2021-12-11T21:35:31+00:00June 18th, 2020|

1. Introduction
“Non-conformity” investigation is very common term being used in production and product quality improvement areas in the Pharmaceutical and Medical Devices world. It is mandatory and considered as a regulatory requirement. As far as the non-conformity investigation process will be carried out systematically and significantly, the better the effectiveness of the corrective and preventive actions implementation stage.
The CAPA process is one of the cornerstones of GMP in the Pharmaceutical and Medical Device industries.
Investigation process according to “root cause analysis” methodology have to be implemented for Pharmaceutical and Medical-Device companies.
In order that the CAPA process will be performed at the required standards, it must be assimilated in the company’s organizational culture.
Sometimes in large companies, it is very difficult to establish an effective CAPA system.On the other hand,  for mid size companies, who has a single production site, in which relevant functions familiar with each other and working together closely on a daily basis, it’s much easier to establish effective CAPA system. When it comes to big companies, a systematic and simple approach is recommended in order to achieve the desired outcome.
Often, “problematic” CAPA system can be a result of insufficient systematic approach and lack of relevant procedures. In this case, large companies may have inefficient CAPA system as a result of discrepancies between the different production sites. Non-conformities usually will be handled separately and sometimes differently for each site, resulting in communication difficulties, inefficiency and waste of resources. Large organizations should establish a basic CAPA system and cross-organizational processes that will enable the company to examine the processes performed in the organization and to implement preventive measures that will be effective for the entire organization.

2. Glossary
2.1 Correction- Action to eliminate nonconformity. The correction can be made in conjunction to corrective action.
2.2 Corrective action- Action to eliminate the cause of a detected non-conformity or other undesirable situation.
2.3 Preventive action- Action to eliminate the cause of a potential non-conformity or other undesirable situation, in order to determine what steps must be taken to neutralize the cause of any potential non-conformity and to prevent their recurrence.
2.4 Root cause analysis-Investigation that is being done in order to reach the root of the non-conformity.

3. Working stages
3.1 Most of the time, CAPA investigation begins within a specific event such as a laboratory investigation, inconsistencies in the manufacturing process, GMP audit or customer’s complaint. All of these non-conformities will be investigated using CAPA methodology.
In general, the recommended process of root cause investigation will include the following steps:
3.1.1 Corrective Action
• Identify of the non-conformity, including customer complaints review.
3.1.2 Evaluation
• Evaluate the scope of the non-conformity including Risk Assessment.
• Evaluate the need to take an action in order to assure the non-conformity will not re-occur in the future.
3.1.3 Investigation
• Investigate using all relevant functions in the company (engineering, maintenance, QA, production, process engineering, QC etc.).
3.1.4 Analysis
• Analyze, identify and document the root cause for the non-conformity.
3.1.5 Corrective action
• Determine corrective actions to be taken, responsibilities and implementation timelines.
3.1.6 Documentation
• Document the corrective action’s implementation (actions, results etc.)
3.1.7 Corrective actions effectiveness and time lines
• The effectiveness of the corrective actions implemented should be presented in objective and measurable manner.
• Verify whether the non-conformity was resolved.
• Verify the implicated solution can be qualified/validated for the long run.
• Verify that the solution implemented will still be effective in the future.
3.1.8 Preventive action
• Identify potential problem/non-conformity.
• Examine the need for action aimed at preventing the recurrence of non-conformity/potential problem (or problem that almost happened) proactively.
3.1.9 Analysis
• Analyze, identify and document the root cause for the non-conformity.
• Determine and implement the necessary preventive actions.
3.1.10 Documentation
• Document testing procedures and results.
3.1.11 Effectiveness
• Determine the effectiveness of the preventive actions that were implemented.

4. Examples of topics handled using Corrective Actions mechanism
• Delay in product delivery
• Machine breakdown
• Lack of customer satisfaction from the product
• Trends in customer complaints
• Product quality problems
• External / internal GMP audit report
• Risk Analysis

5. Examples of topics handled using Preventive Action mechanism
• Unstable production process which can produce a low quality product
• Safety problem identification
• Trend analysis
• Product / system annual review
• Temperature variation
• Single raw material supplier
• Risk Analysis
• Staff meeting
• Management review discussions
• Customer feedback

6. Root cause analysis
6.1 Make sure that the investigation was performed so the root cause analysis was identified clearly.
6.2 Avoid root cause process that will support your initial theories regarding the investigation.
6.3 Avoid ignorance of the other possible causes to the non-conformities. Focus on the process itself rather than factors such as employees in general or specific employees, in particular as root cause to the non-conformity.
6.4 Avoid focusing on a single cause. There may be several factors together that are the source of the nonconformity.
6.5 First, understand what is causing the problem. Then, continue investigating till root cause identification. Rather focus the whole process, instead the direct cause for the non-conformity.
6.6 Use statistical and other relevant tools such: Pareto chart, Risk Analysis, 5 why’s, Fish-bone diagram, flowcharts etc.

7. CAPA implementation
Many CAPA systems are managed manually. Sometimes, in order to make the CAPA system more efficient, we need to use Quality Management software.

CAPA investigations should include an orderly flow chart describing the various stages of the process. Quality Management System can also provide a clear indication for specific CAPA status and general status of the whole CAPA process, which activities were carried out, whoever is responsible etc.
Organizational culture has a crucial influence on successful CAPA system implementation. It’s recommended that employees will understand the importance of the CAPA system and its great contribution to GMP compliance of the company.

8. Summary
In order to initiate the CAPA process correctly, in any case non-conformity was discovered, the manufacturer need to ask the questions:
• What is the non-conformity?
• Where the non-conformity does occur?
• How often and what is the scope of the non-conformity?

Once we know what the cause of the non-conformity is, we can move forward to the next step of tests and experiments.
Companies should ensure that investigations are being performed according to the CAPA system, examining all possible causes and exploring the most suspicious ones, to ensure beyond doubt what is the real reason for the non-conformity.
After identification of the root cause, corrective and preventive actions will be implemented to complete the entire CAPA process. The company must distinguish between symptoms and the root cause.
The organization employees should remember that the CAPA system is a tool which improve product quality and business bottom-line.

9. Tips
9.1 Understand what the real problem is that caused the non-conformity.
9.2 Document a clear description for what was observed, why, where, when, what etc.
9.3 Avoid identifying the solutions. First, focus on identifying problem.
9.4 Record your observations and collect as much as data as you can for decision makers.
9.5 Analyze the data using charts, graphs, images to describe the non-conformity clearly.
9.6 Describe the non-conformity clearly and document your description
9.7 Avoid that non-conformity description will include suggestions for non-conformity solutions.
9.8 Corrective actions which must be repeated, indicate that the problem was not resolved for the first time and therefore the CAPA process is ineffective and therefore should be revised.
9.9 Identify what action has been implemented to correct the non-conformity and what happened as a result of that.
9.10 Try to examine the effect of CAPA on the whole process and not only on part of it. Actions may impact the whole process