By Mauricio Rodriguez, July 27, 2020

Interpreting FDA QSR Subpart 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”

From 2002 to 2009, an average of 85 percent of medical device warning letters cited CAPA deficiencies, one of such deficiencies which we had the opportunity to work with during an FDA warning letter remediation project for a major medical devices company, was related to what is commonly known as Corrective Action/Preventive Action (CAPA) Verification of Effectiveness. The FDA finding was described as follows:

“The following deficiencies with your firm’s Corrective and Preventive Action Procedure were noted: The procedure does not include requirements to verify or validate the corrective and preventive action to ensure such action is effective and does not adversely affect the finished device where applicable”

and continued to specify:

“The site QMS procedure lacks a clear provision for ensuring that Process Validation, Design Verification and Design Validation activities are executed prior to or as part of the implementation of a Corrective or Preventive Action. The Verification of Effectiveness phase of the CAPA process should not include these activities as some changes require these activities prior to implementation.”

What’s inside of FDA QSR Subpart 820.100(a)(4)?

QSR Subpart 820.100(a)(4) comprises three different elements that should be clearly defined and executed as part of your CAPAs:

• Verification and Validation (V&V) Prior to action implementation: A short-term, acute verification or validation effort on the proposed corrective or preventive actions prior to implementation
• Adverse effects analysis: An analysis, and discussion on why the proposed actions will not produce adverse effects on the product and,
• Verification of effectiveness: A long-term verification activity to determine that the implemented actions are effective in eliminating the root cause(s) of the issue(s)

Verification and Validation (V&V) Prior to action implementation

During the execution of a CAPA project, after the team has come up with the root causes and has agreed on the corrective and/or preventive actions, it is required to make sure that those actions will work in obtaining the desired results from implementation. This does not mean, as it is sometimes interpreted, that evaluation of effectiveness is required for all corrective or preventive actions prior to implementation, which will be practically impossible.

Making sure actions will work: Verification and/or validation (V&V)

If the corrective and/or preventive actions affect a validated item, e.g.:

• Validated Design
• Validated Test Method
• Validated Equipment
• Validated Process

Then, some validation / re-validation work needs to be performed prior to implementing the action. Design control and process validation procedures and change management procedures should clearly indicate the criteria for conducting verification and validation or re-validation activities. These V&V activities should be conducted because your quality management system and procedures require it, not just because you are implementing a corrective or preventive action within a CAPA.

If, instead, the corrective and/or preventive actions are only clarifying a written procedure, instruction or form without major changes to a process, then validation is not required and the formal process of document control which establishes the roles and responsibilities of who can change the document, who must approve it, and the associated training requirements, can be considered as the verification of acceptability of the change.

Adverse effects analysis.

In order to justify the corrective and/or preventive action implementation, a discussion on why the proposed actions will not produce adverse effects on the product, in alignment with ISO 13485:2016, 8.5.2e and 8.5.3d – “Verifying that the corrective and preventive action does not adversely affect the ability to meet applicable regulatory requirements or the safety and performance of the medical device.”, must be performed with an assessment which may include multiple studies (depending on the product). See our article: “Regression Analysis”, how to test for unintended consequences in your corrective actions

Verification of effectiveness.

Once corrective and/or preventive actions are implemented, it is time to verify the effectiveness of such actions. Verification of effectiveness (VOE) consists on the activities to determine that the implemented actions are effective in eliminating the root cause of the issue. It is important to note here that there is a common misconception that VOE consists in demonstrating that the actions were implemented, rather than demonstrating the effectiveness of such actions, verification on implemented actions is objective evidence of the completion of such actions and should be done as part of the action implementation activities of the CAPA.

A common method to verify action effectiveness is to observe the process for issue symptoms, if it is possible to demonstrate that symptoms are coming from the same root cause of the issue addressed in the CAPA, it can be concluded that the actions were ineffective. Verification of effectiveness (VOE) activities also involve the necessary time required to demonstrate that the implemented actions were effective in eliminating the issues on the product or process. A simple fixed time will not always be sufficient as there is a probability that the initial output of the process or product may not have the identified issues, instead a statistically based sample size based on the frequency of the process or product, is required to establish a certain level of statistical confidence and reliability that should be aligned with the level of risk of the CAPA according to the company risk management procedures.

Key Takeaways

The corrective and preventive action system within your quality system, also known as CAPA is of vital importance given its criticality and the number of associated deviations or interpretations, making it the most impacted to regulatory actions by the FDA and foreign regulators. An adequate interpretation an execution will ensure your compliance and minimize the risk of notified body nonconformances, 483s or warning letters. Share your thoughts in the comments below.