Corrective Action & Preventive ActionPresentation Transcript

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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

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Drug Regulations : Online Resource for Latest Information 1/2/2014 2 Visit

http://www.drugregulations.org for latest information from the world of Pharmaceuticals. Drug
Regulations is a non profit organization which provides free online resource to the Pharmaceutical
Professional. This presentation is compiled from freely available resources like the websites of FDA,
EMA, WHO.

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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 Drug Regulations : Online Resource for Latest Information 1/2/2014 3

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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. Drug Regulations : Online
Resource for Latest Information 1/2/2014 4

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CAPA methodology should result in product and process improvements and enhanced
product and process understanding. Drug Regulations : Online Resource for Latest Information
1/2/2014 5

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In the frame of the management review, management should be notified about the costs and
impact of failure including the respective corrective actions. Drug Regulations : Online Resource for
Latest Information 1/2/2014 6 Agreed corrective actions should be closely followed-up and
monitored until their completion. A systematic investigation should be performed to determine the
reason(s) for the non-conformities and to agree upon appropriate corrective action. Corrective
action may arise e.g. from manufacturing deviations, OOS investigations, complaints, audit findings,
recalls. Corrective action is aiming to correct an existing non-conformity and to avoid reoccurrence
of the same non-conformity.

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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) Drug Regulations : Online Resource for
Latest Information 1/2/2014 7

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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. Drug Regulations : Online Resource for Latest Information
1/2/2014 8 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). 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. Preventive action is aiming to avoid the initial occurrence of a nonconformity by proactively implementing improvements.

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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) Drug Regulations : Online
Resource for Latest Information 1/2/2014 9

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Responsibilities of a quality control unit...to assure that no errors have occurred or, if errors
have occurred, that they have been fully investigated. Drug Regulations : Online Resource for Latest
Information 10

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Written production and process control procedures shall be followed . Any deviation from
the written procedures shall be recorded and justified. Drug Regulations : Online Resource for Latest
Information 11

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Any unexplained discrepancyor 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. Drug Regulations : Online Resource for Latest Information 12

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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. Drug Article 10
Production Regulations : Online Resource for Latest Information 13

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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. Drug Regulations : Online Resource for Latest
Information 14 Any complaint concerning a defect shall be recorded and investigated by the
manufacturer Article 14 - Inspections Article 13 - Complaints

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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. Drug Regulations : Online
Resource for Latest Information 151.4 A Pharmaceutical Quality System appropriate for the

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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. Drug Regulations : Online Resource for Latest
Information 161.4 A Pharmaceutical Quality System appropriate for the

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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

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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

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Summarize the problem in a detailed and concise description. Drug Regulations : Online
Resource for Latest Information 19 Collect all available information, ask questions: Who, when,
what, why, how To enable an efficient root cause investigation, the problem has to be clearly
defined.

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Deviations Nonconformance Out of Specifications Out of Trend Equipment Data Yield Data
Rework Data Returned Products Self Inspections Incoming Inspections Process Control Data Drug
Regulations : Online Resource for Latest Information 20 Supplier Audits

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Complaints Customer Audits Warning Letter Adverse Events Regulatory Audit Recalls Drug
Regulations : Online Resource for Latest Information 21 483 Observations

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Employ appropriate statistical methodology where necessary to detect recurring quality

problems. Drug Regulations : Online Resource for Latest Information 22 What is the process for
events that trigger a CAPA Not every complaint is a CAPA Not every non-conformance is a
CAPA

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Common Statistical Techniques Drug Regulations : Online Resource for Latest Information
23

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Other Analysis Techniques Management reviews Quality review Material review Other
internal reviews Drug Regulations : Online Resource for Latest Information 24

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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 Drug
Regulations : Online Resource for Latest Information 25 immediate, corrective and preventive
actions and the level of action required, based on the impact and risk of the problem. The evaluation
should include: The problem must be evaluated to determine the need for

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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. Drug Regulations : Online Resource for Latest
Information 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

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Top down Drug Regulations : Online Resource for Latest Information 27 Bottom up Fault
Tree Analysis (FTA) Used early for potential problems Failure Mode Effects Analysis (FMEA)
Hazard analysis Determine priorities Assign resources Determine the severity of impact
Determine the depth of investigation Common tools Risk analysis allows a manufacturer to:

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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) Drug
Regulations : Online Resource for Latest Information 28 Immediate action is necessary, when the
quality, efficacy or safety may be compromised by the problem.

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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): Drug Regulations : Online Resource for
Latest Information 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.

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go far enough Training, appropriate corrective and/or preventive actions. These root
causes suggest that the failure investigation did not potential root cause can help to prove the root
cause. Finding the primary root cause is essential for determining 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 List all potential root causes and evaluate their likelihood (also operator
error or similar obvious root causes Drug Regulations : Online Resource for Latest Information 30

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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. Drug Regulations : Online Resource for Latest Information
31 Summarize the impact and the risk for the customer and/or company. Summarize the identified
root cause(s).

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Pay attention on correct order of activities. Drug Regulations : Online Resource for Latest
Information 32 Enough detail must be included regarding the required action and the expected
outcome. The plan assigns responsibilities and due dates for implementation. 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.

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Closure of CAPA after successful implementation. Drug Regulations : Online Resource for
Latest Information 33 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. The actions that were taken are documented.
The Action Plan is executed and all tasks are completed.

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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

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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 35

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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 firms 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. Drug Regulations :
Online Resource for Latest Information 36Warning Letter to a Canadian Company

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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 CAPAs 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); Drug Regulations : Online Resource for Latest Information 37Observation from form
483 from an International Sterile
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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. Drug Regulations : Online Resource for Latest Information 38Warning
letter to a large Indian Company

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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? Drug Regulations : Online Resource for
Latest Information 39 Expect FDA to review the actions taken

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Did the solution work? Did it create other potential non-conformances? Drug
Regulations : Online Resource for Latest Information 40 preventive action to ensure that such
action is effective. Effectiveness: Verifying or validating the corrective and

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Review the effectiveness of the corrective and preventive actions by reviewing data to
determine if similar quality problems exist after implementation. Drug Regulations : Online Resource
for Latest Information 41 Review data associated with verification or validation activities Verify that
verification/validation protocols were established

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Implement and record changes in methods and procedures needed to correct and prevent
identified quality problems. Drug Regulations : Online Resource for Latest Information 42

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Document control for products and processes Change control Ensure that controlled
documents are reviewed and approved if changes are made. Drug Regulations : Online Resource for
Latest Information 43Tie CAPA implementation to:

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Implemented changes Expect FDA to verify implementation of changes by viewing actual

processes and equipment may directly link to design or production and process controls Drug
Regulations : Online Resource for Latest Information 44

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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. Drug Regulations : Online Resource for Latest Information 45

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Need management awareness and buy-in so that resources are allocated, Drug Regulations
: Online Resource for Latest Information 46 The significance of the problem impacts the level of
management review. Submit relevant information on identified quality problems, as well as
corrective and preventive actions, for management review.

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Document all activities and their results. Drug Regulations : Online Resource for Latest
Information 47

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CAPA Subsystem is all about identifying and resolving problems that can or have resulted in
nonconforming product. Drug Regulations : Online Resource for Latest Information 48 Feedback
Loop between CAPA, Complaints, and Nonconforming Product is essential firms Quality System is
operating Strong CAPA systems are usually indicative of strong Quality Systems CAPA is a
pulse check for FDA on how well a

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CAPA is much more than just corrective actions and preventive actions. Any opportunity to
improve quality in your organization is a CAPA! 49

50.

Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.

Drug Regulations : Online Resource for Latest Information 1/2/2014 50 Drug Regulations is a non
profit organization which provides free online resource to the Pharmaceutical Professional. This
presentation was compiled from freely available resources like the websites of FDA, EMA, WHO.