Anisfield - Investigating PDF

Effective Investigations
and
Corrective Actions (CAPA)
P
Proper Investigation
I i i off Quality
Q li E Events
Michael H. Anisfeld
Globepharm Consulting
What Do You Do When The Bad Stuff Happens?
Ignore
I It Pretend It Never Happened
Curse !#&*!$%...
Advise Boss
Advise Your Buddy
Walk Away
It’s a One-Off
Fix It Investigate + Fix
Blame Someone Else Investigate
Investigate, Fix + Document

2
© Copyright, Globepharm Consulting, 2008 1

Failure/Deviation System
The purpose of
Th f a failure/deviation
f il /d i i system is i
to assure that each failure/deviation does not
adversely impact product quality and that
effective corrective action is taken to reduce
the probability of such failure in the future

Contributors to Failure
Materials
Facilities
Equipment
Instrumentation
People
Processes
Procedures
Failure / Deviation
Definition
F il
Failure
Product does not meet specification.
Failure may be detected in/by
Production
Laboratory
Deviation
Change in procedures, equipment, materials,
personnel related to product manufacture having
an impact on product quality

Definitions
Immediate Cause
Situation directly causing the problem
Root Cause
Basic Causal Factor, which if corrected or removed prevents a
repeat of the problem
Intermediate Cause
Reason for problem at more fundamental level than the
immediate cause, but not the root cause [why-2, why-3]
Root Cause Analysis

Structured questioning process enabling identification of
underlying beliefs and practices that result in poor quality
Causes of Failure
Common
C mm n Cause
C [End mi – S
[Endemic Systematic]
t m ti ] (Variation)
(V i ti n)
Originates from the basic elements of the process:
Machines
Materials
Methods
Manpower
Measurement
Assignable Cause [Special] (Variation)

An unplanned variation originating outside expected
operating process conditions [special cause variation]

Failure/Deviations
Measures
There are three key steps in this process and each of these should
be monitored regularly
Recording the failures and deviations

Total number
Number by department
Action on product batch(es) involved

Audit by sampling to verify that corrective action was taken
Corrective action on root causes

There should be an elimination of failures/deviations due to causes
for which corrective actions have been implemented
Regulators Expectations
Comprehensive,
C h i H
Honest A
Approachh To
T
Investigate OOS Results/Failures
Evaluation Using Scientifically Valid Principles
Learning From Experiences
Permanent Solutions To Problem
Authorities Not The Ones To Find The
Problem
10

11
What to Do
When the Unexpected Happens
UNEXPECTED?
OOS
Laboratory
Manufacturing
Water System
OOT
OOE
OOY
Reconciliation – Yield Check
Reconciliation – Packaging Material
Deviation
Discrepancy
Unusual Event
12

13
What Do The US Regulations Say?
Investigation
“In ti ti n” specifically
p ifi ll stated
t t d in the
th cGMPs:
GMP :
§211.22 - Responsibilities of quality control unit.

§211.125 - Labeling issuance.
§211.170 - Reserve samples.
§211.180 - General requirements.
§211.186 - Master pproduction and control records.
§211.188 - Batch production and control records.
§211.192 - Production record review.
§211.198 - Complaint files.
§211.204 - Returned drug products.
14

What Does The EU Guide Say?
“I
“Investigation”
ti ti ” specifically
ifi ll stated
t t d iin th
the GMP
GMPs:
1.3 Quality Assurance

1.4 Quality Control
2.7 Production/QC Responsibilities
5 39 Production
5.39
5.56 Packaging Operations
6.2 Quality Control
8.1 Complaints
15
Future Regulations
An international
i i l harmonized
h i d
approach to
Risk Management
ICH-Q9
16

ICH-Q9
initiate Risk Management
risk management process
risk assessment
risk identification
nagement tools
s
risk analysis
risk evaluation
risk control unacceptable
risk reduction
risk
i k acceptance
t
Risk man
risk communication OK
risk communication risk acceptance
output/results of the review event

17

CAPA
19
How do you know

what’s happening?
R
Recognize
i that
h there
h is
i a problem:
bl
Capture The Data
Analyze The Data
Trend The Data
Then
hen Fix the problem
problem:
Investigate the Cause
Attempt to Get to “Root Cause”
Implement Effective Fixes
Monitor the Fix
20

21CFR820.100 - CAPA
§820.100 Corrective and preventive action

(a) Each manufacturer shall establish and maintain procedures
for implementing corrective and preventive action. The
procedures shall include requirements for:
(1) Analyzing processes, work operations, concessions,
quality audit reports, quality records, service records,
complaints, returned product, and other sources of quality
data to identify existing and potential causes of
nonconforming g p
product,, or other quality
q y problems.
p
Appropriate statistical methodology shall be employed
where necessary to detect recurring quality problems;
(2) Investigating the cause of nonconformities relating to
product, processes, and the quality system;
(3) Identifying the action(s) needed to correct and
prevent recurrence of nonconforming product and other
quality problems; 21
21CFR820.100 - CAPA
§820.100 Corrective and preventive action (continued)

(4) Verifying or validating the corrective and preventive action
to ensure that such action is effective and does not adversely
affect the finished device;
(5) Implementing and recording changes in methods and
procedures needed to correct and prevent identified quality
problems;
(6) Ensuring that information related to quality problems or
nonconforming
f mi productd t iis disseminated
di mi t d tot th
those di
directly
tl
responsible for assuring the quality of such product or the
prevention of such problems; and
(7) Submitting relevant information on identified quality
problems, as well as corrective and preventive actions, for
management review.
(b) All activities required under this section, and their results,
shall be documented 22

CAPA – Analyzing Sources
of Quality Data
Environmental
E i l
Monitoring Process
Complaints/ Deviations
Returns or Failures
Acceptance
Repairs/
Activities
Ser icing
Servicing CAPA
Stability
Calibration/
Data
Maintenance
Audits Yields/Scrap
23
What To Track
T
Track
k By:
B
Product In-process, release, stability, validation
Event Reason for investigation
Operator/Analyst If cause is operator/analyst error
Instrument/Equipment If cause instrument related
Cause Investigation conclusion
Corrective Action Remedy and prevention
Timeliness Time to complete investigations
24

CAPA Data Collection
Incidents Reported - 2003
Question:
250 Are we Getting Better as a Company?
210 Or Dropping Off in Capturing Incidents?
200 186
178
165 171
150 143
132 130
Incidents 119
100 98 92
85
50
0
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
25
Run Charts: Trend Charts

Environmental Data – Purified Water System
Specification
Upper Limit
OOT? / OOE?
Specification
Lower Limit
26

Tracking / Trending
Paper/Pen
Spreadsheet (Excel, Oracle)
Dedicated Computer Systems

Trackwise
(Sparta Systems: http://www.sparta-systems.com)
CATSweb
(AssurX: http://www.assurx.com/catsweb.html)
p
MetricStream
(Metric Stream: http://www.metricstream.com)
SmartCAPA
(SmartCAPA: http://www.pilgrimsoftware.com)
Others …..
27
SmartCAPA®
(www.pilgrimsoftware.com)
28

29
Purpose of Investigation
The
Th purpose off an investigation
i i i iti to
determine the cause of the failure.
Even if the batch is rejected based on the OOS

result, the investigation is necessary to determine
if the result is associated with other batches of
the same drug product or other products
FDA: Draft OOS Guideline, September 1998
30

Failure / Deviation – What To Do
Failure/Deviation
F il /D i ti Detected
D t t d I f
Inform QA
24 hours
Perform Investigation Batch Disposition
Immediate Fix
30 days
Root Cause Analysis
Communicate to Management
Corrective/Preventive Action
Assess Effectiveness of Fix

31
Investigations:
You’ve Got to Be A Detective!
32

Investigations 101
P p
Purpose off ann In
Investigation
ti ti n
Obtain facts as to cause
Common
Special - Assignable
Process of an Investigation
Complete
p description
p of problem
p
Validity of inputs
Review key process variables
Determine scope of investigation
Document investigation
33
Learn How To Be A Detective
What Equipment,
Equipment
Machine, Tool?
What Is Wrong?
What Is the
Complaint?
What is the Undesired

Behavior?
34

Wh is
Who i Involved?
I l d?
Staff
Consultants
Vendors
Visitors
Name names/positions!
35
When does
Wh d the
th problem
bl
occur?
Day
Date
Time
Shift
Phase of operation
When in equipment life
cycle
Are there time patterns?
36

Whi h
Which:
Unit
Area
Department
Line
Machine
Location of defective
item, or where on
defective item
37
How is the “what”

what or “who”
who
impacted?
Injury / Death
Shut-Down /Start-Up
Damage
Type
Classification of Defects
How Much
How Many
How Big An Issue
What resources are needed
to handle/resolve the issue!
38

Change Analysis
PROBLEM?
E COMPARISON?
What is the object or What similar object or

process with the problem? process doesn’t have the
WHAT?
problem? What else could be
What is wrong? wrong?
Where does the problem Where else could the
WHERE?
occur problem occur?
When did the problem When did the problem not

WHEN?
happen? happen?
HOW BIG? How large is the problem? How large could it be?
39
Investigation Documentation
A B C D E
40

Investigation Documentation
Date
D t pproblem
bl m occurredd
Statement of the Problem
Listing of batches impacted
List of personnel interviewed
Statement of each person’s opinions and memory of event
Discussion of potential causes
Discussion of potential impact
Discussion of extent of problem
Recommendations for fixes
Statement of actions taken to fix
Final decisions regarding batch
Management approvals
41
42

Root Cause Analysis
Corrective
C ti actions
ti tto observations
b ti ((usually
ll symptoms)
t )
have limited effect on sustained improvement or
elimination of recurrence of the failure
Corrective actions need to address the underlying

causes and root causes of a problem in order to
eliminate the situation from recurring
43
Root Cause Analysis
Equipment Management Systems

Design, Capability
Design Qualified Supervision
Maintenance Audits
Operator Error Feedback
Prior Corrective Actions Taken
Procedures Communication
No Procedure Planning
Wrong Procedure Used Process Capability
Procedure Not Available Adequate Time To Perform Task
Procedure Difficult To Use Standards
Training Manpower
None Information Available
When Adequate
Effectiveness Timely
Personnel Problems
Quality Control Training
Inspection Required Fail/Safe Processes
Inspection Performed Environment
Lighting
Noise
Fatigue
44

Corrective Action
What
Wh is i the
h lowest
l level
l l at which
hi h we
can do something to prevent the
problem from re-occurring?
45
46

Investigation Tools
Brainstorm
B i t th
the iissues
Flowcharting
Fishbone Analysis – Cause/Effect diagrams
Why-Why Analysis
Pareto Charts
Run Charts
Force Field Analysis
Six-Sigma Analysis - MAIC
Kepner-Tregoe®
47
Brainstorming
Possible
P ibl ttargett questions
ti to
t serve as the th focal
f l point
i t of
f
the brainstorming process:
What would solve the problem?
What strategy could resolve the root cause?
What solutions have already been thought of?
What solutions have not been thought of?
How can we prevent the situation recurring?
What different methods might work?
What crazy ideas might help?
48

Fishbone Analysis
Manpower Management
People too busy

People not paying attention
Batch
Record
Errors
Methods Machines
49
Why-Why Analysis
Oil Drops
D On
O FlFloor
Dripping Engine
Oil Can to Collect
Funnel in Oil Can
Raise Funnel
Unless you’ve gone
5 levels of questions
you probably have
not got to root cause!
50

Pareto Analysis
Pareto: 80 – 20 rule
Batch Record Problems
90 87
80
70
60
50
40
30
23
20 18
12
10
0
Signatures Data Errors Other
51
Process Shift, F-440 Particle Size

APR – Annual Product Review
53
Force-Field Analysis
Th Positive/Negative
The P iti /N ti What
Wh t would
ld make
k What
Wh t would
ld make
k
Analysis for Solutions the problem the problem
can stimulate thinking better? worse?
just as a the force-field
1. 1.
format did in the past.
Since we are looking for 2. 2.
solutions, the two 3. 3.
columns play “better”
better 4. 4.
against “worse”. 5. 5.
6. 6.
7. 7.
8. 8.
54

Six Sigma Problem Solving – MAIC
Measure A nalyze Improve Control
(1) Describe the (4) Identify Potential (5) Analyze (9) Determine Best Solution (12) Implement
Problem Causes Existing Data Solution
0.251
0 251
IS IS NOT
0.250
Control Plan
What Item
(2) Lid
Function
Prevents Spills
Failure Mode
Lid falls off due
to looseness
Causes
Lid diameter
too large
Effects Control
Burn Go-no go gauge
0.249 Body diameter Burn Go-no go gauge

to small
Where Leaks from drinking hole

Surfaces too slick
Hole too large

Burn
Stain
Sampling Plan
Pin gauge
Hole has too Stain

0.248 direct of path
T M B T M B T M B T M B
When 1 2 3 4 (10) Pilot Solution

Spill when removing lid Lid diameter
too small
Body diameter
to large
Burn
Burn
(above)
(above)
Material catches Burn Sampling Plan
Extent
(6) Construct List of (7) Compare
Verified Facts Causes to Facts
(2) Determine When
Problem Started FACTS
Fact 3
Fact 4
Fact 5
Fact 1
Fact 2
(1) All Machines
19
(2) Second Shift (11) Verify Solution Works
Cause 1 O X X O A
(3) Certain Codes Cause 2 X O A AO
12.5 LSL USL
(4) Started 8/22 Cause 3 O
C O AA O
6
(5) Steadily Worse Cause 4 X A X O O
Jan '87 Jul '87 Jan '88 Jul '88 (6) All Operators Cause 5 O O OO X
Month
15 20 25 30 35
(8) Collect Additional Data
Seal Strength
(3) Measure Problem Until Root Cause Identified
Magnitude OC Curve
10.2 1.0
70 Upper Control Limit
K = 20
T
Number
60
10.0
O
R 50
Radius Pa 0.5
Q K = -20 9.8 Lower Control Limit
40
U
A B C D E F G H E 30
9.6
0.0
1 5 10 15 20 0 2 4 6 8 10
Code 36.0 37.0 38.0
55
L Percent Defective
Subgroup
© Copyright 2000, Taylor Enterprises Inc.
56

ICH-Q9
initiate Risk Management
risk assessment
risk identification
nagement tools
s
risk analysis
risk evaluation
risk control unacceptable
risk reduction
risk
i k acceptance
t
Risk man
risk communication OK
risk communication risk acceptance
output/results of the review event

57
Tools To Prioritize
Fixes and Efforts
FME
FMEA - Failure
F il M
Mode
d Eff
Effect Analysis
l i
FTA - Fault Tree Analysis
HACCP - Hazard Analysis,

Analysis
Critical Control Points
58

Bibliography
Root Cause Analysis:
- Kepner and Tregoe, “The New Rational Manager”
- Paradies and Unger, “Taproot: The System for Root Cause Analysis,
Problem Investigation & Proactive Improvement”
- Ammerman,
Ammerman “TheThe Root Cause Analysis Handbook”
Handbook
- Pokras, “Systematic Problem-Solving and Decision-Making”
Risk:
McDermott et al., “The Basics of FMEA”
Human Error:
Lorenzo, ABS Consulting, “A Manager’s Guide to Reducing Human Error”
g
Management’s Role:
Harbour and Kieffer, “Managing the Quality System”
FDA:
“Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production” (Guidance), September 1998
Quality Systems Approach to Pharmaceutical GMPs, September 2004
59
Stay In Touch
Michael
Mi h l HH. Ani
Anisfeld
f ld
Globepharm Consulting
313 Pine Street
Deerfield IL 60015, USA
Phone: USA +1+847 914 0922

Fax: USA +1+847 914 0988
E-mail: manisfeld@globepharm.org
Website: www.globepharm.org
60

61
Questions?
62

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Effective Investigations

What Do You Do When The Bad Stuff Happens?

Fix It Investigate + Fix

Blame Someone Else Investigate

Investigate, Fix + Document

© Copyright, Globepharm Consulting, 2008 1

© Copyright, Globepharm Consulting, 2008 2

© Copyright, Globepharm Consulting, 2008 3

Root Cause Analysis

Assignable Cause [Special] (Variation)

© Copyright, Globepharm Consulting, 2008 4

Recording the failures and deviations

Action on product batch(es) involved

Corrective action on root causes

© Copyright, Globepharm Consulting, 2008 5

© Copyright, Globepharm Consulting, 2008 6

What Do The US Regulations Say?

§211.22 - Responsibilities of quality control unit.

© Copyright, Globepharm Consulting, 2008 7

1.3 Quality Assurance

© Copyright, Globepharm Consulting, 2008 8

risk control unacceptable

output/results of the review event

© Copyright, Globepharm Consulting, 2008 9

How do you know

© Copyright, Globepharm Consulting, 2008 10

§820.100 Corrective and preventive action

§820.100 Corrective and preventive action (continued)

© Copyright, Globepharm Consulting, 2008 11

Product In-process, release, stability, validation

Event Reason for investigation

Operator/Analyst If cause is operator/analyst error

Instrument/Equipment If cause instrument related

Cause Investigation conclusion

Corrective Action Remedy and prevention

Timeliness Time to complete investigations

© Copyright, Globepharm Consulting, 2008 12

Incidents Reported - 2003

Run Charts: Trend Charts

© Copyright, Globepharm Consulting, 2008 13

Spreadsheet (Excel, Oracle)

Dedicated Computer Systems

© Copyright, Globepharm Consulting, 2008 14

Even if the batch is rejected based on the OOS

FDA: Draft OOS Guideline, September 1998

© Copyright, Globepharm Consulting, 2008 15

Perform Investigation Batch Disposition

Assess Effectiveness of Fix

© Copyright, Globepharm Consulting, 2008 16

Learn How To Be A Detective

What is the Undesired

© Copyright, Globepharm Consulting, 2008 17

Learn How To Be A Detective

Are there time patterns?

© Copyright, Globepharm Consulting, 2008 18

Learn How To Be A Detective

How is the “what”

© Copyright, Globepharm Consulting, 2008 19

What is the object or What similar object or

When did the problem When did the problem not

© Copyright, Globepharm Consulting, 2008 20

© Copyright, Globepharm Consulting, 2008 21

Corrective actions need to address the underlying