CAPA systems will factor into survival of firms in regulated life sciences markets

By James Jardine, MasterControl Inc.

The primary objective of a corrective and preventive action (CAPA) is a solution to the problem for which the CAPA was generated. If CAPA efforts are not driving toward a solution they are nothing more than a waste of time and resources. For organizations in regulatory environments, CAPA is an overarching umbrella–all control points flow through to the CAPA system.

Some organizations are suffering from “death by CAPA”–their companies are being strangled because too many elements are included in their CAPA systems. At its most fundamental level, there are just two conceptual ingredients that make up a CAPA system. The first component is the experience, expertise, and wisdom of the personnel involved with conducting CAPA processes. If personnel do not have a prior track record with CAPA, this may be an area where an organization has less control over CAPA activities. The second core facet of CAPA, one where more organizational control can be demonstrated, is process. The CAPA process requires critical thinking and an effective determination of the exact questions that need to be asked in order to come up with proper solutions.

The regulatory perspective

From the standpoint of regulatory agencies like the U.S. Food and Drug Administration (FDA), CAPA is perceived as the central component that affects all control points including design controls, production and process controls, records and documents change controls, material controls, and facility and equipment controls. Since more than half of Form 483 observations and warning letters cite CAPA deficiencies, it is evident that FDA investigators are likely to look first at a company’s CAPA system during their inspections. In recent years, the FDA has been promoting the adoption of closed-loop CAPA systems where CAPA is the tool that drives reports and keeps management informed.

The FDA’s 21 CFR 820, better known as the Quality System Regulation (QSR), may be specifically intended for the regulation of medical device manufacturing but provides good rules of thumb for CAPAs conducted in any GxP environment. The 820.100 regulatory guideline states that:

(a) Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. The procedures shall include requirements for:

1. 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;
2. Investigating the cause of nonconformities relating to product, processes, and the quality system;
3. Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;
4. Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;
5. Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;
6. Ensuring 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; and
7. Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.

(b) All activities required under this section, and their results, shall be documented.¹

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In her “Quality Program, CAPA and Audits”² presentation at the 3rd Annual FDA and the Changing Paradigm for HCT/P Regulation Conference, Mary Malarkey, director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research (CBER), succinctly outlined the fundamental expectations of regulatory agencies in regard to CAPA. While some of her comments were addressed specifically toward current Good Tissue Practices (cGTP), these regulatory expectations can reasonably be applied to all GxP processes across the board. Malarkey made the following points:

• Organizations must be able to ensure that appropriate corrective actions pertaining to core current good tissue (or laboratory, manufacturing, clinical, etc.) practice requirements, including re-audits of deficiencies, have been taken and documented as necessary.
• Corrective actions must be verified to ensure that such actions have been effective and are in compliance with current good practices.
• In situations where it is appropriate, corrective actions must include both short-term action to address the immediate problem and long-term actions that will prevent the recurrence of the problem.

Malarkey also referred to guidance documents stating that documentation of corrective actions must include, where appropriate, identification of the affected product and a description of its disposition; the nature of the problem for which a corrective action was required; a description of the corrective action taken; and the date or dates the corrective action took place.

The 21 CFR Part 211.192 regulation and controls guideline was referenced in that same presentation by Malarkey and provides a good insight into regulatory expectations in regards to unexplained discrepancies that might or should lead to a CAPA investigation: “Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated whether or not the batch has already been distributed. 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 followup.”²

CAPA essentials

Most companies doing business in regulatory environments could improve their CAPA processes by implementing better methodologies and applying effective risk-based filters.

At minimum, a good closed loop CAPA system is comprised of the following elements:

• Identification
• Prioritization
• Assignment/acknowledgement
• Investigation
• Correction
• Implementation
• Verification
• Close

The first element of a CAPA, of course, is the identified input that opens the CAPA: a customer complaint, a nonconformity report, an out-of-spec finding, an internal audit finding, and so forth. There are four core modules of an open CAPA: issue review, investigation (or failure analysis), effectiveness checks for verification, and preventive action.

Issue review is the evaluation phase, a scoping process where a determination is first made whether or not an investigation is warranted. The three main components of issue review are sometimes referred to as CSG (concern, specifics, and gateway).

Once the concern has been identified, issue review specifics can be defined by asking the five “W” questions:

• What?
• Where?
• When?
• Weight (magnitude)?
• Who?

An organization’s ability to successfully close a CAPA is directly related to how capably it is able to narrow down these five dimensions and arrive at a defensible decision. Designing and utilizing an issue review worksheet can facilitate CAPA investigations and streamline the gathering of accurate and specific answers to these five “W” questions.

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The “gateway” component of CAPA issue review revolves around the impact (safety, hazard, severity, visibility, etc.) and magnitude (i.e., frequency and/or size) of the situation. A gateway score chart can help managers hone in on magnitude specifics based on qualitative and/or likelihood in comparison with descriptions of the input event occurrence (continually, frequently, occasionally, rarely, etc.). Likewise, an impact chart can provide a gateway scorecard for the severity of the event (critical, important, minor, or negligible). Most issues will likely be categorized as important or minor events. Specific scores can be assigned according to impact and magnitude scales to determine if the event is acceptable (no action required), undesirable (may or may not be put in the formal CAPA system), or unacceptable (CAPA opened and a resolution is required).

Taking action

When the CAPA issue review specifics have been defined and impact and magnitude scores have been determined, it is time to take action. Depending on the impact and magnitude results, possible actions will include the following:

Adaptive action: These actions allow the organization to live with or adapt to the issue and continue to operate according to organizational objectives.

Interim/correction actions: “Band-aid” or containment actions alleviate the effects of the issue and buy time before a corrective action is implemented. (Containment is a backup plan if a problem cannot be resolved).

Corrective actions: Problem prevention and containment actions permanently eliminate the issue.

Preventive actions: These actions anticipate potential problems and eliminate the most likely causes of the problems so they are less likely to occur.

Approaches to investigations

As in any problem-solving situation, there are three basic approaches to CAPA investigations:

Trial and error: This is a risky method that may work for some companies, but it also has the potential to exacerbate the problem. A company may get lucky, but it also may complicate the issue.

Design of experiments, fishbone diagrams (a.k.a. Ishikawa diagram), and brainstorming: These quality tools are usually better solutions than trial and error, but they are also dependent on past experience and potentially useless if the root cause lies outside the realm of personnel expertise. Scrap and downtime are potential complications with these approaches.

Comparative approach: A deductive thinking approach is the ideal method in that it provides understanding of what is not the problem. Investigators can use a comparative approach to discover what sets the problem apart. A fact-based, objective comparative approach investigation should yield clues that identify the problem’s root cause, which will then initiate a corrective action.

The PICCC investigation tactic

One valuable investigative tactic is sometimes referred to as the PICCC or PI-cubed methodology (problem, investigate, clues, compare, and cause).

Problem: The first step in the PICCC method is to determine and understand exactly what has gone wrong.

Investigate: Once the problem has been defined, investigators can gather data that can be used in comparisons and determinations of what is not the problem.

Comparison: Asking “is not” questions (comparing time periods, locations, types of defects, etc.) further refines the investigation.

Clues: The clues uncovered during the investigation are inferences of the facts. At this stage, the investigators are finally able to formulate some solid answers as to why the problem has occurred.

Cause: Investigators can now take the clues and build a cause that can explain the problem or deviation. An assessment can be made regarding the impact of the event and preventive measures, if necessary, can be identified and implemented.

At this stage, the Problem Prevention Analysis model (a modified FMEA tool) can be useful for developing mitigation strategies. The model consists of four basic rudiments:

• Result
• Problem
• Prevent
• Contain

CAPA verification and documentation

Every good CAPA process should have a built-in effectiveness checking mechanism to verify and validate that the CAPA system is working. Data tracking is another mandatory component of CAPA that allows an organization to guarantee that all CAPA-related information can be confirmed, monitored, measured, and, if necessary, corrected.

The ability to document CAPAs according to regulatory requirements is another vital factor to take into account. Because regulatory requirements mandate that CAPA data must be easy to access and analyze, every phase of a by-the-book CAPA investigation should be forms based. Automating forms-based processes like CAPA can not only facilitate regulatory compliance but will also save a company time and resources. Commercial off-the-shelf (COTS) software packages are available that can comprehensively document CAPA investigations and integrate the CAPA process with other processes critical to regulatory compliance such as change control, customer complaints, and audits. An effective CAPA software solution should be configurable and user-friendly and should include features such as:

• Automated routing, notification, delivery, escalation, and approval of CAPAs and all related documentation.
• A secure, centralized, and web-based repository for all CAPA documents.
• System oversight of quality incidents that escalate to CAPAs (i.e., customer complaints, audit findings, etc.).
• Efficient reporting capabilities and advanced analytics.
• Form-to-form launching capabilities.
• Revision and approval history tracking features.
• Best-practice electronic forms and workflow routes that can be used out-of-the-box or customized based on company requirements.

With all of the necessary steps in place, an effective CAPA system will provide all of the critical information for companies involved in the life sciences markets to make meeting regulatory requirements easier and conduct their operations using industry best practices without repetitive quality issues, which waste valuable time and resources.

James Jardine is a marketing communication specialist at MasterControl Inc., a global provider of GxP process and document management software solutions for life science companies (www.mastercontrol.com).

References

1. Title 21 Code of Federal Regulations Part 820–Quality System Regulation, U.S. Food and Drug Administration, updated Mar. 31, 2006.
2. M. Malarkey, “Quality Program, CAPA and Audits,” pres. at 3rd Annual FDA and the Changing Paradigm for HCT/P Regulation Conference, Jan. 25, 2007.