A structured approach to the investigation process should be used with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9.

1. This presentation is compiled by “ Drug Regulations” a
non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
1/2/2014
1

2. This presentation is compiled from freely
available resources like the websites of FDA,
EMA, WHO.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.

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3. ◦ Collect
and
Analyse
Information
based
on
appropriate Statistical Methodology as necessary to
detect recurring quality problems
◦ Identify and Investigate Existing and Potential
Product and Quality Problems
◦ Take Appropriate, Effective, and Comprehensive
Corrective and/or Preventive Actions
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4. ◦ A structured approach to the investigation process
should be used with the objective of determining
the root cause.
◦ The level of effort, formality, and documentation of
the investigation should be commensurate with the
level of risk, in line with ICH Q9.
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5. ◦ CAPA methodology should result in product and
process improvements and enhanced product and
process understanding.
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6. 
Corrective action is aiming to correct an existing non-conformity and to
avoid reoccurrence of the same non-conformity.•

Corrective action may arise e.g. from manufacturing deviations, OOS
investigations, complaints, audit findings, recalls.•

A systematic investigation should be performed to determine the
reason(s) for the non-conformities and to agree upon appropriate
corrective action.•

Agreed corrective actions should be closely followed-up and monitored
until their completion.

In the frame of the management review, management should be notified
about the costs and impact of failure including the respective corrective
actions.
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7. ◦ Corrective Action: Action to eliminate the cause of a
detected
nonconformity
or
other
undesirable
is
taken
to
situation.
◦ NOTE:
Corrective
action
prevent
recurrence whereas preventive action is taken to
prevent occurrence. (ISO 9000:2005)
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8. 
Preventive action is aiming to avoid the initial occurrence of a non-conformity by
proactively implementing improvements.

Preventive action may result i.e. from trending of in process data, of analytical
data, of audit findings, trending of root causes for non-conformities or
complaints, from product quality reviews (annual product reviews), quality risk
analyses, etc.

Similar to corrective actions, agreed preventive actions should be closely
followed-up and monitored until their completion. Effectiveness of preventive
actions should be reviewed regularly, i.e. as part of the product quality review
(annual product review).•

Information regarding preventive actions including costs and cost savings should
be regularly subject to management review in support of maintaining and
improving the effectiveness of the Quality Management System.
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9. ◦ Preventive Action: Action to eliminate the cause of a
potential
nonconformity
or
other
undesirable
is
taken
to
potential situation.
◦ NOTE:
Preventive
action
prevent
occurrence whereas corrective action is taken to
prevent recurrence. (ISO 9000:2005)
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10. 
Responsibilities
of
a
quality
control
unit...to assure that no errors have
occurred or, if errors have occurred, that
they have been fully investigated.
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11. 
Written production and process control
procedures shall be followed …. Any
deviation from the written procedures
shall be recorded and justified.
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12. ◦ Any unexplained discrepancy…or the failure of a
batch or any of its components to meet any of its
specifications shall be thoroughly investigated…
◦ The investigation shall extend to other batches of
the same drug product and other drug products
that may have been 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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13. 
Article 10 Production

1. The different production operations shall be carried out
in accordance with pre established instructions and
procedures and in accordance with good manufacturing
practice. Adequate and sufficient resources shall be made
available
for
the
in
process
controls.
All
process
deviations and product defects shall be documented and
thoroughly investigated.
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14. Article 13 - Complaints

◦
Any complaint concerning a defect shall be recorded and
investigated by the manufacturer…
Article 14 - Inspections

◦
The manufacturer shall conduct repeated self-inspections as part
of the quality assurance system in order to monitor the
implementation and respect of good manufacturing practice and
to propose any necessary corrective measures. Records shall be
maintained of such self-inspections and any corrective action
subsequently taken.
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15. 1.4 A Pharmaceutical Quality System appropriate for the

manufacture of medicinal products should ensure that:
◦
(xiv) An appropriate level of root cause analysis should be applied
during the investigation of deviations, suspected product defects
and other problems.
◦
This
can
be
determined
using
Quality
Risk
Management
principles. In cases where the true root cause(s) of the issue
cannot
be
determined,
consideration
should
be
given
to
identifying the most likely root cause(s) and to addressing those.
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16. 1.4 A Pharmaceutical Quality System appropriate for the

manufacture of medicinal products should ensure that:
◦
(xiv). Where human error is suspected or identified as the cause,
this should be justified having taken care to ensure that process,
procedural or system based errors or problems have not been
overlooked, if present.
◦
Appropriate
(CAPAs)
corrective
should
be
actions
identified
and/or
and
preventative
taken
in
actions
response
to
investigations.
◦
The effectiveness of such actions should be monitored and
assessed, in line with Quality Risk Management principles.
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17. Identification
Define the Problem
Impact / Risk Assessment
Initial assessment of the impact and the magnitude of the problem.
Immediate Action
Protect the customer from the problem.
17

18. Root Cause Investigation:
Identify the root cause of the problem by using a systematic approach.
Conclusion and Quality Decision
Final thorough conclusion on the impact and magnitude of the problem,
decision regarding the use of the product, etc.
Action Plan
Define corrective and preventive actions
Implementation and Follow-up:
Implement corrective and preventive
actions and verify their effectiveness
(global approach).
18

19. 
To
enable
an
efficient
root
cause
investigation, the problem has to be clearly
defined.•

Collect
all
available
information,
ask
questions: Who, when, what, why, how

Summarize the problem in a detailed and
concise description.
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20. Deviations
Nonconformance
Out of
Specifications
Out of Trend
Equipment
Data
Yield Data
Rework Data
Returned
Products
Self
Inspections
Incoming
Inspections
Process
Control Data
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Supplier
Audits

21. Complaints
Customer
Audits
Warning
Letter
Adverse
Events
Regulatory
Audit
Recalls
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483
Observations

22. 
What is the process for events that “trigger”
a CAPA
◦ – Not every complaint is a CAPA
◦ – Not every non-conformance is a CAPA

Employ appropriate statistical methodology where
necessary to detect recurring quality problems.
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23. 
Common Statistical Techniques
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24. 
Other Analysis Techniques
◦ Management reviews
◦ Quality review
◦ Material review
◦ Other internal reviews
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25. The problem must be evaluated to determine the need for

immediate, corrective and preventive actions and the level
of action required, based on the impact and risk of the
problem.
The evaluation should include:

◦
Potential Impact of the problem.
◦
Risk to its customers and/or the company (i.e. risk to the patient
related to the quality, efficacy or safety of the product; risk for the
reputation of the company; risk of adverse regulatory actions;
financial risk)
◦
Immediate action that may be required
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26. 
FDA expects that the degree of corrective and preventive
action taken to eliminate or minimize actual or potential
nonconformities must be appropriate to the magnitude of
the
problem
and
commensurate
with
the
risks
encountered…

FDA does expect the manufacturer to develop procedures
for assessing the risk, the actions that need to be taken
for different levels of risk, and how to correct or prevent
the problem from recurring, depending on that risk
assessment.”
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27. Risk analysis allows a manufacturer to:

◦
Determine priorities
◦
Assign resources
◦
Determine the severity of impact
Determine the depth of investigation
◦
• Common tools

Hazard analysis
◦

Used early for potential problems
Failure Mode Effects Analysis (FMEA)
◦

Bottom up
Fault Tree Analysis (FTA)
◦

Top down
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28. 
Immediate action is necessary, when the
quality,
efficacy
or
safety
may
be
compromised by the problem.

Examples for immediate action:•
◦ Product recall
◦ Blockage of the stock of a product
◦ Rejection of a batch
◦ Interruption of the production (i.e. until problem is
assessed and fixed)
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29. 
A systematic approach should be applied to
ensure that no potential root cause is lost
through focusing only on a few assumed
root causes.

Tools
can
be
applied
to
facilitate
the
investigation, i.e.
◦ Start with a brainstorming, i.e. using an Ishikawa
diagram (fishbone or cause and effect diagram):
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30. List all potential root causes and evaluate their likelihood (also

using available supportive data and information):
◦
Likely–
◦
Possible (but less likely)–
◦
Remote, unlikely
If more than one root cause is likely, a simulation of the

potential root cause can help to prove the root cause.
Finding the primary root cause is essential for determining

appropriate corrective and/or preventive actions.
These “root causes” suggest that the failure investigation did not

go far enough–
◦
Training, operator error or similar „obvious“ root causes
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31. 
Summarize the identified root cause(s).•

Summarize the impact and the risk for the
customer and/or company.

Document the quality decision, i.e.–
◦ No impact of the deviation on the product quality,
efficacy or safety – product can be released.–
◦ Product is rejected due to major impact of the
failure on product quality.–
◦ Product is recalled.
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32. 
Based on the result of the root cause analysis,
all tasks required to correct the problem and
prevent
a
reoccurrence
are
identified
and
included in an action plan.

The plan assigns responsibilities and due dates
for implementation.

Enough detail must be included regarding the
required action and the expected outcome.•

Pay attention on correct order of activities.
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33. 
The Action Plan is executed and all tasks are completed.•

The actions that were taken are documented.•

The appropriateness and effectiveness of the actions
taken is evaluated:–
◦
Have all recommended changes been completed and verified?–
◦
Have all objectives been met?–
◦
Has training been performed to ensure that all affected
employees understand the changes that have been made?–
◦
Was an assessment made that the actions taken have not had an
adverse effect on other properties or aspects of a product or
process.

Closure of CAPA after successful implementation.
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34. Inspections
2001 to 2006
Non-conformances
Expand scope;
Emphasize investigation
quality;
little risk management
1995 to 2001
Quality Incidents
Expand scope to include
more
types of discrepancies
Management Review &
Quality Plan
Risk Based Approach
Implemented
Inspections
Prior to 1995
Deviation Reports
Report only major
departures from
procedure
Overwhelmed the
System with Numbers
Life Cycle Approach
Today
Non-conformances
Risk based, Strong
Governance with action
oriented management
review
1/2/2014
34

35. Pharmaceutical
Development
Product
or
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
process CAPA can be used as CAPA should be used CAPA
should
variability is explored. an effective system and the effectiveness continue after the
CAPA methodology is for
useful
feedback,
feed of the actions should product
where forward and continual be evaluated.
is
discontinued.
The
corrective actions and improvement.
impact on product
preventive actions are
remaining
incorporated into the
market
iterative design and
considered as well
development process.
as
should
other
which
on
the
be
products
might
be
impacted.
1/2/2014
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36. Warning Letter to a Canadian Company

◦
In addition, our investigator found that you do not determine and
implement corrective and preventive actions (CAPAs) in a timely manner
to prevent recurrence of manufacturing deviations.
◦
For example, the inspection noted that some CAPAs remained open for
approximately 500-700 days (one was open for 761 days) without
implementation of corrections.
◦
Your firm’s response stated that you have now completed these CAPAs.
◦
However, you failed to address why you had not completed these CAPAs
in a timely manner to prevent repetition of manufacturing problems.
◦
We are concerned that your response corrects the FDA 483 observation,
but does not provide for a systematic and sustainable correction to
ensure timely and effective CAPAs.
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37. Observation from form 483 from an International Sterile

Manufacturer.
◦
d. A 1/20/2010 CAPA, TRK# 93875, was implemented to address
execution of varied manual interventions (b)(4) specifically defined
interventions) performed during aseptic filling operations.
◦
However, not all of the personnel that are currently engaged in the
manufacture of finished products have completed the CAPA’s requisite
training.
◦
The number of employees and manual interventions range, for example,
from (b)(4) employees performing “stopper bowl change out” and “use
trayer plastic to tray vials, respectively (Note: aforementioned examples
are not intended to be an all inclusive lists of the number of employees
and manual interventions to be accomplished);
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38. Warning letter to a large Indian Company

◦
The inspection found that the laboratory manager had documented “NIL,”
(i.e. no growth for this plate), while the same laboratory manager
confirmed microbial growth in the presence of the investigators.
◦
Later during the inspection, the FDA investigator asked to see the original
plate and was told that it had been destroyed.
◦
On December 21, 2010, your firm prepared a corrective and preventive
action (CAPA) stating that the laboratory manager misread the plate
count, and that this deficiency was the result of a human error.
◦
We are concerned that your firm lacks documentation to support this
conclusion and moreover, that the original plate was destroyed during
the FDA inspection, as reported.
◦
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39. 
Expect FDA to review the actions taken

Be prepared to discuss the
◦
appropriateness of the action taken
◦
Why was corrective action taken?
◦
Does the corrective action extend to include
any additional actions (component suppliers,
training, acceptance activities, field actions) if
necessary?
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40. Verifying or validating the corrective and

preventive action to ensure that such
action is effective.
Effectiveness:

◦
Did the solution work?
◦
Did it create other potential non-conformances?
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41. 
Verify that verification/validation protocols
were established

Review data associated with verification or
validation activities

Review the effectiveness of the corrective
and preventive actions by reviewing data to
determine if similar quality problems exist
after implementation.
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42. 
Implement and record changes in
methods and procedures needed to
correct and prevent identified quality
problems.
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43. Tie CAPA implementation to:

◦
Document control for products and processes
◦
Change control
◦
Ensure that controlled documents are
reviewed and approved if changes are made.
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44. 
Expect FDA to verify implementation of
changes by viewing actual processes and
equipment

Implemented changes may directly link
to design or production and process
controls
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45. 
Ensure that information related to
quality problems or nonconforming
product is disseminated to those directly
responsible for assuring the quality of
such product or the prevention of such
problems.
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46. 
Submit relevant information on identified
quality problems, as well as corrective and
preventive actions, for management review.

The significance of the problem impacts the
level of management review.

Need management awareness and buy-in
so that resources are allocated,
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47. 
Document all activities and their results.
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48. CAPA is a “pulse check” for FDA on how well a

firm’s Quality System is operating –
◦
Strong CAPA systems are usually indicative of strong
Quality Systems

Feedback Loop between CAPA, Complaints, and
Nonconforming Product is essential

CAPA Subsystem is all about identifying and
resolving problems that can or have resulted in
nonconforming product.
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49. CAPA is much more than just “corrective
actions” and “preventive actions”.
Any opportunity to improve quality in your
organization is a CAPA!
49

50. 
This presentation was compiled from freely
available resources like the websites of FDA,
EMA, WHO.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
Drug Regulations : Online
Resource for Latest Information
1/2/2014
50