous trends/limits.
Out-of-Specification Results (OOS): A test result that does not meet
established specifications or acceptance criteria. In stability testing the test
result does not meet shelf life specifications.
Out of Trend (OOT): A stability result that does not follow the expected
trend, either in comparison with other stability batches or with respect to
previous results collected during the stability study.
 Human Errors are errors or mistakes caused by humans in the GMP
environment or which may have effect on GMP. Errors and mistakes might or
might not lead to a GMP related incident.
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Quality of Investigations
Definitions (2/3)
 Incident is an event that may adversely affect the quality, safety,
identity, strength, purity, availability (supply) or efficacy of a
commercial product or clinical trial material and/or may compromise
the Novartis Quality System and the global Novartis reputation. Any
such incidents must be brought to the attention of the management
through a system of sequential or concurrent notifications.
 Unintentional errors against approved and communicated norms.
The action (or lack of action) can be accidental or caused by lack of
correct knowledge or be a consequence of incorrect knowledge. This
category also includes situations where the approved norms were
communicated but for some reason the individual was not aware or
capable of properly executing the process or using the machine (for
example not understanding the training, disturbing environment or
complicated interface).
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Quality of Investigations
Definitions (3/3)
 Intentional mistakes (misconduct) require conscious decision (fault)
of acting against approved and communicated norms which the
individual had or should have had knowledge of. The mistakes can be
active or passive, including situations where the individual should
have known the right procedures or use of the machine/device but
didn't understand the consequences of their actions or negligence.
Mistake can be caused by misjudgment, carelessness, or
forgetfulness. This category also includes covering-up unintentional
errors.
 Enforced misconducts are when individual is ordered, forced or
otherwise pressured against individuals will to act against approved
and communicated norms.
 Hypothesis is an idea or theory that is not proven but leads to further
study or discussion.
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Quality of Investigations
The Overall Process
Event Occurs
Root Cause/
ID CA/PA
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Notify
SQU/Area
Management
Complete
Investigation
SQU
Classify/Assign
Investigation
Review &
Approval
Investigate
CA/PA
Implemented
CA/PA
Effectiveness
Quality of Investigations
The Investigation – Key points to consider
 The investigation process is a simple process.
 It consists of:
• Evaluate situation
• Collect and evaluate information
• Draw a conclusion
• Compare information
• Revisit conclusion
• Challenge conclusion
• Challenge outcome
• Re-evaluate, etc.
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Quality of Investigations
Key points to consider
Key Steps………
A.
STOP!!!!
B. Assess/Evaluate
C. Determine Next Steps
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Quality of Investigations
Key points to consider
You also stop because……
 Allows for a “preservation” of the “scene.”
•
•
•
•
•
•
•
•
Documents (Batch Records, Data Sheets, etc.)
Equipment/instruments
Glassware
Materials/Excipients
Reagents
Sample
Standard and sample solutions
Anything related to the activity
 Note: It is critical that all solutions, glassware,
etc. everything used in the process/analysis
are retained.
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Quality of Investigations
Key points to consider
 Considering Laboratory OOS investigations
• Level 1 – Preliminary Investigation
- Allows for the elimination of obvious errors, i.e., Laboratory Assigned Cause
- MUST be completed with 5 working days from discovery
• Level 2 – Full Scale Investigation (Quality Oversight required)
- Notification to Quality and Manufacturing
- MUST be completed within 30 calendar days
 Important to remember
• Cannot perform investigational testing, such as retests in Phase 1.
• Those activities are performed in a Phase II Investigation activity and typically
require an approved plan/protocol.
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Quality of Investigations
Strategy Meetings – Critical Success Factors
 Problem statement – clearly define the issue (DEVIATION)
 Team Membership - who should participate
• R & D, Laboratory, Operations, Technical Services, Quality Assurance,
Engineering, Others?
• Appropriate technical experience
• Availability
 Scope of the meeting must be communicated in advance
• At this stage actions should be towards Data collection and Analysis
 Share all relevant background information
• Results in a more effective meetings by giving the attendees the opportunity
to be prepared
 Facilitation of the meeting to enable productive problem solving
analysis
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Quality of Investigations
Data Collection & Analysis
 In order to determine if the conclusion is appropriate, we
must first review the objective evidence (data) that supports
the conclusion.
Data Collection and Analysis
Objective & Subjective
Hard information
(data/facts)
Soft Information
(no data)
Hard plus Soft plus Experience = Judgment
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Quality of Investigations
Data Collection & Analysis
Fact versus Theory
Facts
• Can be measured or photographed
Judgments, Opinions, Assumptions are not facts!
Exception: Eye Witness Reports
Example: too much, insufficient, poor …
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Quality of Investigations
Data Collection & Analysis
 Manufacturing Records (examples)
• Batch records
• Applicable SOPs
• Equipment records
• Temperature Charts , etc.
• Training Records
• Other?
 Laboratory Records (examples)
• Notebook pages/data sheets
• Test Methods
• Applicable SOPs
• Sample Receipt
•
•
•
•
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−
−
What do I look at?
Sample characteristics
Chromatograms, data printouts,
temperature charts, etc.
Training Records
Equipment/Instrument Records
Other?
Quality of Investigations
Data Collection & Analysis
An interview is so important to an investigation as it may:
 Provide information that has not been recorded in the
notification to Quality or
 Add clarity to what was recorded
 Eye Witness..................
 Provide historical data or information
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Quality of Investigations
Documentation of Investigation Activities
• Capture all information
• Be Accurate
• Document every step of your
investigation.
Ensure there is no “testing into
compliance”……….
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Root Cause Analysis
Overview
 Basic Problem Solving Tools
• Quality Control Tools: Run Chart, Pareto
Chart, Control Chart, Flowchart, Cause and
Effect Diagram, Process Mapping
• Creativity Tools: Brainstorming, Picture and
Word Associations
• Management and Planning Tools: Affinity
and Tree Diagram
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Root Cause Analysis
Brainstorming
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Root Cause Analysis
Process Mapping
 Process Map
• A method for displaying processes that illustrates
how a product or transaction is processed
• It is a visual representation of the work flow either
within a process or an image of the whole operation
• Comprises a stream of activities that transforms a
well defined input or set of inputs into a predefined
set of outputs
 Process mapping is useful in instances when there
is a need to evaluate multiple processes, and in
instances of a parallel evaluation of an analytical
test method and a batch record.
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Root Cause Analysis
Process Mapping – Visual Mapping – Example 1
 Process Mapping - Test Method (word document)
• Buffer Solution: Transfer 3.48g of K2HPO4 into a 1000mL volumetric
flask, dissolve, dilute with HPLC grade water to volume and mix. Filter
through 0.45um PTFE filter prior to use.
Transfer 3.48g to
1000mL volumetric
Dilute to volume
with HPLC water
Filter using 0.45um
PTFE filter
• 10 mol/l KOH Solution: Weigh 56.1 of KOH pellets into 100mL
volumetric flask, add 70 mL of water and shake to dissolve. Use flowing
water to prevent solution from heating. Fill flask to mark with water and
shake. Filter solution with 0.45um PTFE filter.
Weigh 56.1 KOH into
100mL volumetric, add
Water…mix
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Use flowing water,
to prevent heating
Filter using 0.45um
PTFE filter
Root Cause Analysis
Process Mapping – Visual Mapping – Example 2
Air
Dispensing
Fluidized
Bed Dryer
Sieving
Scale
Granulation
Magnesium
Stearate
Air
Blending
Sieving
Tableting
Packaging
Coating
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Root Cause Analysis
Root Cause Analysis – Cause & Effect
 What is a Fishbone diagram?
• Invented by Dr. Kaoru Ishikawa
• It is an analysis tool that provides systematic way of looking at effects
and the causes that may create or contribute to those effects
• Creates a picture of the possible causes of the problem
• Prevents the team from jumping to conclusions without evaluating and
challenging the possible causes
• Helps to build support for the identified corrective and preventive action(s)
that will address the problem
 When should it be used? When the “team” :
• Needs to study a problem and determine the cause
• Needs to study all possible reasons why a process is beginning to have
difficulties, problems or breakdowns
• Needs to identify areas for data collection
• Wants to study why a process is not performing properly or producing the
desired results
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Root Cause Analysis
Cause & Effect – Site Example
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Root Cause Analysis
5 Whys
Why?
Answer and observation
Why was Zone A contaminated by Staph. Aureus?
Because operator caused contamination
Why did operator cause contamination?
Because operator was not present during training
regarding plant hygiene
Why was operator not present during training?
Because operator was on vacation
Why was there no training follow up when he
returned from vacation?
Because there is no procedure defined for follow
up of missed trainings
Why was there no procedure defined for follow up
of missed trainings?
The SOP was not updated to align with the
requirement
Why was SOP not updated according to
requirement?
Because there is not process established to
ensure that all local SOPs are updated to align
with new or updated Global SOPs
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Root Cause Analysis
Other Tools
 The qualitative tools we have just discussed are examples of those
most commonly used when performing root cause analysis
 There are other “Problem Solving” tools as well.
 For example:
 Failure Mode and Effects Analysis (FMEA)
 Interrelationship Diagrams
 Map out relationships between all possible causes
 Kepner Tregoe (KT)
 Others?
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Root Cause Analysis
Kepner Tregoe Basics
KT Matrix - Helpful Questions
IS
IS NOT
WHAT
• What thing or group of things
is having the problem?
• What is wrong with it or them?
• What thing or group of things could be having
the problem, but is not.
• What could be wrong with it or them but is not?
WHERE
• Where geographically, is the
thing when the problem is
noticed?.
• Where is the problem located
on the thing?
• Where could the thing be when the problem is
noticed but is not?
• Where could the problem be located on the
thing but is not?.
• When was the problem first
noticed? (date / time)
• When has the problem been
noticed since the? (date/ time)
Any pattern?
• When, in the history or
lifecycle of the thing, was the
problem first noticed?
• When could the problem have been first
noticed, but was not? (date / time).
• When could the problem have been noticed
since then, but was not? (date / time).
• When, in the history or lifecycle of the thing,
could the problem have been first noticed but
was not?
• How many units of the thing
have the problem?
• What is the size of a single
defect?
• How many flaws or defects
are on any one unit?
• What is the trend (in object, in
defect)?
• How many units of the thing could have the
problem, but do not?
• What other size could the defect be, but is not?
• How many flaws or defects could be on any
one unit but are not? What could the trend be
but is not?
What IS the
deviation ?
WHEN
EXTENT
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Distinctions
Changes
What could be
the deviation,
but IS NOT ?
Quality of Investigations
Root Cause Analysis
Decision Making
Gather
additional
data
Eliminate
unreasonable
causes
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Continue to
search for root
causes until
possibilities are
exhausted!
Identify new
potential causes
Compare causes
against the facts
Quality of Investigations
Root Cause Analysis seeks to identify the CAUSE of the deviation
 There are generally three types of causes:
 Physical - Tangible, material items failed in some way (for example, an
equipment failure occurs).
 Human - People do something incorrectly, or did not doing something
that was required. Human error typically leads to physical causes (for
example, no one checked the fluid level, which led to the failure).
 Organizational - A system, process, or procedure is faulty (for example,
no one person was responsible for maintenance, and everyone assumed
someone else had performed the required maintenance).
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Quality of Investigations
Human Factor
 Human error is typically not the root cause
 Human errors are symptoms of deeper causes (symptom versus
the disease)
 We must perform in depth investigations to determine the cause of
the “Human Error”
• Interviewing is the most critical step in the investigation
 Key points to consider:
 Poor design of facility and/or equipment
 Inadequate procedures and processes
 Ineffective training
 Inadequate supervision
 Inadequate staff and resources
 Ineffective communication
 Roles and responsibilities not clearly defined
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Quality of Investigations
Contributing factors of Human Error
• Processes
- Inadequate checks,
verification, control
- Change in process
- Lack of robust design
- Not user tested
- No user centered design
• People
- Fatigue
- Lack or loss of focus
- Stress
- Automatism
- Superman syndrome (It
won’t happen to me)
- Not understanding the
impact of their actions
- State of mind
- Ignore a suspected issue
- Disregards established
procedures
- Circumvents the process
(workarounds)
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• Organization
- Training
- Right people in the right
roles
- Peer Pressure
- Proper Resourcing
• Governance / Metrics
- Speed is more important
than right
- Quantity over Quality
- Performance Pressures
- Unclear accountability and
responsibility
- Deadlines
- Budget
- Unclear / insufficient
communication
• Procedures
- Unclear Instructions
- Procedure doesn’t match
the process
- Overly complicated
- No user-centered design
• Tools
- Improper tools and
equipment
- Unnecessarily complex
• Physical
Environment
-
Noise
Climate
Lighting
Interruptions & Distractions
Workspace design
- Cleanliness / Order
• Product
Quality of Investigations
Human Factor
 Stepwise approach for Human Factor investigations:
• Detection of potential HFs including evaluation
 Skill Based Errors
 Rule Based Errors
 Knowledge Based Errors
•
Investigation leading to identifying most probable root cause
and contributing factors.




Individual
Environmental
Process/interface
Non Human Factors
• Consequences including CAPAs and disciplinary or
administrative actions
• Follow-up
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Quality of Investigations
Human Factor
 Key elements of an Error Free Workplace:
 Speak up about errors
 What behaviors are we driving (and how) that increase
human error?
 Strive for perfection in order to achieve excellence
 Eliminate repeat human errors
 Personally recognize and reward success
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Corrective and Preventive Action
Introduction
 Effective Corrective & Preventive Action
(CAPA) and remediation management
of quality, compliance and risk related
issues is essential for a closed loop,
continuous improvement process.
Root Cause
Identified
Effectiveness
Check
 Relying on stand-alone solutions or
paper-based processes to manage
CAPA and remediation processes may
fail to address systemic problems due
to limited reach and visibility.
CAPA
Identified
Continuous
Improvement
Impact
Assessed
CAPA Verified
CAPA
Implemented
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Quality of Investigations
Definitions
 Correction/Remedial Action – Actions taken to eliminate the
existing nonconformity
 Corrective Action - An action taken to eliminate the cause
of an existing deviation, non-conformity, defect, or other
undesirable situation in order to prevent recurrence.
(REACTIVE)
 Preventive Action – An action taken to detect and eliminate
the causes of potential deviations, non-conformity or defect
in order to prevent occurrence. (PROACTIVE)
• Preventive actions are actions to reduce the probability that a
potential problem will occur.
 Effectiveness Check – An action taken to verify that the
expected results are achieved I.e., that the corrective and or
preventive actions prevent occurrence or recurrence of
the event. (Has the root cause of the problem been solved?)
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Quality of Investigations
The Investigation Package
 What does it look like?
• Must be a “stand alone” document
• A “Table of Contents” is a bonus!
 What is the expectation?
• All relevant documentation must be included
and/or referenced as to its location
 The Report
• Must be clear and concise
• Contain all supporting Documentation
•
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Raw Data
Analytical Test Methods
Metrics/Charts
Batch Records
Maintenance/Calibration Records
Training Records, etc.
Quality of Investigations
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