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Corrective And Preventive
Action
CAPA: A Risk Mitigating Quality
System
Conducted by Gamal Amer, Ph.D.
PrincipalPrincipal
Premier Compliance Services, Inc.
© All rights reserved. Do not copy without permission. 1

FDA Initiative August 2002
Pharmaceutical CGMP for the 21st Century:
A Risk-based Approach
A science and risk-based approach to product quality regulation
incorporating an integrated quality system approach

Mitigating Risk
FDA Progress Reports discusses three
QA systems to mitigate risk:QA systems to mitigate risk:
1. Process Analytical Technology (PAT)
2. Corrective and Preventive Action (CAPA)
3. Quality by Design (QbD)

Risk
What Is Risk?
What Causes It?
Risk to Whom?Risk to Whom?
Risk Manifestation?
Risk Level?

Quality Events Which May CauseQu y ve s W c y C use
Increased Risk
• A problem occurs during clinical trials (patient
complains/suffers)complains/suffers)
• A deviation occurs during the manufacturing
A i f i t f il hil th• A piece of equipment fails while the process
is engaged.
• Analytical result is not what was expected

E t P t ti ll I iEvents Potentially Increasing
Risk
No negative quality event occurred, but:g q y
• Patient complaints show a negative trend.
i d if i / di d i• Operation drifting/trending towards action
limit.
• Analytical data trending towards
unacceptable.

These Events Pose:
• Risk to the patient/public
• Risk to the productRisk to the product
• Risk to the personnel
Ri k h i• Risk to the environement
• Risk to the company

What Is Risk?
The combination of the probability ofThe combination of the probability of
occurrence of harm and the severity of that
harm.*
*Guidance for Industry; ICH Q9 Quality Risk Management; June 2006

What Is The Risk?What Is The Risk?
• In Drug Application:
– The pros and cons of the treatment
• In Process Design:
– Failure to recognize source of variability and how CPP
affect CQA of product
• In Process Qualification:In Process Qualification:
– Failure to qualify a critical (high risk) portion of the
process.
• In Manufacturing:
– Quality events occurring as the process is engaged

Some Sources of Increased Risk
in Manufacturing?
• Processing Deviations and Non Conformance
A ti P i• Aseptic Processing
• Labeling Errors (Majority of drug recalls due to
mislabeling)mislabeling)
• Analytical and Measuring Errors
D li ith t t d• Dealing with potent compounds
• People Errors

Defining Level of RiskDefining Level of Risk
F i fFunction of:
– Severity
F– Frequency
– Detectability
• These three factors determine the numerical
Risk Priority Number (RPN)Risk Priority Number (RPN)
• Qualitative risk (low, medium, and high)

CAPA = Corrective Action /CAPA Corrective Action /
Preventive Action

Risk Within the Context ofRisk Within the Context of
CAPA Systemy
• A non-conformance or deviation occurs or a potential
problem is identified.p
• These pose risk.
• CAPA should define the risk, its level, and means to
mitigate itmitigate it.
• CAPA should then implement the actions to mitigate
the risk and track to ensure closure.
M i i i ff i d did• Monitor to ensure action is effective and did not
introduced new risk(s).

Non-conformance and Deviation
Non-Conformance:
Failure to meet a specified requirement.p q
Deviation:
Failure to follow or implement an establishedFailure to follow or implement an established
requirement. Typically this term is used
relevant to processes (as in a “processrelevant to processes (as in a process
deviation”).

Risk Level Factors: Severity
• What are the consequences of the non-conformanceq
or deviation?
• How deleterious is that non-conformance or
deviation to the consistent quality of the product?
• How high is the risk to the patient’s well being?

Risk Level Factors: Frequency
• What are the probability of the reoccurrence
of the non-conformance or deviation?
• Were attempts made to reduce such
frequency and how effective?frequency and how effective?
• Review process history to determine.

Risk Level Factors: Detectability
• What is the probability of the non-conformance or
d i i b i d d?deviation being detected?
• Can the effect/result of the non-conformance or
d i ti b dil d/ ?deviation be readily measured/seen?

Change Control is an ImportantChange Control is an Important
Component of CAPA

Change Control: A Regulatory
I iImperative
• Is a regulatory requirementIs a regulatory requirement
• 211.68(b) Appropriate controls shall be exercised
over computer or related systems to assure thatp y
changes....
• 211.100 (a) ....written procedures, including any( ) p , g y
changes, shall be drafted, reviewed, and approved
by the appropriate organizational units and
reviewed and approved by the quality control unit.

211 160( ) h i h ifi ti• 211.160(a) change in such specifications,
standards, sampling plans, test procedures, or
other laboratory control mechanisms shall beother laboratory control mechanisms, shall be
drafted by the appropriate organizational unit and
reviewed and approved by the quality control unit.
• Guidance to Industry on Process Validation: The
qualification plan for the facility and utilities
should identify 1) studies.... 2)Criteria to assess
outcome...It should also include the firm's
i t f th l ti f hrequirements for the evaluation of changes.

• ICH Q7-API GMP (13) A formal change control
system should be established to evaluate all
changes that could affect the production and
control of the intermediate or API.
A l f GMP l h h ld• Any proposals for GMP relevant changes should
be drafted, reviewed, and approved by the
appropriate organizational units and reviewed andappropriate organizational units and reviewed and
approved by the quality unit(s).

What is a Change ControlWhat is a Change Control
System?
It is a formal system which is designed not to
prevent change but rather document and control itprevent change, but rather document and control it.
Its main purpose is to ensure that a
system/process/operation is always in a GMPy p p y
compliant and validated state, regardless of changes
made to it. It is usually implemented using a
procedure.

System?
ICH Q9 – Quality Risk Management
T h b d k l d d• To manage changes based on knowledge and
information accumulated in pharmaceutical
development and during manufacturingdevelopment and during manufacturing.
• To evaluate the impact of the changes on the
availability of the final product.availability of the final product.

System?
• To evaluate the impact on product quality of
changes to facility equipment materialchanges to facility, equipment, material,
manufacturing process or conducting technical
transfers.
• To determine appropriate actions preceding the
implementation of a change, e.g., additional testing,
(re)qualification, (re)validation, communication
with regulators.

The Compliance/Validationp
Life Cycle-
Compliant &
Validated System
Implement ChangeChange Control
SystemSystem
Modified System

Importance of Change ControlImportance of Change Control
• Not to prevent change• Not to prevent change.
• To control and document change.
• Required by the regulations.
• Identify GMP and validation implications.y p
• Ascertain process remains in a state of
controlcontrol.
• Must be implemented using a procedure.

Change Control procedure
Change requiredChange required
GenerateGenerate
Change Request
End
GMP
Implications?
No
Yes
Implement Change
Maintenance
NoRequalification?
Revalidation?
Yes
Implement Change
& Insure GMP
Requirements Done
Issue GMP
Report
Obtain Approval
Yes
Change is
Permanent
Requalify
Revalidate &
Issue Reports
Obtain
Approvals
Change is
Permanent
End

CAPA: Mitigating Risk
The degree of corrective and preventive
action taken to eliminate or minimize actual
or potential nonconformities must be
appropriate to the magnitude of the problempp p g p
and commensurate with the risks
encountered. (ICH Q9)( Q )

Risk Level and Appropriate Corrective Action
Risk Level
(RPN) Low Medium HighCorrective Action
No Further Investigation ,
No Corrective action
required
No Further Investigation
(Cause Evident),
Corrective action required
Further Investigation (Root
Cause Analysis), Correctivey ),
action required (Immediate;
e.g.. Recall), Prevent Cause

What Is CAPA?

CAPA Is:
• A quality based system• A quality based system
• Uses Non-conformance, Deviations and/or an
Expectation of such as inputExpectation of such as input
• Uses many of the quality systems in place as tools:
– Historical Quality Issues and Audit Reports
– Environmental and Process Monitoring Data
– Product Complaints
– Equipment Service & Maintenance Records
– Process and scientific Knowledge
– Operating Procedures and Methodology

CAPA Uses:
• Policies and proced res to in estigate• Policies and procedures to investigate
quality problems.
• Policies and procedures to identify and• Policies and procedures to identify and
implement corrective and preventive
actionsactions.
• A tracking mechanism to ensure
investigation and proper corrective actionsinvestigation and proper corrective actions
are conducted and implemented on a timely
basis.

CAPA InvestigationCAPA Investigation
• Investigate the cause of non-conformity or
deviation as it relates to the product, processes,
and the quality system. (reactive)
I ti t t ti l i k f t d• Investigate potential risk of an expected or
anticipated event. (proactive)
• Depending on risk severity the investigation mayDepending on risk severity, the investigation may
need to define the “Root Cause.”
• Use tools such as HAZOP, HACCP, Failure Mode, ,
& Effect Analysis, Fault Tree Analysis, What If,
etc.

CAPA Identification
• Identify the action needed to correct, reduce, or
prevent recurrence of nonconformance of productp p
and other quality problems.
• Identify the action needed to correct and preventIdentify the action needed to correct and prevent
recurrence of the deviation in the process.
• Identify the action needed to prevent the potential• Identify the action needed to prevent the potential
occurrence of an anticipated quality event.

Possible Corrective Actions
• Design Changes*
• Manufacturing Process Changes*
• Removal of product from the market through
recall
• Operator Training• Operator Training
• Labeling changes*
• Patient education• Patient education
________________________________________________________________________________
* Keep in mind that making changes must be managed using change control in order to
avoid introducing additional risk.

Tracking CAPA Activities
• What to track?
– The quality event and timing for initiating an investigation
– Timing for completing assessment
– Timing for developing action plan
– Timing for implementing all necessary actions (changes,
training, document modification, etc.)
– Timing for completing the necessary documentationTiming for completing the necessary documentation
– Completion of the actions and closure of the deviation or
nonconformance

Tracking CAPA Activities
• How to track?
– Manual TrackingManual Tracking
• Too much paper
• Very cumbersome and time consuming
• Limited Access
– Software Packages (Part 11 compliant)
• Trackwise (MS Outlook)
• Livelink (Lotus)

Post CAPA Monitoring
• Ensures actions were effective in mitigating
the risk.
• Ensure actions were effective in
correcting/preventive the problem.
• Ensures no additional risks were introduced
due to the actions taken.
• Required as part of GMP compliance and
process validation (FDA Guidance 1/2011).

Typical CAPA Overall Approach
Quality Event
Ri k
Quality Event
Identify Risk Risk
Acceptance Document
History
Monitoring
Analyze Risk Risk Reduction
Track&
Monitor
Complaints
Science &
Evaluate Risk
A i RPN
Risk
Elimination/
Communicate
Review
Knowledge
Procedures, Service
& Maintenance
Assign RPN
Risk
Assessment/
Investigate
prevention
Review
Identify &
l A i
Document, Track,
Monitor &
Implement Actions
Monitor &
Communicate

System Components
D i ti ti d i ti ti d• Deviation reporting and investigation procedure.
• Rework Procedures.
M i d hi i l D li di• Maintenance records, historical Data, quality audit
results, etc.
P d i t l it i• Process and environmental monitoring programs.
• Change Control Procedure.
Ri k A l i P d h HAZOP• Risk Analysis Procedures such as HAZOP,
HACCP, Fault Tree Analysis, etc.

CAPA
Steps to Be Taken

Label and Segregate Non-Label and Segregate Non-
conforming Product
• Ensure nonconforming product is properly
labeled (for example HOLD REJECTlabeled (for example, HOLD, REJECT,
QUARANTINE).
E t f i d t• Ensure suspect or non-conforming product
is properly labeled and segregated (not
d) t t f th diused) to prevent further use pending
disposition.

Document The Issue
• Record nonconformance on a
Nonconforming Materials Report.g p
• Record Deviation on a Deviation Reporting
FormForm.
• Document all studies and decisions made
during the investigation of the quality eventduring the investigation of the quality event.

Segregate Material & Equipment
A h i l ( d ) i• Assure that suspect materials (non-product) is
segregated and labeled.
• Assure all suspect lots batches units materials• Assure all suspect lots, batches, units, materials,
etc are identified and segregated.
• Assure that the segregation (who, what, where,g g ( , , ,
when, how) is documented on the
nonconformance report.
T d l k ll i d f h• Tag and lock all equipment and parts of the
process which maybe suspect.

Evaluate
• Review the event, the circumstances surrounding the event.
• Document relevant details as part of the nonconformance
or deviation reportor deviation report.
• Risk to quality should be linked to protecting the patient.
• Use RPN to help determine need for in-depth investigation
and Corrective/Preventive Action (in other words: the
effort, formality and documentation should be
commensurate with the level of risk and be based on
science*).
__________________________________________________________________________
*Guidance for Industry; ICH Q9 Quality Risk Management; June 2006

Risk Level and Appropriate Corrective Action
Risk Level
(RPN) Low Medium HighCorrective Action
Further Investigation (Root
Cause Analysis), Corrective
action required (Immediate;
e Re ll) P e e t C ee.g.. Recall), Prevent Cause
No Further Investigation
(Cause Evident),
No Further Investigation , NoNo Further Investigation , No

Take Action
M k h d i k• Make necessary changes to reduce risk or
eliminate it.
• Invoke Change Control• Invoke Change Control.
• Track to ensure CAPA closure in a timely fashion.
• Evaluate the actions to ensure they were effectiveEvaluate the actions to ensure they were effective
in mitigating the risk as intended.
• Monitor the process to ensure it has not beenp
negatively affected by changes and that no
additional or different risks were introduced.

Benefits of a Robust CAPA
System
• Fulfills the promise of continuous improvement
• Leads to better customer satisfaction and less risk
h blito the public.
• Better use of resources through a structured QA
systemsystem.
• Facilitate better and more informed decisions by
manufacturers.
• Makes good business and financial sense.
• Increasing your compliance quotient.
g y p q

Summaryy
• CAPA is a regulatory requirement which makes business sense.
• CAPA is a risk mitigating approach, which fulfills the promise of
continuous improvementcontinuous improvement.
• Non-conformances, deviations or anticipated quality events are
input to the CAPA program.
• All aspects of the CAPA program should be thoroughly• All aspects of the CAPA program should be thoroughly
documented.
• Risk level assessment, as part of CAPA:
provides the means for rationalizing the scope andp g p
extent of investigation and/or corrective action
necessary.
helps management assign resources to tasks providing
the most al e and ha ing the biggest impact onthe most value and having the biggest impact on
quality and customer satisfaction.
• Tracking, reviewing, and monitoring CAPA related activities is an
important aspect of the program.
important aspect of the program.

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