CAPA: A Risk Mitigating Quality System

Corrective And Preventive
Action
CAPA: A Risk Mitigating Quality
System

Conducted by Gamal Amer, Ph.D.
Principal
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:
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 Manifestation?
Risk Level?


Qu y ve s W c
Quality Events Which May Cause
y C use
Increased Risk
• A problem occurs during clinical trials (patient
complains/suffers)

• A deviation occurs during the manufacturing
• A piece of equipment fails while the process
i f i t f il hil th
is engaged.
• Analytical result is not what was expected


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

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


What Is Risk?

The 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?
• 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:
– 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 Processing
Aseptic P i
• Labeling Errors (Majority of drug recalls due to
mislabeling)
• Analytical and Measuring Errors
• D li with potent compounds
Dealing ith t t d
• People Errors


Defining Level of Risk
Function of:
F i f
– Severity
–FFrequency
– Detectability

• These three factors determine the numerical
Risk Priority Number (RPN)
• Qualitative risk (low, medium, and high)


CAPA = Corrective Action /
Preventive Action


Risk Within the Context of
CAPA System
y
• A non-conformance or deviation occurs or a potential
p
problem is identified.
• These pose risk.
• CAPA should define the risk, its level, and means to
mitigate it.
it
• CAPA should then implement the actions to mitigate
the risk and track to ensure closure.
• M i to ensure action is effective and did not
Monitor i i ff i d
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 established
requirement. Typically this term is used
relevant to processes (as in a “process
process
deviation”).


Risk Level Factors: Severity

• What are the consequences of the non-conformance
q
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?
• Review process history to determine.


Risk Level Factors: Detectability

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


Change Control is an Important
Component of CAPA


Change Control: A Regulatory
Imperative
I i
• Is a regulatory requirement
• 211.68(b) Appropriate controls shall be exercised
over computer or related systems to assure that
p 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( ) change in such specifications,
211.160(a) h i h ifi ti
standards, sampling plans, test procedures, or
other laboratory control mechanisms shall be
mechanisms,
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
requirements for the evaluation of changes.
i t f th l ti f h


• 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 proposals f GMP relevant changes should
Any l for l h h ld
be drafted, reviewed, and approved by the
appropriate organizational units and reviewed and
approved by the quality unit(s).


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

© All rights reserved. Do not copy without permission. 22 22

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


System?
• To evaluate the impact on product quality of
changes to facility, equipment, material,
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/Validation
p
Life Cycle -

Compliant &
Validated System

Change Control
Implement Change
System

Modified System


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


Change Control procedure
Change required

Generate
Change Request

No
GMP Implement Change
Implications? Maintenance End

Yes

Requalification? No Implement Change
Issue GMP Obtain Approval
Revalidation? & Insure GMP
Requirements Done Report

Yes

Requalify
Obtain Change is
Revalidate & Change is
Issue Reports Approvals Permanent 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 p
pp p g problem
and commensurate with the risks
encountered. (ICH Q )
( Q9)


Risk Level and Appropriate Corrective Action

Risk Level
(RPN) Low Medium High
Corrective Action

No Further Investigation ,
No Corrective action
required

No Further Investigation
(Cause Evident),
Corrective action required

Further Investigation (Root
Cause Analysis), Corrective
y ),
action required (Immediate;
e.g.. Recall), Prevent Cause


What Is CAPA?


CAPA Is:
• A quality based system
• Uses Non-conformance, Deviations and/or an
Expectation 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 procedures to in estigate
proced res investigate
quality problems.
• Policies and procedures to identify and
implement corrective and preventive
actions.
actions
• A tracking mechanism to ensure
investigation and proper corrective actions
are conducted and implemented on a timely
basis.

CAPA Investigation
• Investigate the cause of non-conformity or
deviation as it relates to the product, processes,
and the quality system. (reactive)
• I
Investigate potential risk of an expected or
ti t t ti l i k f t d
anticipated event. (proactive)
• Depending on risk severity the investigation may
severity,
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
p
prevent recurrence of nonconformance of product
p
and other quality problems.
• Identify the action needed to correct and prevent
recurrence of the deviation in the process.
• 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
• Labeling changes*
• 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 documentation
– Completion of the actions and closure of the deviation or
nonconformance


Tracking CAPA Activities
• How to track?
– Manual 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

History Identify Risk Risk
Ri k
Acceptance Document
Monitoring

Complaints Track&
Analyze Risk Risk Reduction Monitor
Science &
Knowledge

Procedures, Service
Risk Communicate
& Maintenance Evaluate Risk Elimination/
Assign
A i RPN prevention
Review
Risk
Assessment/
Identify & Document, Track,
Investigate
Monitor &
Implement Actions
l A i Communicate

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


CAPA
Steps to Be Taken


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


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


Segregate Material & Equipment
• A
Assure that suspect materials (non-product) i
h i l ( d ) is
segregated and labeled.
• Assure all suspect lots batches units, materials
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 and lock all equipment and parts of the
Tag d l k ll i d f h
process which maybe suspect.


Evaluate
• Review the event, the circumstances surrounding the event.
• Document relevant details as part of the nonconformance
or deviation report.
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 High
Corrective Action

Further Investigation (Root
Cause Analysis), Corrective
action required (Immediate;
e.g.. Re ll) P e e t C e
e Recall), Prevent Cause

No Further Investigation
(Cause Evident),

No Further Investigation , No


Take Action
• M k necessary changes to reduce risk or
Make h d ik
eliminate it.
• Invoke Change Control.
Control
• Track to ensure CAPA closure in a timely fashion.
• Evaluate the actions to ensure they were effective
in mitigating the risk as intended.
• Monitor the process to ensure it has not been
p
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
to the public.
h bli
• Better use of resources through a structured QA
system.
system
• Facilitate better and more informed decisions by
manufacturers.
• Makes good business and financial sense.
• Increasing your compliance q
gy p quotient.

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


CAPA: A Risk Mitigating Quality System

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