Significance of Root Cause Analysis and Challenges in Implementing Appropriate CAPA
Dr B V Sivakumar,Chief Scientific Officer, Enaltec Labs

Identifying the root cause for market complaints, out of specifications (OOS ), deviations can be challenging, but a number of tools can help to investigate the root cause so that corrective and preventive actions can be effectively implemented.

FDA's Quality System Regulation as well as the new guidelines on "Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations" requires effective corrective and preventive actions (CAPA) with root cause analysis (RCA) as reactive tool for system improvement to ensure that significant problems do not re-occur. The CAPA system is the most frequently inspected subsystem. No or inadequate procedures for corrective and preventive actions (CAPA) and missing root cause analyses are amongst the most frequently found deviations in FDA warning letters. Having compliant procedures for CAPA and compliant management is a must for any firm in the Medical Device manufacturer, Pharma Industry, regardless of marketplace.

Successfully implementing and documenting corrective and preventive actions (CAPA) is one of the critical processes in a medical device and pharmaceutical manufacturing company's day-to-day quality operations. CAPAs carry significant implications for both product quality and compliance with FDA regulatory directives, and remain vital to any company's ability to address incidents that inevitably arise in the manufacturing processes. Due to this, it is critical to take necessary steps to prevent them from re -occurring.30 percent of the warning letters issued by FDA is due to- failure to establish and maintain procedures for implementing corrective and preventive action and root cause analysis, as required by FDA.

According to BRC Global Standards, root cause analysis is a problem solving process for conducting an investigation into an identified incident, problem , concern or nonconformity. Root cause analysis is a completely separate process to incident management and immediate corrective action, although they are often completed in close proximity.

The individual(s) tasked with ascertaining the underlying root cause must look beyond the obvious and make a serious attempt to pinpoint root cause. The good news is that there are tools available for investigators to facilitate their quest for ascertaining root cause.

Most regulatory bodies have similar requirements for CAPA and complaint management or contain pointers to a standard such as ISO 13485:2012. Table 1 depicts some of the common regulatory requirements faced by device manufacturers and Pharma Industries.

Understanding Root Cause: To determine root cause, it's essential to first understand what the term means. The best way to explain root cause analysis is to use the example of a weed. Weeds can be difficult to remove once they start to grow and spread. On the surface, the weed is easy to see; however, the underlying cause of the weed, its root, lies below the surface and is not so obvious.

Conversely, the word root in root-cause analysis refers to all underlying causes and not just one. That is why it is imperative to be open-minded and objective when performing root-cause analysis. Beginning an analysis with a preconceived idea of what appears to be an obvious root cause could result in the incorrect root cause being identified and the wrong correction being implemented.

Effective Root Cause Analysis: There is a plethora of tools available for assisting in the identification of root cause. The underlying goal is to achieve an accurate root cause, so the appropriate corrective actions can be pursued to prevent recurrence. If the incorrect root cause is identified, it is inevitable that the incorrect solution will be implemented . Some of the tools available for quality professionals to employ in ascertaining root cause include the following:
  • The five whys, a simplistic approach exhausting the question "Why?"
  • Fishbone diagram, a causal cause and effect diagram also known as the Ishikawa diagram.
  • Pareto analysis, the 80/20 rule premised on a predefined database of known problems.
  • Fault tree analysis, a quantitative diagram used to identify possible system failures.
  • Failure modes and effects analysis (FMEA), which lists all potential failure modes and the potential consequences associated with each failure mode.
The Five 'Why's?
The Five Whys Model:
The five whys model is a root-cause analysis tool originally created by Japanese inventor and industrialist Sakichi Toyoda. The effectiveness of the model became apparent in the Japanese automotive market in the 1960s and 70s'. Toyota became a big proponent of the five whys model, which ultimately became a critical component of the company's problem-solving training and the foundation for its scientific approach to performing root-cause analysis . The 5 Whys is a technique used in the analyse phase of the Six Sigma DMAIC , eg, Define, Measure, Analyse, Improve, and Control methodology. It is a great Six Sigma tool that does not involve data segmentation, hypothesis testing, regression or other advanced statistical tools, and in many cases can be completed without a data collection plan.

Determine the Root Cause: 5 Whys
By repeatedly asking the question "Why" (five is a good rule of thumb) you can peel away the layers of symptoms which can lead to the root cause of a problem. Very often the ostensible reason for a problem will lead you to another question. Although this technique is called "5 Whys," you may find that you will need to ask the question fewer or more times than five before you find the issue related to a problem.

How to Complete the 5 Whys:
  1. Write down the specific problem. Writing the issue helps you formalise the problem and describe it completely. It also helps a team focus on the same problem.
  2. Ask why the problem happens and write the answer below the problem .
  3. If the answer you just provided doesn't identify the root cause of the problem that you wrote down in Step 1, ask Why again and write that answer down.
  4. Loop back to step 3 until the team is in agreement that the problem's root cause is identified. Again, this may take fewer or more times than five Whys.
The Fishbone Diagram
It has been made famous by Kaoru Ishikawa and is similar to the five whys model in that it captures the cause-and-effect relationship of problems. The fishbone diagram is prevalently used as a tool to identify defects associated with design, development, and product realisation activities. The underlying premise is that defects are typically driven by process variation . Sources of variation are placed into six categories to facilitate the root -cause analysis process: people, methods, machines, material, measurements, and environment.

Pareto Analysis
The Pareto analysis is better known as the "80/20 Rule." The fundamental concept of Pareto analysis is the identification of the most likely sources of variation that are resulting in product defects and QMS non-conformances. As a part of the root-cause investigative process, the investigator and/or investigative team identifies a number of potential sources causing defects and non-conformances to occur. The sources of the most prevalent causes become the focus of the investigative process. Pareto analysis is an excellent tool for supporting risk management activities because of the need to focus on big-picture product issues.

Fault Tree Analysis
Fault Tree Analysis is a deductive investigative process in which an undesired state of a system is analysed using Boolean logic to combine a series of lower-level events. This analytical method is employed as a tool for ascertaining system failures and identifying risk removal and risk mitigation activities. For example, in system engineering the fundamental goal is assess and address all "undesired states." As high-level events associated with fault tree analysis, each failure condition is categorised premised on the severity of its effect. Simply stated, the more severe a condition, the more extensive the fault tree analysis.

Failure Mode and Effect Analysis (FMEA)
The Failure Mode and Effect Analysis method called FMEA is an established and proven method. It was developed and introduced in the sixties by the NASA and continuously expanded. Nowadays it is used routinely in many industries such as automotive, automation, chemical industry. The FMEA method is also expanding to the pharmaceutical and medical device industry. It is the first risk analysis method mentioned in the list of Methods and Tools in the ICH Quality Risk Management Q9 guideline. Users of the method are appreciating the tool because its results are condensed in a very compact central document easy to review. The FMEA helps to detect failure in a preventive way, to implement corrective action and continuously record the improvements. Moreover, the FMEA process itself triggers a great team building, training and quality awareness and spirit among the team members: a central aspect to provide excellent products and processes.

Challenges Associated with CAPA
One of the biggest challenges for companies is to complete investigations and actions in a timely manner. In many cases, incorrect assumptions are made that everything is an isolated incident. In other instances, problems are not corrected and everything is blamed on a single employee or a simple laboratory error or the system fails to ensure that a problem does not extend to other lots and the incident recurs. The ultimate criterion for adequate correction is to ensure that it doesn’t happen again. CAPA was adopted as a new quality management tool following the introduction of the ICH Q10 guideline. According to the ICH Q10 document, which was adopted by the FDA in April 2009 as an industry guideline, a pharmaceutical Quality Management System (QMS) consists of four central elements:
  1. Process performance and product quality monitoring;
  2. Corrective action and preventive actions;
  3. Change management;
  4. Management review of process performance and product quality.
The guideline states that a pharmaceutical company should have a system in place to detect and evaluate non-conformances to take respective corrective and preventive actions. Among other things, the information regarding non -conformances can result from complaints, deviations, recalls, observations at audits and inspections, or from monitoring findings. The examinations within the system must have the objective of determining the actual root cause. As a result, the process and product should be better understood so that improvements can be continual.

Sources that lead to Corrective and Preventive actions include, but are not necessarily limited to: Quality Audits (Internal/External); Non-Conforming Results/Products; Customer Complaints; Risk Management; Process Performance Monitoring; Management Review; Failure. One of the most fundamental steps in the CAPA process is completing an evaluation of the actions that were taken. These evaluations must not only verify the successful completion of the identified tasks, but also assess and adequately document the appropriateness and effectiveness of the actions taken. Have all of the objectives been met? Did the actions correct or prevent the problem (root cause) with adequate assurance that the same situation will not happen again ? Have all the recommended changes in adequate detail been completed, verified, and fully documented? Has training and appropriate communications been implemented to assure that all relevant employees understand the situation and the changes that have been made?

Conclusion
It is difficult to fathom the logic behind telling FDA that a manufacturer has no intention of complying with any aspect of the QSR. Pharma Industries and the Medical Device industries should have robust requirements for pursuing corrective action and the need for addressing Customer Complaints, OOS, and Deviations. Regardless of the industry, it is imperative that accurate root cause be ascertained. There is a plethora of tools available to support root-cause analysis. If proper training is not provided to employees and accurate root causes are not determined, chances of manufacturers from pharma and other industries implementing incorrect solutions may increase. Applying the wrong solution may potentially impact device safety and efficacy, so it is imperative that great care and attention to detail be employed as part of the root-cause investigative process.

References:
  1. "www.fda.gov/www.edqm.eu/"
  2. "Corrective and preventive action". wikipedia.org/wiki/Corrective_and_preventive_action
  3. "Complete Procedure of CAPA for Pharmaceutical Industry", formulation.vinensia.com/2012/01/complete-procedure-of-capa-for_06.html
  4. Guidance for Industry, fda.gov/.../2005-4136b1_05_pharmaceutical%20CGMP.pdf
  5. FDA-compliance-pharmaceutical-industry, caracorp.com/FDA-compliance-pharmaceutical-industry.php
  6. FDA, EU expecting manufacturers to use CAPA to halt OOS, determine 'root cause' Find articles.com/p/articles/mi_hb5677/is_9_5/ai_n29033453
  7. CFR code of federal Regulations Title21, accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820References
  8. ISO 13485:2012
  9. ICH Q9, Q10