Investigation Process and CAPA Management

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Investigation Process and CAPA

Management

A complete guide

Before starting the process of investigation, let’s understand briefly about Corrective Action and Preventive Action (CAPA), its linkages with the guidance and regulations and how it links with the investigation. We shall also look at the few examples of the regulatory citation because of deficiencies related to investigation and CAPA. In this article, most of the

examples and regulatory linkages are used with respect to pharmaceutical industry.

However, the similar approach can be used to carry out an investigation and defining the CAPA.

Introduction to the Corrective Action and Preventive Action (CAPA):

To introduce Corrective Actions and Preventive Actions (CAPA), let’s understand few definitions.

“Correction” action to eliminate a detected nonconformity

1. A correction can be made in conjunction with a corrective action 2. A correction can be, for example, rework or re-grade

“Corrective action” action to eliminate the cause of a detected non-conformity or other undesirable situation

1. There can be more than one cause for nonconformity 2. Corrective action is taken to prevent recurrence

3. There is a difference between correction and corrective action

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“Preventive action” action to eliminate the cause of a potential non-conformity or other undesirable situation

1. There can be more than one cause for a potential nonconformity 2. Preventive action is taken to prevent occurrence

Reference: ISO 9000:2005 (E)

Mature Quality

system detects

problem before it

occur and required

controls put in

place

Image source: https://www.thema-med.com/en/corrective-preventive- actions-causes-investigation/

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Evolution of CAPA:

In regulatory environment, the CAPA system in evolved

gradually from reporting the events to the risk based life cycle approach.

The diagram alongside is self-

explanatory. Reference: www.fda.gov

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Regulations and its linkages with CAPA:

When you look at the regulations, US, Europe or any other regulations, all the regulations are linked with the requirement of Corrective Action and Preventive Actions (CAPA).

US Regulation: 21 CFR Part 211.22 - Responsibility of

Quality Unit

US Regulation: 21 CFR Part 211.100 - Written

Procedures

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US Regulation: 21 CFR Part 211.192 - Production

record review

European Commission Directive: 2003/94/EC

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European Commission Directive: 2003/94/EC

EudraLex: Vol 4: Chapter 1 Pharmaceutical Quality

System

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EudraLex: Vol 4: Chapter 1 Pharmaceutical Quality

System

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Example of Investigation and CAPA deficiencies:

Many organizations came across the situation where they got the FDA Warning Letter for Failure to include adequate documentation during investigation. I have removed the name of an organization in this article.

Observation: Failure to include adequate documentation during complaint investigation.

Your firm received complaint #(b)(4) for (b)(4) USP batch #(b)(4) due to failing assay results.

The original investigation, approved on March 29, 2013, indicated that the complaint was received on February 26, 2013. During the review of that investigation, our investigators found a test record from January 8, 2013 (prior to the date you documented receiving the complaint) that reported failing HPLC assay results of the retain sample of batch (b)(4). This record was not included in the investigation report. Your response to the Form FDA-483 observation included an addendum to the investigation report that indicated the

complaint/query was actually received on January 8, 2013.

Observation: Failure to ensure that all test procedures are scientifically sound and

appropriate to ensure that your raw materials, intermediate and API conform to established standards of quality and purity.

The inspection documented that your test methods were not robust.

Investigation report OOS/2015/037, related to an OOS assay result for (b)(4) intermediate API, concluded that the standard preparation degraded because the HPLC auto sampler temperature was held at (b)(4)° C. According to your response, the test method was revised to incorporate the (b)(4) of the auto sampler at (b)(4)° C, because your method previously lacked the needed specificity. Your CAPA did not extend to specificity of your laboratory’s other test methods to ensure their parameters were sufficient.

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Reference: www.gov.uk

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Process of investigation and identification of CAPA:

Here we have tried to simplify the process steps to investigate using seven steps method.

These steps are identification of an event, risk evaluation, investigation of an event, root cause analysis, defining and action plan, implementation of planned actions and finally closure of an event. The event could be process deviation, laboratory event, complaint investigation, or any other kind of investigation.

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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Let’s understand each step one by one in detail in the following sanction of an article.

Step 1: Identification of an event

Identification of problem includes clearly defining and explaining the problem. This step is very much important because correct definition of the problem will take you in correct direction during the investigation. Incorrectly defined problem will take you to the wrong direction and root cause of an event would be very difficult to identify.

Problem: The term problem means “Non-conformity, defect or un-fulfillment of a requirement in a product or system or process”.

Identification description must include source, complete information of event or problem and collection of document evidence.

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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To identify the complete information we can use simple tool called as 5W2H. This

methodology will help to describe the event very precisely. Let’s understand each element of as 5W2H.

What: Details of abnormality

When: Date, Shift and Time of Event Where: Location/ Plant/ Line

Which: Machine/ Product/ Batch number

Who: The person who identified or noticed the event How: Mode or situation of occurrence

How Many: Batches, number of times

The problem identification could be done by internal source or external source as explained in the following schematic.

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Step 2: Risk evaluation

The identified problem needs to be assessed for the risk. The risk assessment is required to be done to determine the need for immediate action/ countermeasure, level of actions, and investigation required. A potential risk could be the product safety, efficacy, quality,

material rejection, yield, delay in processing, etc.

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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An evaluation includes

• Potential impact of the event

• Risk to company and customer

• Remediation action

Image source: securityboulevard.com

You can classify a risk using a qualitative or quantitative approach. In broad terms, risk categories are Critical, Major, or Minor. The most preferred method of categorization of risk is the quantitative approach. One can apply the tools such as the Failure Mode Effect

Analysis (FMEA) where, the Risk Priority Number (RPM) calculated using the Severity (S), Detectability (D), and Probability of occurrence (P).

Remedial actions/ countermeasures - The required measures are decided based on potential impact and risk assessment. The risk assessment helps to understand whether immediate action is needed to remedy the situation until a permanent solution or not.

Immediate communications - Timely inform to all the concerned authorities is an essential step. In case of a critical event, the defect may result in the product recall or restriction in the product supply. Such an event needs immediate communication to the customers, regulatory agency, and relevant stakeholders who could have been affected by the event.

In some cases, remediation action may be sufficient. It does not require additional CAPA.

The event can be closed with logical and scientifically sound rationale.

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Step 3: Investigation of an event

Definition of investigation

“the action of investigating something or someone; formal or systematic examination or research.”

Google dictionary meaning

“the act or process of examining a crime, problem, statement, etc.

carefully, especially to discover the truth”

Cambridge dictionary meaning

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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Steps of preliminary investigation and detailed investigation

 Write down an objective

 Formation of cross functional team

 Collection of supporting information and evidences

 Documentation

 Decision on CAPA

Image source: stockfresh.com

Objective: The objective of a preliminary investigation is to collect the maximum possible and available information. The information is about the event and clues responsible for the cause of an event. An objective statement is critical to draw the investigation path.

Cross functional team: It is essential to build a cross-functional team as quickly as possible to collect first-hand information. The team members should know the subject, analytical thinking, logical thinking, training, experience, or a combination of these skills.

The collection of first-hand information and relevant data is critical to identify the root cause. Take care that all possible data is collected and nothing is overlooked. Data collection may include area, equipment, associated lot numbers, environmental conditions, personnel involved in the process, prior knowledge and training of involved personnel, batch

document, lab notebook, or any physical condition of the area or object associate with the event.

The investigation should cover a comprehensive review of all the circumstances such as Machine, Material, Method, Measurement, Mother Nature, and Man.

The data collected shall be organized into formats for easy comparison and data analysis.

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“Many manufacturers tend to overuse training as a corrective action and do not adequately address the systemic corrective action” [source of the quote is FDA presentation by Kimberly Lewandowski-Walker]

Perform data analysis using statistical tools such as graphs, histograms, standard deviations, or non-statistical techniques. It will help to identify the root cause of the event.

Histogram to determine frequency distributions and magnitude

The control chart to understand process changes over time

tabulate the number of yes

& no answers, than calculate for % of each

Decision on with further root cause analysis or conclude on investigation:

Based on the preliminary investigation, data compilation, and data analysis, the event can be closed. Carefully evaluate such a situation before deciding the closing of an event to avoid any regulatory non-conformance during the inspection. The following could be scenarios where the event can be closed at this stage.

 Incident is happened for the first time and risk associated with the incident is negligible.

 Similar incident had happened in recent past, to which a corrective action and preventive actions are under implementation.

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Step 4: Root cause analysis

If the root cause is not identified after the preliminary investigation, the root cause analysis can be done as explained in this section.

Collecting relevant data

Investigating all possible causes

Determine root cause/ most probable cause

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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Regulatory reference

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 product, or other quality problems.

Appropriate statistical methodology shall be employed where necessary to detect recurring quality problems.

Reference: 21 CFR 820.100(a)(1)

“FDA emphasizes that the appropriate statistical tools must be employed when it is necessary to utilize statistical methodology. FDA has seen far too often the misuse of statistics by manufacturers in an effort to minimize instead of address the problem. Such misuse of statistics would be a violation of this section.”

Reference: www.fda.gov

Common Statistical Techniques:

 Pareto charts

 Run charts

 Control charts

 Mean and standard deviation

 T tests for comparisons

 Experimental design (DOE)

 Graphical methods (fishbone diagrams, histograms, scatter plots, spreadsheets, etc.) Reference: www.fda.gov

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Pareto charts:

A Pareto chart, named after Vilfredo Pareto, is a type of chart that contains both bars and a line graph. Descending order by bars represents individual values. The lines represent the cumulative total.

A Pareto Chart is a chart that indicates the frequency of defects and their cumulative impact.

Histogram:

A histogram is an accurate representation of the distribution of numerical data. It is an estimate of the probability distribution of a continuous variable and was first

introduced by Karl Pearson. To construct a histogram, the first step is to "bin" the range of values. Divide the entire range of values into a series of intervals and then count how many values fall into each interval. The bins are usually specified as consecutive, non- overlapping intervals of a variable.

Bin Count

−3.5 to -2.51 9

−2.5 to -1.51 32

−1.5 to -0.51 109

−0.5 to 0.49 180 0.5 to 1.49 132 1.5 to 2.49 34 2.5 to 3.49 4

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Different types of histogram are demonstrated as follows.

Normal Distribution

Skewed Distribution

Double-Peaked or Bimodal

Plateau or Multimodal Distribution

Edge Peak Distribution

Comb Distribution

Truncated or Heart-Cut Distribution Dog Food Distribution

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Commonly used root cause analysis tools:

 Fishbone diagrams

 5 “whys”

 Fault-tree analysis

 Among others Reference: www.fda.gov

Fishbone or cause-and-effect diagram

Fishbone diagrams are also called Ishikawa diagrams, herringbone diagrams, cause-and- effect diagrams, or Fishikawa. Professor Kaoru Ishikawa created Cause and Effect Analysis in the 1960s to solve problems at the Kawasaki shipyards. Root cause analysis should be a team process to identify underlying causes of an incident, deviation, complaints, adverse event, or near-miss.

The fishbone tool can help in brainstorming to identify possible causes of a problem. The tool makes the process structured approach to understanding potential causes of the issue to be solved. The method is a visual way to look at cause and effect.

1. Five step easy process to create Fishbone Diagram:

Following are simple steps to be followed to solve a problem with Fishbone Analysis Step a: To carry out an investigation, identify the cross-functional team (CFT)

members who have domain knowledge, Subject Matter Experts (SMEs) of the processes and systems involved in the problem or event.

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Step b: Write the Effect/ problem to be solved in the right side box.

Step c: The next step is to decide possible contributing causes and write them down in bones under various categories and subcategories. For the manufacturing or process domain, generally considered items are Machine, Method, Materials,

Measurement, Man, and Mother Nature/ Environment. However, depending on the nature of the problem and situation, the categories can be varied.

Step d: Perform brainstorming by CFT for all the possible causes of the problem by asking Why. Answer to all “Why” to be placed in the appropriate category.

Step e: Answer to the first “Why” will provide a preliminary potential cause of the problem. For each probable factor, drill down causes by asking ‘why’ to the primary reason/cause. The answer to the question should be branched further to further subcategory.

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With the help of CFT, generate all the potential reasons for the problems. Analyze all the identified probable reasons for available controls, processes, procedures, and detectability aspects for the problem. The tool will help to understand the potential cause or root cause of the problem. Additionally, it also helps to identify all other probable reasons for the occurrence for which procedural or automatic control can be implemented. This is the beauty of this tool.

2. Tips to perform brainstorming while using Fishbone:

 Focused on the causes of the problem, rather than the symptoms

 Continue to generate ideas from all team members one by one all ideas are exhausted

 All ideas should equally consider as important. Encourage everyone to participate in a brainstorming exercise

 Consider man/ people as a cause of concern at the end. If system, process, or procedures are deficient, people tend to do the mistake.

3. Advantages and Disadvantages of Fishbone Diagram:

a. Advantages

 Useful to identify cause and effect relationships for an underlying issue

 Comprehensive

 Guide for structured brainstorming

 Help to identify all potential cause for the problem b. Disadvantages

 The potential causes are based on hypothesis; it need supporting to confirm

 Inappropriate potential causes may create confusion

 Sometime difficult to draw when issue is complex

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Why-Why or 5 Why analysis:

Five why or why-why technique is the most effective tool for problem-solving and root cause analysis.

Sakichi Toyoda, the Japanese industrialist, inventor, and founder of Toyota Industries, established the Why-Why or 5 Why analysis technique in the 1930s. The method popularized in the 1970s.

Taiichi Ohno, which is known as the father of the Toyota Production System, said that “The basis of Toyota’s scientific approach is to ask why five times whenever we find a problem … By repeating why five times, the nature of the problem as well as its solution becomes clear“.

Let’s understand how the method works.

In this article, a three-step process is described to carry out 5 Why or Why-Why analysis.

Step i: When a problem is identified, create a clear and crisp problem statement by asking questions such as What is going wrong, when did it happen, where did it happen? Who found the problem?

 Include process where defect produced

 Also include Why problem not detected

Step ii: Move backward by asking why every time. To identify the root cause try to identify within the process or a system failure. Opportunity for system or process improvement is generally real root causes. Exclude operator/ staff error and try to find process failures that ensured the operator made an error.

Step iii: Bad process or system will beat good people hence; focus on the process and system issues rather than people.

KEY to the five why or why-why technique is Focus on the cure, not the symptoms

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Do it with team, don’t do it alone…

This is a simple and effective tool, but word of warning. Do not try it at your desk and do not do it on your own. However, don’t over crowd with 15 to 20 people.

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1^st Why _ Clear problem statement. 1st 'why' should be short. Do not justify it at this stage. Write even though it is obvious to you. It may not be obvious for others.

2^nd Why  To get into the technical part. The explanation can branch out to several different potential causes. For each of the probable causes, identify the remaining 3 Whys.

3^nd Why  Do not jump to conclusions yet. Follow the regular thought process even though some underlying root causes may start surfacing already.

 This 3rd why is critical for a successful move between the obvious and the not so obvious cause.

 You can visualize the process mapping and narrow down the most probable sources for the problem.

 You may be missing the obvious by rushing into logical reasoning.

4^th Why  Remove preconceived cause from the mind and start the fourth why with an honest approach

 Explore all potential causes

 Even if many of them are not the root cause, they may lead to

continuous improvements or help to eliminate the potential cause for similar issues

5^th Why  At the fifth why it is likely that you have found a systemic cause

 If you have reached the fifth why and you still fill that you can further drill down the process-related probable cause, you may ask further whys to find out the systemic cause

Stop at implementable Why

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Example of Five why or why-why:

Image source: www.educational-business-articles.com/5-whys/

You can refer to the practical example video where an issue at Jefferson Memorial was solved using a why-why analysis. https://www.youtube.com/watch?v=BEQvq99PZwo The video is by ASQ TV.

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Step 5: Defining an action plan

Identify the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems

21 CFR 820.100(a)(3)

Action may either of following or in combination

• No further action necessary

• Correction

• Corrective Action

• Preventative Action

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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The Preamble on Risk and Degree of Corrective and Preventive Action

…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. . .

Preamble, Comment 159 Reference: www.fda.gov

Identify Required Actions - 21 CFR 820.100(a)(3)

Identify the action(s) needed to correct and prevent recurrence of non-conforming product and other quality problems.

Beware of terminology!

A Preventive Action is NOT required for all situations; however, a Corrective Action to prevent recurrence is required.

To generate solutions, one can use a free-brainstorming method or can use a structured approach called SCAMPER.

Brainstorming:

Brainstorming is a team-driven process used to generate fresh and creative ideas for problem solution

• Do not criticize so that most of the members can give ideas freely

• It produces many solutions for one problem

The following rules are necessary for every brainstorming session.

• Every suggestions counts

• Do not drilldown on proposed ideas

• Do not demoralize anyone using killer words

• Encourage all participants to give ideas - nothing right or wrong at this stage

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• Allow all participants to complete their ideas – listen to every one

Image source: segalbenz.com

SCAMPER:

SCAMPER was proposed by Alex Osborne in 1953, and was further developed by Bob Eberle in 1971 in his book; SCAMPER: Games for Imagination Development

Image source: www.biggerplate.com

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SCAMPER Substitute Substituting part of the

product or process for something else

Replace cap with USB

Image source: www.usbmemorydirect.com

Combine Combining two or more parts of the product or process to make something new

Combine sink with toilet bowl Adapt Parts of the product or

process could be adapted or way to change the nature of the product or process

Adding a pizza holder on a scissor Modify or magnify Modifying part or the entire

product or process

Modify a fork into finger fork

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Put to other uses You might put a certain product or process to other use

Image source: in.pinterest.com

Eliminate You eliminate certain parts of the process

Image source: www.slideshare.net

Rearrange or Reverse

Parts of the product or process worked in reverse way or it sequenced differently

Image source: www.invertedumbrella.in

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Step 6: Implementation of planned actions

Implementation

Implement and record changes in methods and procedures needed to correct and prevent identified quality problems. 21 CFR 820.100(a)(5)

Communicating CAPA Information

Disseminate information related to quality problems or nonconforming products to those directly responsible for assuring the quality of such product or the prevention of such problems. 21 CFR 820.100(a)(6)

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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Employee training is a critical part of any change implementation and should be a part of the action plan. For effective implementation of the CAPA, all modifications and changes made in the system must be communicated to all persons, departments, suppliers, etc. that were or will be affected.

Execution of implementation plan and useful tools:

 Activity listing: List down all identified actions

 Prioritize: Prioritization can be done with the help of tools such as effort benefit analysis or cost benefit analysis.

 Planning and mapping activities: The best way to plan the activities is to use a structured approach to organize activities and broken down into smaller tasks.

Various program management methods are available such as Gantt chart, Process Mapping, Value stream mapping, etc.

o Gantt chart: A Gantt chart is a tool used for the planning and scheduling of activities. It is useful for simplifying complex tasks.

o Process mapping: A process mapping is a way of planning and management by visually describing the flow of work.

o Value stream mapping: A value stream mapping is a detailed visualization of all the steps of the work process and visualization of tasks in a single glance.

 Assign responsibility: The key to timely completion of the activity is to assign it to the responsible person and make them accountable for the task.

 Determine resource and plan budget: Resource planning is a systematic way to get the optimum utilization of time and people. For any implementation, budget planning is critical. The budget is not only the money but also time to complete the task.

 Risk assessment and mitigation strategy: While planning any actions as an outcome of proposed CAPA implementation, the risk with respect to upstream and

downstream process needs to be evaluated. The action taken to eliminate or prevent issues or events should not end up with additional issues or conflict already

implemented systems. In case of any potential risk identified, an adequate mitigation strategy should be in place alongside the implementation plan.

 Change management process: Any changes to be made in the system must route through defined Quality Management Tools or Change Management process.

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Step 7: Closure and effectiveness review

Closure and effectiveness review is an important step to evaluate actions taken. It's divided into sub-steps.

 Verification of action completion

 Effectiveness verification of implemented Corrective Action and Preventive Action

Identification of an event

Risk evaluation

Investigation of an event

Root cause analysis

Defining an action plan

Implementation of planned actions

Closure and effectiveness review

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Verify and Validate - 21 CFR 820.100(a)(4)

Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device.

• 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

To verify the closure of the Corrective Action and Preventive Actions (CAPA) you should ask following key questions:

 Are all the proposed actions implemented as planned and outlined in the action plan?

 Is the implementation done through proper change management system and documented?

 Relevant trainings and communications have been completed?

To validate the effectiveness of the implemented Corrective Action and Preventive Actions (CAPA) you should ask following key questions:

 Is the objective of action proposal is been met?

 Is any change resulted in another adverse event?

 Is sufficient amount of data available to validate the implemented CAPA?

KEY - Verify the changes with evidences and document it

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Effectiveness verification is done to ensure

• Root cause of problem is addressed

• Issue will not reoccurrence in future

• No adverse effect noticed on implementation of actions

• Adequate controls or detection mechanism is established

References:

I. ICH Q9 and Q10 II. ISO 9000:2005 (E) III. 21 CFR 820.100

IV. 21 CFR 211.192, 21 CFR 211.100, 21 CFR 211.22 V. EudraLex - Volume 4 Chapter 1

VI. COMMISSION DIRECTIVE 2003/94/EC VII. www.fda.gov

VIII. www.gov.uk

IX. http://alvamed.com/about-medtech-compliance-company/newsletter- i.

articles/2015-fda-form-observations/

X. www.educational-business-articles.com/fishbone-diagram/

XI. Book; SCAMPER: Games for Imagination Development XII. www.mindtools.com