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A Systems Approach to Root Cause Analysis and CAPA Investigations

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 A Systems Approach to
Root Cause Analysis and CAPA Investigations
Ronald D. Snee, PhD
Snee Associates, LLC

IVT Laboratory Week

Philadelphia, PA
December 4-6, 2017
1

Ron Snee, PhD is Founder of Snee Associates,
LLC, a firm dedicated to the successful
implementation of process and organizational
improvement initiatives. He provides guidance to
pharmaceutical and biotech senior executives in
their pursuit of improved business performance
using Quality by Design, Lean Six Sigma and
other improvement approaches that produce
bottom line results.
He has authored several articles on how to
successfully implement QbD, coauthored 3 books
on QbD tools and speaks regularly at
pharmaceutical and biotech conferences.
2
About the Speaker …..
He is also an Adjunct Professor in the
pharmaceutical programs at Temple and Rutgers
Universities. He worked at DuPont for 24 years prior
to starting his consulting career.
Ron received his BA from Washington and
Jefferson College and MS and PhD degrees from
Rutgers University. He is an academician in the
International Academy for Quality and Fellow of the
American Society of Quality, American Statistical
Association, and American Association for the
Advancement of Science.
Ron is an Honorary Member of ASQ and has been
awarded ASQ’s Shewhart, Grant and Distinguished
Service Medals, and ASA’s Deming Lecture, Dixon
Consulting and Gerald J. Hahn Quality and
Productivity Achievement Awards.
He is a frequent speaker and has published 6 books
and more than 300 papers in the fields of quality,
performance improvement, management, and
statistics. He recently received the Institute of
Validation Technology’s Speaker of the Year Award.
 Abstract
Problem solving is critical to successfully maintaining and improving
pharmaceutical and biotech processes. Processes are dynamic and
as predicted by the 2nd law of thermodynamics will deteriorate over
time if left alone. Federal Regulation Title 21 requires that an
organization’s quality system include a process for Corrective and
Preventive Action (CAPA). Central to an effective CAPA system is the
identification of root causes of problems. Systematic approaches for
problem solutions have been called for but few have appeared.
Problem solutions tend to be handled individually. The frequent
result is root causes are not identified and the problems reoccur.
A systematic approach based on process and systems thinking and
the DMAIC problem solving and improvement framework is
presented, discussed and illustrated. The focus is on getting to root
cause and putting permanent fixes in place so that he problems do
not occur again. The concepts and methods involved illustrated with
pharmaceutical and biotech case studies and examples.

3 
 Agenda
 What is Root Cause Analysis?
 Current Approaches: Strengths, Limitations and Tools
 Systematic approach – Roadmap and Tools
 Use of DMAIC Problem Solving Framework - Define,
Measure, Analyze, Improve and Control
 Integrating Corrective Action and Prevention
 Sustaining the Elimination of Root Cause
 Importance of Management Review (Secret Sauce)
 Systematic Approach for Deviation Reduction
 Summary and Conclusions

4
QMS, CAPA, Problem Solving and Root Cause

Quality Management System CAPA is Part of QMS

 Process performance and  Problem Solving (Reactive)
product quality monitoring  Corrective and
system Preventive Action
 Corrective action and  Improvement (Proactive)
preventive action (CAPA)  Preventive Action
system
 Change management Root Cause Analysis is Essential
system to Successful
 Management review of  CAPA Projects
process performance and
 Successful problem solving and
product quality
process improvement

5
 What is a Root Cause Analysis (RCA)?
 Root cause analysis aim is to
 Improve products or processes
 Get to the bottom of a problem or unexpected event by:
 Identify the factors that produced the problem
 Determine what behaviors, actions, and conditions need to be changed; to
prevent recurrence

 Steps in a root cause analysis are:

 Describe the problem (Define)
 Gather data associated with the problem (Measure)
 Identify potential causes for the problem (Analyze)
 Identify and implement solutions to correct problem and prevent
reoccurrence (Improve)
 Monitor changes to ensure problem stays fixed (Control)

Systematic Approach
Is Needed for Root Cause Analysis to Be Effective
6
 Identifying Root Causes
Digging Deeper than the Symptoms

7
 Some Sources of Needs for CAPA and RCA

 Out-of-spec (OOS) product

 Deviations
 Adverse trends (OOT)
 Customer Complaints
 Audits and Inspections – Internal and External
 Adverse events
 Raw material inspections

Need for CAPA and Root Cause Analysis Goes

Beyond Out-of-Spec Product

8
Corrective and Preventive Action Required by
Code of Federal Regulations – Title 21
Example # 1: Citation
“Your firm failed to establish, maintain, and implement a
corrective and preventive action procedure, as required by
820.100(a). For example,
– Your firm has no CAPA procedures as defined in the QS
regulation including: failure investigation, procedures to
analyze quality data…procedures to verify/validate
corrections, procedures that ensure that information related
to quality problems is disseminated and for submitting
relevant information on identified quality problems to
management for review.”

K. Lewandowski-Walker. FDA Office of Regulatory Affairs (2012)

9
 Example #2 Warning Letter

Citation
“The procedures addressing verification or validation of
corrective and preventive actions were not implemented as
required
by 21 CFR 820.100(a)(4). Specifically,– CAPA Procedure 100-
0025, Rev 4, requires documentation of verification and
validation, but this was not completed for CAPA #0225.”

K. Lewandowski-Walker. FDA Office of Regulatory Affairs (2012)

10
 Example #3 Warning Letter
Citation
“Failure to implement procedures addressing documentation of
corrective and preventive action activities as required by 21 CFR
820.100(b). Specifically: – The Corrective and Preventive Action
procedure (GP.1401, Ver. 6.0) establishes requirements to (i.) " ***
Design and implement corrective or preventive action, including
verification or validation that such action does not adversely affect the
finished device or system" and (ii.) "Demonstrate and document the
effectiveness of corrective and/or preventive action(s)." The procedure
also states, (iii.) "The corrective action and preventive action changes
shall follow design, process, or Quality System change process
requirements.“ However, the validation of patient management
recommendations (implemented in CAPA 644 as part of the lead
fracture corrective action and October 15, 2007, recall) was not
reviewed and documented appropriately.”

K. Lewandowski-Walker. FDA Office of Regulatory Affairs (2012)

11
 General Principles
 Root cause analysis must be performed systematically to be effective
 There can be several tools involved in a root cause analysis.
 Teamwork is typically required.
 There may be more than one root cause for a problem
 Root cause analysis must define cause and effect relationships
Y=f(X)
 Prioritization is needed so most important problems are addressed
 Problem definition is critical and can define identified causes
 Process view is needed
 Several problems can be associated with the same process
 Solution effectiveness, cost and simplicity are important concerns
 Root cause analysis can help transform culture: “passive” to “active”
 Changes due to root cause analysis will be a threat to many
 Culture change is often met with resistance.

12
 Limitations and Realities
 The quality of RCA is dependent on
 Accuracy of the input data
 Team capability to identify and implement solutions
 Focus is on one problem when the issue is more complex.
 Team dynamics and behaviors can be a barrier to success
 Atmosphere of trust, openness, and honesty is critical to
encourage sharing of process knowledge, data and experiences.
 Problems need to be prioritized so the
 Most important problems are addressed
 Resources are used most effectively
 Planning is critical so that the team has adequate resources,
time, and feedback to carry out its task effectively.

13
 Some Tools for Root Cause Analysis

 Problem Solving Framework  Summary Statistics

 Plan-Do-Check-Act  Average
 8D  Standard Deviation
 Seven Step Process  Graphics
 Kepner-Tregoe  Histogram
 DMAIC  Run Chart
 Cause and Effect Diagram  Control Chart

 5 Whys  Statistical Tools

 Pareto Analysis  t-test
 Analysis of Variance
 Failure Modes and Effects
 Design of Experiments
Analysis (FMEA)

How Do We Know What Tool to Use When?

14
 CAPA and Statistical Analysis

“FDA emphasizes that the appropriate statistical tools must be

employed when it is necessary to utilize statistical
methodology.
FDA has seen far too often the misuse of statistics by
manufacturers in an effort to minimize instead of address the
problem. Such misuse of statistics would be a violation of this
section.”
61 Fed. Reg. at 52633-52634, Comment 159

K. Lewandowski-Walker. FDA Office of Regulatory Affairs (2012)

15
 People Methods Measurement
Measurements Material Personnel
Generic
Root Cause
Categories
Problem

Environment Methods Machines

Materials Machines Environment

 People – Anyone involved in the process

 Methods – How process is performed – SOPs, etc
 Machines – Any equipment, information tech, tools
 Materials – Parts, components, ingredients. etc
 Measurements – Test methods and data generated
 Environment – Ambient conditions and organizational culture
16
 Some Possible Root Causes
Categories
 Design
 Manufacturing
 Supervision and Management
 Change Control
 Purchasing/Supplier
 Quality Testing
 Documentation
 Maintenance
 Training – Often a Symptom
 Employee Performance
 Equipment
 Work Environment
 Procedures and SOPs
 Materials
Process, Science and Engineering
17
Frequent Causes
“The Usual Suspects”
 Raw Material Variation
 Equipment Differences
 Tablet presses
 Bioreactors
 Test instruments
 Human Intervention
 Operating teams
 Lab Analysts
 Production lines
 Day of Week
 Production Shift
Always Consider Underlying
Knowledge
 Some Symptoms ---- Not Root Causes

 Lack of training
 Human error
 Procedures not followed
 Equipment malfunction
 Poor performance
 Process/Method not validated
 Multiple raw material batches
 Equipment with expired calibration

Symptoms Are Valuable

Provide Clues to Sources of Root Causes

18
 Identifying Root Causes
Symptoms, Causal Factors and Root Causes
Symptoms

Root Causes
(Xs)

Symptom Causal Factor Root Cause

High Sample Variation Sampling Procedure Poor direction and
not followed supervision
Equipment Inadequate Maintenance not
Malfunction Maintenance discussed in SOP
Blend not uniform Mixing Procedure not Mixing procedure not
followed clear

19
10 Reasons for Root Cause Analyses Gone Wrong

1. Not thinking in terms of Cause (Xs) and Effect (Y) Y=f(Xs)

2. Lack of a Systematic Approach
3. Narrow view of sources of potential root causes
4. Inadequate use of data
5. Single Big X Mindset vs Possibility of multiple root causes
6. Too many root causes assigned as “human error”
7. Fixing “Symptoms” not “Causes”
Training - Often a Symptom - Overused as a Root Cause
8. Team composition – Wrong members, too big (4-6 is ideal)
9. Tools used are not adequate – e.g.; using only 5 Whys
10. Inadequate control plan – gains not held
Use of a Systematic Approach
Avoids Many Mistakes in Searching for Root Cause

20
 Manufacturing Crisis
Background
 Major product – Skyrocketing # of Customer Complaints
 12 person team assigned – no progress after 3 months
 Right things seem to be in place
 Critical issue has senior management support
 Team mission clear with well-defined metrics
 Team: Cross-functional, skilled, dedicated and knowledgeable
 Data available but not analyzed
New Approach – Analyze the Available Data
 Time plots identified when the problem began to occur
 Defect more prevalent in one brand of the product than another
 Examination of clues lead to a solution within days
Result - Process Change made – Customers Delighted

Takeaway – Problem Solving Framework Should

Include the Collection and Analysis of Data
21
Developing A Systematic Approach for
Process Control and Improvement

Guiding Principle
If you want something to happen on a regular and
sustained basis you need to have a management
system in place to guide and sustain the effort
Management System
Framework of processes and procedures used to
ensure that an organization can fulfill all tasks
required to achieve its objectives. (Wikipedia 2011)

“What Get’s Measured,

and Paid Attention To,
Gets Done”

22
 Process Management System Use of Data
Process Control, Improvement and Design Integrated

Customers Process
Design/Redesign

Process Process
The Process Improvements
Performance
Data

Feedback Process Improvement

Adjustments Feedback
Projects

Reports & Periodic Process

Information to Analysis and Improvement
Management Reviews System

23
Periodic Reviews of Process Performance
A Team Sport

Review Team Timing

Process Operators Daily/Hourly
Area Managers and Staff Weekly
Site Managers and Staff Monthly
Business Manager and Staff Quarterly

Periodic Reviews Are

Critical to Success

24
 Production Monitoring System
Batch
Production
Over Time

Batch Process Process

Models
Quality Data Adjustment Y=f(X)

Periodic
Monitoring Tools Data Analysis Process
• Control Charts and Improvement
• Capability Analysis Review
• Variance
Components
Special
• Histograms DMAIC
Cause
• Pareto Charts
Problems
25
 DMAIC Process Improvement Framework

Sense of Lean Six Sigma

Tools Results ($$)
Urgency
Data Control

Improve

Analyze
Leadership
Measure Teamwork
Stakeholder Building
Define Project Management
26
 Many Process Problems are Due to
Special Cause Variation
Sources of Variation Outside the Process
If special causes of variation are present, the process
output is not stable and is not predictable

Special Causes:
 Due to outside influences
 Affect some of the process outputs
Examples
 Ambient Temperature
 Raw Material Lot
 Equipment

27
Tracking Special Cause Variation to
Improve Process Stability (Predictability)
Special Causes – “The Usual Suspects”
 Raw Material Lot Variation
 Differences between Pieces of Equipment
 Tablet Presses
 Bioreactors
 Test Instruments
 Sources of Human Intervention
 Operating Teams
 Lab Analysts
 Production Lines
 Day of Week
 Production Shift
28
 BioPharm Process Yield Improvement
Daclizumab Fermentation Yield
Lot 1 Total Grams

Here we see a step 1100 UCL=1083

change in yield 1000 Lot 2
900
What is the cause?
800 Mean=799.9

Grams
700
Raw Material Lot
600
Variation LCL=516.5
500

Better Raw Material 400

Lot 3
Specs Adopted 300
200
Process Yield Subgroup 0 10 20 30 40 50 60
increased 25% A:Batch 62 72 84 94 104

Used DMAIC to Identify Key Drivers of Process Yield

Raw Material Lot Variation Had the Largest Effect

29
 Tablet Content Variation Study
Variation Due to:
Time Series Plot of % ACTIVE INGREDIENT
5.3
 Raw Material Lot? No
 Tablet Press? No
5.2  Analyst?
% ACTIVE INGREDIENT

5.1

5.0

4.9

4.8

4.7

4.6
1 12 24 36 48 60 72 84 96 108
Batch

30
Tablet Content Variation Study
Results Reported by Analysts A, B, C and D
Time Series Plot of % ACTIVE INGREDIENT
5.3
C
C

5.2
A
B
% ACTIVE INGREDIENT

A B
5.1 CC
B B B
A B B
A BA B B BB B B BBB BBB BB BB B B B
A A BB A B BBB B
5.0 B B BB BB B B B B B B B B B
AA B B B B D
B B C A B B
A B BB B
C B
A B A B B B A A D DD B
4.9 D
B D
A B B BB C
B B
4.8 A
A B CC
A A D
A
A
4.7
A
A
A
Work of
A A
Analyst B
4.6
1 12 24 36 48 60 72 84 96 108
Batch

31
 Tablet Content Variation Study
Analyst B Has the Least Amount of Variation
Dotplot of % ACTIVE INGREDIENT vs ANALYST

A
ANALYST

Work of
Analyst B
B
C
D
4.68 4.77 4.86 4.95 5.04 5.13 5.22
% ACTIVE INGREDIENT

32
 Production Process
Box Plot - Process Yield by Team
2200
Yield

2100

2000

1 2 3 4
Team

Team 4 – The Most Experienced Team - Has the Highest Yield

33
On-Time Delivery vs Day of the Week

Best On-Time Delivery

Occurs on Fridays

34
Process Problem - % Off-Spec Product

 Variables Showing Variation

 Shift (1, 2, 3)
 Press (1, 2, 3, 4)
 Pressure Level (1, 2, 3, 4)
 Response Y = % OffSpec
 Data for 72 consecutive Batches

Multiple Root Causes

Shift, Press and Pressure Level
35
 % Off-Spec Product
Variation Due to Shift, Press and Pressure Level
Have Significant Effects

Process Improvements - Fixes

• Shift 3 performs as Shifts 1 and 2
• Presses 1,2,3 perform as Press 4
• Hold Pressure at lowest level

36
 % Off-Spec Product - Predicted Performance
Removing Special Causes Reduces Off-Spec Product by 40%
Process Improvement
• Shift 3 performs as Shifts 1 and 2
• Presses 1,2,3 perform as Press 4
• Hold Pressure at lowest level
30
Observed Performance

Predicted Process
20 Performance As Is Impvd
Avg. 14.3 8.8
OffSpec

StdDev 4.9 2.9

10 Process Average and

Process Std Dev
Both Reduced
Approximately 40%
0
Shift 50 100
Batch
37
 Preventive Action System
Should be Part of the Periodic Process Review –
Weekly and Monthly Reviews

38
 Preventive Action
Creating Stable Operations by
Reducing Special Cause Variation

A System is Needed
Should be Part of the Improvement Review Process

39
 System for Preventive Action
Process Problem List Operations
 Low Yield
 Temperature Deviations
 Equipment Malfunction
 Operator Errors
 SOP Not Followed
 Raw Material Issues

Pareto Analysis by
Process Type
# Deviations

Process to be
Improved

Type of Process

Improvement DMAIC
Implemented and Improvement
Confirmed Process
40
 Systematic Approach to
Preventive Action

 Redesign the process by which problems are

corrected and reduced
 Use of statistical and other improvement tools
 The new process will:
 Enhance identification of root causes
 Make the corrections more sustainable
 Improve the execution of the root cause and
preventive action work

41
 Deviation Reduction - Experiences
One Company’s CAPA Experience
 Focused on reducing deviations
 Results after 3 months
 Deviation backlog decreased
 Level of “new deviations” remained the same
 Conclusion: Not getting to root cause, problems not fixed

Systematic Approach Is a Better Way to Get to Root Cause

Aspect CAPA Systematic Approach
Handle Deviations Individually System and Process View
Result Root Cause often Process improved
Missed Problem doesn’t reoccur
Methodology Focus Narrow Broad, Holistic
Sustainability Low High

42
 “Classic” Approach to Deviation Reduction
An Evaluation
Limitations
 Root cause of the deviation is often not identified
 Thorough systems analysis is rarely used
 Corrective action plan may be poorly executed
Sources of these limitations
 Deviations are analyzed individually - not systemically. The
result is a lessened chance that:
 Root cause is found
 Correction is sustained
 Structured methodology is not used
 Correction identification and execution is limited

43
 Deviation Management - A Systematic Approach

 Deviation Reduction Method – Two critical aspects:

1. Corrective Action
2. System Failure Analysis
- Opportunity Identification
- Improvement project completion
 These two aspects:
 Deal with the correction and prevention phases of
deviation reduction.
 Compliment and support each other

44  Slide 44
 Corrective and Preventive Action
DMAIC Phases and Tools
Phase Activity Tools Used
Define Identify Deviation Project Charter Statement
Investigate Deviation Flow Chart, Data Collection
Measure Collect Data Run Chart, Histogram
Scatter Plot,
Data Stratification
Analyze Identify Root Causes Pareto Chart, FMEA
Solution Identification
Improve Correct Problem Implementation Planning
Prevention of Mistake Proofing
Control Reoccurrence Control Plan, Checklists

Ref: The Checklist Manifesto – How to Get Things Right,

A. Gawande. Picador Books, NY, NY (2009)
46
 Integrating Problem Containment Actions
with The DMAIC Framework

No Short-Term Yes
Fix
Needed?
Containment Actions
Problem Solving  Define the issue
and  Measure short-term severity
Process Improvement  Analyze problem symptoms
using DMAIC  Create short-term fix
 Add controls, keep fix in place

After Containment Actions Are in Place

47
 DMAIC
Has Many Advantages over Competing Approaches
 Simple and Easy to understand, remember and use
 Phases:
“Define”, “Measure”, “Analyze”, “Improve” and “Control”
tell you what work needs to be done to solve the problem
 Works in any culture - within an organization and Globally
 Important steps are part of the process:
 Define the Problem
 Collect Data
 Corrective Action – Test and Implement improvements
 Preventive action – Hold the gains

DMAIC -The Best Available

Problem Solving and Process Improvement Framework

48
 Batch Records Release
Case Study
REF: Snee, R. D. and R.W. Hoerl (2005) Six Sigma
Beyond the Factory Floor, FT Prentice-Hall, Upper
Saddle River, NJ.

49
 Batch Records Release
Problem
 Reduce the cycle time of the batch records
release process by 50% to increase order
response time and reduce inventory
Results
Cycle Time Inventory
Product Reduction Reduction
A 55% $3.6MM
B 36% $1.6MM

 Costs reduced $200,000/yr due to decreased

capital costs, floor space and handling

50
 Project Definition
 Two bio-pharmaceutical products experiencing excessive
batch record review time
 Product “A”
 Stock-outs due to manufacturing variability
 Product “B”
 Expected significant increase in demand
 Project Goal
 Reduce batch record review time by >50%
 Financial Impact
 Reduction of Inventory and less carrying costs

“A Problem Well Defined Is a Problem Half Solved”

Charles Kettering

51
 Project Definition (cont’d)

 Expected Timing – complete in six months

 Key Deliverables:

 Reduced cycle time through improved processes

 Sub-process targets and measurement system
 Team based solutions
 Seven person cross functional team (Ops, QA, Docs)

 Time Estimate - approximately 25 hrs/person

 Boundaries/constraints – Investigations not included

52
 Use DMAIC to Drive Down the
Batch Record Review Time

DEFINE MEASURE ANALYZE IMPROVE CONTROL

Process Map Baseline data Pareto Quick Wins Measurement

process
Bottlenecks 11 lots Prod. A Histograms Targets
Review mtgs
Key variables 15 lots Prod. B Fishbone Measurement

Measurement Metrics Run Charts Long Term

points
Cycle Time MBR

Errors Error Metrics

Steering Steering Steering
Consistency
Committee Committee Committee
Resources

53
 Batch Records Release
Measure Phase
Measure the Performance Gap

54
 Detailed Process Map to Identify Potential Bottlenecks

Test Approve
Labs
Samples Table Cycle 1 – Mfg Loop

SAP Overview
Operator Samples Review data Respond to
Review & (mtls. for lot
(Production) To Labs Create table Questions from
Send charged)
Mfg
Completed BR
Supervisor
to Reviewer
No
Review M
M No Sign off
Is record Hold till all
Organize,
Mfg Create Traceability Review records sufficient Yes records complete
Review For Entire Lot, File and calculations )
M Log,
QA/BRR Review Release Look at Map
Priority Plan Look at Priorities,

QA
Shop Floor M

IR Process

M Measurement Point

55
Identify Key Critical to Quality Variables
Issue Mfg Time Mfg
Time Review

Batch Record Manufacturing Mfg 1st Review

Issued Sign-off

Hold after
Mfg Review
QA Receipt
QA
Review

QA Loop Hold
Time after QA
Final Approval Send Back to QA 1st Review
Manufacturing

56
 Batch Records Release
Analyze Phase
Identify the Root Causes

57
 Product “A” Areas to Tackle
Mfg Review, QA Loop, Hold after Mfg
Product A Cycle Time by Process Step

16 120%

14
100%

12

80%
10
Time Index

Percent
8 60%

Cycle Time Index

6
Cumm Percent
40%

20%
2

0 0%
QA Loop Hold after QA 1st Hold after
Mfg Review Mfg Issue
Time Mfg Review QA
Cycle Time Index 15 5 4 3 2 0 0
Cumm Percent 49% 65% 79% 89% 97% 98% 100%

58
Product “A” – Manufacturing Review Process
Cause and Effect Analysis
Resources/Priorities
Other duties of reviewer
Lack of expectations/targets
Only 1 reviewer

Data not to reviewer quickly

Backlog of lots
Ops has other priorities
Poor coordination of
corrections on shop
floor Product “A” –
Mfg Review
Power failure

Lack of feedback (metrics) Inaccurate

Poor communication
w/ vendor Operator mistakes Master batch
record problems
Part # change
Lack of training
Not customer friendly

Equipment issues Errors

59
 Batch Records Release
Improve Phase
Corrective Action
Create and Test Improvements

60
Improvement Phase – Corrective Action
What It Will Take?
 Set Cycle Time Targets - Overall and Sub-Process
 Ongoing Measurement and Reporting
 Cycle time
 Corrections
 Process Changes
 Resources and Training
 Longer Term
 Resources
 Master Batch Record Revisions
 Continuous Improvement Processes

61
 Corrective Action – Process Changes
Schedule Mfg Reviews Like a Production Process
 Both Products
 Restructure tracking meeting – less data gathering, more actions
 Product “A”
 Send sub-records through system as completed – don’t wait to
all done (Lean manufacturing principle)
 Set up weekly meeting for ops/docs/QA
 Resolve issues requiring multiple inputs
 Product “B”
 Batch records sent to Docs as completed – not wait until all done
 Back up or transfer In-process testing to ease operator
constraint
 Regular Wednesday meeting (Docs, QA, Ops) to understand and
resolve issues from QA review
62
 Resources – Training and Resources
 Training
 Twice yearly training of Ops to understand what
QA is looking for and promote error reduction
 QA reviewers observe manufacturing process with
QA shop floor to better understand process and
promote consistency
 Resources (Trained back-ups are essential)
 Train back-ups for Jeff, Valerie and Justin
 Train replacement and back-up for Tom

63
 Product “A”
Batch Record Review Time Reduced 55%

I Chart of ReviewTime(days) by Stage

Before After
50
Improvements
Resulted in a 55%
40 Reduction in Cycle
Time Freeing Up
Individual Value

30 $3.6MM in Inventory

20 UCL=20.79

_
X=12.08
10

Review Time Variation Also Reduced LCL=3.38

0
5 10 15 20 25 30 35 40 45
Lot

64
 Product “B”
Batch Record Review Time Reduced 36%

Improvements
Resulted in a 36%
Reduction in Cycle
Time Freeing Up
$1.6MM in Inventory

Review Time Variation Also Reduced

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 Key Changes Made
Treat Reviews Like a Production Process

 Cross-functional team effort (QA, Ops, Reviewers and Operators)

 Data driven decision-making using DMAIC
 Interim and overall targets across the review process
 New measurement and reporting system
 Tracking meeting redesign
 On-going capture of cycle time and error metrics
 Formalize back-ups for reviewers
 Reduced batching of records
 Twice yearly training of operators

66
Batch Records Release
Control Phase
Preventive Action
Hold the Gains

67
 Control Plan
Preventive Action
 Monitor process cycle times
– Sub-process and overall
 Maintain periodic process tracking sessions
 Train operators twice/year

68
 Preventive Action - Next Steps
 Continuous Improvement
 Monitor measurements to identify problem
areas and systematic solutions
 Set gradually decreasing error targets to drive
errors out of system
 Quarterly reviews (Secret Sauce) by team to
monitor progress and suggest any corrective
action necessary
 Master Batch Record (MBR) Revisions
 Perform MBR revision on problem batches

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 Can’t Find Root Cause – What Do I Do?
 Rethink the problem and the problem solving process
 Start at the beginning – Review steps in DMAIC
 Important variables not investigated?
 Data not collected over the proper time frame?
 Approach used in the data analysis not adequate
 Get more knowledge, experience
 Engage an expert
 Study process learnings developed in previous studies
 Research the literature
 Consider collecting better data – More? Different?
 Has the process changed recently?

70
 Summary and Conclusion
 Root cause analysis is essential to:
 Maintain and improve performance
 Create successful CAPA System
 Data-based systematic approach is needed for successful:
 Corrective and preventive action
 Problem solving and process improvement
 Process and systems thinking are important to identifying
problems and finding root causes
 Management reviews are critical – the secret sauce
 Essential to sustaining elimination of root causes

Increase CAPA System Effectiveness

Strategic, Systematic and a Management Priority

71
 References
Hoerl, R. W. and R. D. Snee (2012) Statistical Thinking – Improving Business
Performance, 2nd Edition, John Wiley and Sons, Hoboken, NJ.
Lewandowski-Walker. K. (2012) “Corrective and Preventive Action –
Background & Examples”, Food and Drug Administration, Division of
Domestic Field Investigations, Office of Regulatory Affairs
McGurk, T. L. and R. D. Snee (2005) “A Systematic Approach to Deviation
Reduction through Lean Six Sigma”, Pharmaceutical Technology Sourcing
and Management, October 2005, Volume 1, Issue 7, 14-18.
Rodriguez-Perez, J. (2011) CAPA for the FDA Regulated Industry, Quality
Press, Milwaukee, WI.
Snee, R. D. (2007) “Adopt DMAIC: Step One to Making Improvement Part of the
Way We Work”, Quality Progress, September 2007, 52-53.
Snee, R. D. and E. C. Gardner (2010) “Firefighting with DMAIC - Use the
Framework to Quickly Contain Short-Tern Problems as Well as Develop
Long-Term Process Improvements”, Quality Progress, October 2010.
Snee, R. D. and R. W. Hoerl (2003) Leading Six Sigma – A Step by Step Guide
Based on Experiences with GE and Other Companies, FT Prentice Hall,
New York, NY.
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 For Further Information,
Please Contact:
Ronald D. Snee, PhD
Snee Associates, LLC
Newark, DE
(610) 213-5595
Ron@SneeAssociates.com

Please visit our website at:

www.SneeAssociates.com
73
 Solving System Failure Problems
 The complexity of operations produce multiple deviations,
many of which are due to common system failures
 Example: Systems associated with a Bioreactor/Vessel/Tank
 Temperature Control
 Charging
 Weighing
 Empting
 Pressure Control
 Addressing deviations individually may not solve systems
failures due to the complexity of the root causes
 An approach to dealing with multiple deviations at a systems
level is needed in this situation

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 Typical System Failure Problems
 Batch release – accuracy and cycle time
 Operations control – blending, compression etc.
 Manufacturing throughput and cycle time
 Analytical method development & improvement
 Content uniformity
 Fill volume control
 Reduce number of excess documents
 Control of budgeting process
 Hiring technical personnel
 Purchasing and Billing effectiveness

Opportunities for Improvement have

Significant Financial as well as Compliance Benefits

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 Agenda
 Today’s Realities
 Current approaches – Strengths, limitations and Tools
 FDA Warning Letters - CAPA and Statistical Analysis
 Principles of Root Cause Analysis
 Systematic Approach – Roadmap and Tools
 Use of DMAIC Problem Solving Framework
 Root Cause Analysis Tools - Linking and Sequencing
 Solving System Failure Problems
 Process Problems – The Usual Suspects
 Integrating Corrective Action and Prevention
 Sustaining the Elimination of Root Causes
 Systems Approach Including Periodic Management Review
 Batch Records Release - Case Study

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