GxP Perspectives

When developing a quality management program you need to discuss the basics of CAPA: corrective and preventative action, and how to come up with a CAPA plan that resolves the root causes of violations. In a guest commentary, veteran GxP consultant Barb Immel discusses CAPA basics. I first met Barb when she was teaching a 3-day drug development course at UC Extension and had invited me as a guest speaker. I sat through the entire three days and learned a lot.

Guest Commentary:

CAPA Basics By Barbara K. Immel

Poor corrective and preventive action (CAPA) and investigations continue to be among top FDA Form 483 deficiencies issued to drug, biologic, and medical device manufacturers. And FDA has been issuing warning letters citing inadequate corrective action to clinical investigators, institutional review boards, contract research organizations, and sponsors. It’s in everyone’s self interest to improve the quality of investigations and CAPA. The most important point to remember?

The depth and intensity of an investigation should match the potential risk to the patient.

1. Start with the requirements. Always follow all applicable regulations and standards, and go above and beyond the minimum requirements. Although the only organizations that are required to establish a CAPA system are medical device manufacturers, it has always been either a requirement or an expectation that all organizations in our industry will perform thorough investigations and implement effective CAPA. Helpful passages include, but are not limited, to:

Device CGMPs. Establishing a CAPA system is a CGMP requirement for medical device manufacturers producing product for the US (21 CFR 820.100).

Drug CGMPs. Conducting certain investigations and documenting and justifying deviations is required for manufacturers making product for the US. Inadequate investigations are a frequent CGMP deficiency (21 CFR 211.192).

Preclinical Requirements. Taking corrective action is required in the GLPs (21 CFR 58) for testing facility management (21 CFR 58.31), the study director (21 CFR 58.33), Clinical Requirements. And taking effective corrective action is implied in the GCPs. Relevant sections include but aren’t limited to the Responsibilities of Sponsors (21 CFR 812.40) and Responsibilities of Sponsors and Investigators (21 CFR 312 Subpart D).

2. Establish good surveillance. Carefully think about the data you need, and the speed with which you will require being notified. A surveillance system is only as good as the information it receives.

• Conduct thorough, frequent audits (most internal operations should be audited at least once a year, and critical suppliers should be audited frequently, such as once every 12-18 months). Ensure audits are done by experienced personnel, and that any identified issues are promptly addressed.

• Require that all employees immediately report to their supervisor when they deviate, make a mistake, or notice something unusual. Require that sites notify you rapidly of any issues or potential issues.

• Set up an effective trending system, to identify potential issues before they become a fire.

• Regardless of where you work in the industry, check out the following documents for ideas:

o AdvaMed Points to Consider When Preparing for an FDA Inspection under the QSIT Corrective and Preventive Action Subsystem:

o Global Harmonization Task Force Proposed Document: Quality Management System — Medical Devices — Guidance on corrective action and preventive action and related QMS processes:

www.ghtf.org/sg3/sg3-proposed.html

Laboratory Requirements:

If you work with a laboratory, see FDA’s Guidance for Industry: Investigating Out-of-Specification Test Results for Pharmaceutical Production

• Ensure your system will allow you to notify FDA of any problems concerning your product or clinical trial within FDA required reporting timeframes (i.e., a field alert, medical device report, biologic product deviation report, adverse event or serious adverse event, etc.).

• Always include a link between your investigation and CAPA procedures and your FDA reporting procedures, including your recall procedure.

Any potential recall situation should immediately be brought to the attention of your QA executive. For recall SOP ideas, see FDA’s regulation (21 CFR 7) and FDA’s Guidance for Industry: Product Recalls, Including Removals and Corrections. Test your recall system at least once a year.

Remember: Each FDA District Office has a Recall Coordinator.

http://www.fda.gov/Safety/Recalls/IndustryGuidance/ucm129259.htm

3. Create (or improve) your SOP(s) and systems. Every organization should have a failure investigation procedure that states the threshold for initiating an investigation. The decision whether to investigate should always be made by an experienced QA employee, and documented.

• Periodically ask employees or others using your system what’s driving them crazy about it, and act on the results.

• Make sure your system requires the early categorization or determination of risk, and the ability to rapidly escalate the importance of items. Your system should include how management will be routinely informed of ongoing investigations and CAPA activities, and how they will be immediately informed of critical issues.

4. Define your terms. For medical device companies, ISO 13485, Medical devices – Quality management systems – Requirements for regulatory purposes, and ISO 9001, Quality management systems –

Requirements, define corrective and preventive action. Since complying with these standards is required to sell devices in Europe, Canada, and Australia, it makes good business sense for device firms to use these definitions. Drug and biologic companies, and clinical groups, are under no such requirement, but define your terms and provide training to all employees so everyone is using the same terminology.

The ISO definitions are:

• Corrective Action: Action to eliminate the cause of a detected nonconformity or other undesirable situation.

• Preventive Action: Action to eliminate the cause of a potential nonconformity or other undesirable potential situation.

5. Train employees. Provide frequent, ongoing training to all employees or staff. Don’t forget to train sales representatives on what a customer complaint is, and how they should rapidly report any that they receive.

• Provide training on the following to individuals performing investigations:

o Your investigation and CAPA procedure(s)
o All applicable regulations and standards
o Root cause analysis
o Solution criteria*
o How to perform an investigation
o Your documentation and reporting requirements
o Report writing (since employees may be moving from simply filling out a form to creating a written investigation report)
o Interviewing (since investigators will need to be able to interview individuals at all levels)

*All solutions should prevent the recurrence of the problem, should not cause an unacceptable problem, should be within the control of your organization to enact, and should provide good value for their cost.

• Teach everyone the key stages of an investigation:

1) identification and definition of the problem,
2) determination of whether to do an investigation (categorization/risk analysis),
3) planning the investigation,
4) root cause analysis,
5) identifying appropriate corrective and preventive action,
6) implementing the action, and 7) measuring the effectiveness of the action.

• Train everyone to carefully evaluate and select possible CAPA actions before they are implemented, and to confirm the effectiveness of the CAPA – and that it didn’t cause a greater problem – after implementation (the effectiveness checks).

• And teach everyone how to do a basic or preliminary investigation. Only ask experienced investigators or employees to perform more serious or difficult investigations (follow-up investigations).

By Barbara K. Immel

For further information take a look at Barb’s website:

http://immelresources.com/

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