An FDAnews White Paper

Even in organizations with successful quality programs, minimizing human error is an ongoing challenge. Experienced people working on established processes sometimes make costly errors in spite of the most diligent efforts to avoid them. Human error is often the primary contributor to failures or adverse events in the pharmaceutical industry, leading to quality problems that require expensive solutions. Despite the industrys awareness of human errors, companies still frequently fail to substantively and correctly address errors. The typical response to a human error is retraining. But studies have now shown that training or lack thereof is responsible for only about 10 percent of the human errors that occur. While training typically is effective when there is a need for a new skill set or the implementation of a new task, it is not an effective response to a human error that is not caused by a lack of knowledge. So, if human error is the cause but training is not the reason behind it, then what is? This FDAnews White Paper examines how organizations can get to the bottom of events and determine what is behind the errors being committed by operators.

Manufacturers Can Control, Investigate Human Error

Research shows that 80 percent of human error can be controlled by managing human factors. This can be done by managing any aspect of the workplace or job that makes it more likely for a worker to make an error. In other words, human factors must be implanted into systems used by employees. The remaining 20 percent of human errors can be controlled by managing the acquired behaviors of humans, otherwise known as habits. As a result, controlling human error is done 80 percent by managing systems and 20 percent by managing people. Organizations can combat problems by identifying system weaknesses and making them stronger. This can be done by finding minor events that could be the precursors to much larger events those that have not yet resulted in losses. Then, pinpoint the reasons why these minor events happened and correct them. It is very similar to what is known in safety systems as near misses. However, if a human error does occur, it must be investigated. When investigating human errors, what often happens in the investigation process is an event is identified and the technical part of the event is investigated. Whenever there is a possibility that human failure is the root cause, however, a (See Control, Page 2)

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Control, from Page 1 human error investigation must be undertaken to comply with the FDA regulations. Thus, once the root cause analysis investigation is complete, a new investigation starts the human error investigation. Human error investigators are people who have specific skills and abilities designed to understand human behavior and understand conditions that could impact behavior in a negative way, leading to human error. In a typical investigation process, the organization gathers and analyzes data, determines the causal factors behind an event, determines the root cause(s), and categorizes and codes those causes. Next, corrective and preventive actions are designed and developed, followed by monitoring and trending of the root causes. Based on the data, the effectiveness of the corrective and preventive actions (CAPA) can be measured, allowing the organization to predict if it has a problem with one of its systems.

For example, an organization discovers it is experiencing human errors related to one of its procedures. The human error investigators identify that the procedure was not being used because it did not exist. Then, if they determine that most of the human error-related events are related to that root cause, the organization can predict that at some point, if it doesnt create a procedure, a mistake will once again be made. Five Whys Using the Five Whys is a simple but powerful technique to help get past the symptoms of a problem and find its root causes. Simply ask the question why several times. For example: 1. Why did the employee make the mistake? He failed to follow the procedure. 2. Why did he fail to follow the procedure? Because there was no procedure. 3. Why was there no procedure? 4. And so on

INSIDE THIS ISSUE

Retraining as a corrective action can worsen a situation ................................................Page 4 Root cause analysis investigations and using diagrams help companies find causes of underlying error causes ................................Page 4 Need for costly, in-depth root cause analysis investigations will vary from organization to organization ..............................................Page 6 Root cause analysis should not be used as punishment tool to assign blame to employees or cause guilt ............................................Page 6 Trending should focus on items with major impact to company ....................................Page 7

CAPAs Are the Key to Strengthening Systems

Whenever an adverse event occurs, corrective and preventive actions (CAPA) must be developed to make an organizations systems stronger. A company will create systems to detect similar future errors or events, which will serve as the alarm that triggers corrective action and recovery. It is essential to establish procedures for a CAPA system, including sources of data. To the FDA, establish means define, document either in writing or electronically and implement. CAPA procedures should describe what the data sources are, how data is collected as well as by whom and when and how data are routed to the CAPA system. Procedures can be conducted manually or electronically; there can be separate procedures for collecting data and for evaluating the root cause. (See CAPA, Page 3)

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CAPA, from Page 2 The sources of information will vary, but at some point all of the data with the results of the investigation must flow into CAPA. Then, recommended and approved actions can be taken, and implementation and verification of those actions can be documented and tracked. Information for CAPA comes from internal and external feedback sources. Sometimes what is internal and what is external is an arbitrary division. The main thing is to make sure that nothing is missed. Internal sources include:

slightly different way than a normal complaint or problem would be. Procedures must be written to assure that the data captured is complete, accurate and timely. If they are not, investigations will not be complete and any corrective or preventive action could be unnecessarily delayed, making the problem worse. The purpose for bringing the data together is to assist with data trending to detect existing or potential nonconformities. This should be done within or across data sources. For example, comparing electronic repair logs and the pieces of equipment that have been serviced or recalibrated in a given time frame to the in-process test results of product made in those pieces of equipment might show a potential situation for future failure. When Equipment Y, for example, is within 30 days of recalibration, in-process batches of drug product A are usually testing in the lower limits of the range. Although there has not been a failure in the lower limits of the range, it might be wise to change the calibration schedule for Equipment Y to prevent a situation where the calibration might affect the product if it is done late and might make it drop outside the range of acceptable product. This is a preventive action. Also documented in the CAPA system should be actual verification or validation of the actions that were implemented. There must be a mechanism for communicating the now known quality problem or nonconforming product to those responsible for assuring the quality of the product and/or the prevention of such problems. There must be communication capabilities to feed the information to those who can most effectively take advantage of it to prevent future problems, to take corrective action or even to make corrections in some cases. Again, actions must be documented. After the actions have been taken, implemented and verified or validated as effective, management (See CAPA, Page 4)

Inspection test data, in-process data, final inspection test information, quality assurance unit inspection findings, scrap and yield rates and process control data. Internal feedback sources can be anything that is routinely tested as well as environmental control data and data regarding scraps and defect rates. Incoming inspection data collected relative to the part number, a supplier, a batch or a lot number. Although they might be relative to products that come in from the outside, these items also are parts of the internal data sources. Internal audits, equipment maintenance and calibration data also can be valuable in understanding processes. Various reports and records that are generated during manufacturing, packaging, labeling and employee training.

External feedback can come from several different places, including:

Complaints. The FDA gets complaints from consumers and employees through various systems like MedWatch, medical device reports, drug adverse event reports, and field service reports relative to products, product returns and journal articles. Legal claims, warranty issues and claims, regulatory audits and client audits.

Companies sometimes forget legal claims and warranty claims. These are handled in a

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CAPA, from Page 3 should again be informed. This is usually done by trending reports during management reviews. It is essential that management is kept informed. The FDA looks favorably on organizations with CAPA programs and outlines its expectations for CAPA in its regulations and guidance documents. One theme throughout the regulations is the need to document. Companies must put into writing actions and decisions including problem identification, the investigations, decisions regarding the problem and solutions, and the actions taken to correct the problem and prevent it from happening again.

Root Cause Analysis Helps Find Causes of Underlying Errors

Root cause analysis (RCA) is a step-by-step method of investigation that should lead to the underlying causes of undesirable events within an organization by the use of tools such as fault trees, causal factor charts or fishbone diagrams. RCA is the way to help trace the progression of events that led up to an incident or human error, much like solving a crime. It can be performed for an organizations internal benefit or may be done if an organization is the subject of an FDA for-cause inspection, when a series of adverse events have been reported to the FDA, or FDA inspections have revealed problems. In the event of an incident, RCA helps answer these fundamental questions: (See RCA, Page 5)

Retraining as Correction Can Worsen Situation

Training or, more specifically, retraining is often used as a corrective action in the pharmaceutical industry. Instead of helping, however, retraining can sometimes make a bad situation worse. Consider this scenario a man is in his doctors office. He has a variety of symptoms that are making him miserable. He enters the exam room, where he waits to see his doctor for 30 minutes. The doctor finally comes in and hands him a prescription without ever examining him. Sound crazy? Perhaps, but that is exactly what often happens in corporations. Training is thrown at problems when it is not even known what the real problem is or the root cause of the problem. Personnel in a quality control unit should be wary about listing retraining as a corrective action in an FDA investigation. By indicating that retraining is being done to correct a problem, they are also pointing out the fact that the original training effort was less than effective. Hence, a vicious cycle seems to be evolving, which the FDA is bound to notice. Instead of retraining, think of effective training as an excellent preventive action. In order for training to be effective, however, the root cause of ineffective training must be identified.

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HOW TO REDUCE HUMAN ERROR BY MANAGING HUMAN FACTORS

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RCA, from Page 4

What went wrong? What were the consequences of the incident(s)? What could cause these events? What changes should be made to the proactive analysis process and the management systems to adequately control risk in the future?

the way back to the root cause or merely breaking the chain of events so the problem cannot recur is a decision manufacturers must make on each occasion. At first blush, an adverse event may look as though it was caused by human failure, but investigations frequently reveal that a much deeper issue is to blame. The recommended levels of an investigative analysis, starting at the uppermost level and digging down to the lowest, are:

The RCA has built into it all of the reasons why systems and people fail. Therefore, it doesnt have to be reinvented each time it is used. It identifies the following human error categories:

Procedure-related errors; Human factor engineering related error; Training-related error; Error reduction; Supervision-related error; Communications-related error; and Individual error.

Human error or equipment failure Task control issues Process control issues Management system issues Organizational cultural issues

Neither training nor the individual has been excluded from this list, but it should be noted that they are just two of the six categories. Each of the categories must be further investigated because procedure-related error, for example, does not fully explain what happened or why. Using the root cause chart, the main goal is to have:

If only the top levels of an event (human error or equipment failure) are investigated, only one problem will be solved. The deeper one digs into the event, the more the investigation will learn about organizational problems. Consider the following example: A fuse blows and causes the lights to go off. A manufacturer can identify the immediate causal factor fuse blew and replace the fuse. It can also identify another cause a short and repair the wire that shorted. If it doesnt identify and correct the factor that led to the fuse blowing, however, (e.g., wiring not maintained because there was insufficient maintenance), other systems may experience similar failures. RCA seeks to identify these deeper systemic problems, such as lack of an adequate maintenance budget, and correct them. Unfortunately, some RCA methods fail to dig far enough. Often, organizations will get down to the management systems level and stop at that point primarily because corrective actions and recommendations must be actionable and measurable, and it may be difficult to do that at the organizational cultural level.

Good and accurate administrative management systems that would assure that there are controls for providing clear, accurate procedures, instructions and other aids; Good human factors engineering of control systems, processes and work environment; Job-relevant training and practice; Appropriate supervision; Good communications; and Fit for duty personnel performance.

The primary goals when investigating an incident are to discover what caused it and why with the eventual goal of making sure it does not happen again. Whether that means going all

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Need for RCA Investigations Will Vary by Organization

Not every problem or nonconformance requires an investigation down to the root cause level. These in-depth investigations can be very costly, and the need for them will vary by organization. If an event has relatively minor consequences, an organization will not learn a lot from performing a root cause analysis (RCA). Companies need to determine how serious a problem is, how frequently it occurs, how it affects the company, etc. These answers will help determine if there is a need for RCA. The key reason to perform RCA is to develop leveraged solutions or recommendations. As the investigative process moves forward, it should result in four levels of recommendations that do the following:

RCA Should Not Be Used As Punishment Tool

Manufacturers should keep in mind that root cause analysis (RCA) is not meant to be used as a process to affix blame or make employees feel guilty. Blame rarely achieves the goal of learning what caused the adverse event. Nor will it eliminate repeat incidents. Rather, RCA should be used to allow effective solutions to be identified, prevent recurrence of adverse events and provide feedback on the operation. If punishment is part of the investigation process, it generally leads to decreased performance and degraded attitudes. Successful RCA programs do not include disciplinary actions as potential corrective action for honest mistakes. (See Punishment, Page 7)

Address the causal factor; Address the specific problem; Fix any similar problems; and Correct the process that created the problems.

Medical Device Complaint Management: A Guide for Compliance

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If the causal factor is not addressed, the problem is not solved. Most organizations address this level. If the specific problem is not addressed, the problem recurs. This level is sometimes ignored. If similar problems are not fixed, these problems will recur as existing issues continue to surface. If the process that created the problems is not corrected, new problems will occur, even if all of the existing problems are solved. Most organizations fail to address this level without an RCA program. The root causes of an event should be directly connected with associated corrective actions (see story, page 2). If upper management does not see a connection between the cause of the event and the recommendations from an investigation, it is unlikely to want to implement them, and failing to correct problems will come at a high cost to an organization.

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Punishment, from Page 6 On the other hand, rewards and discouragements must be a part of a companys normal performance review process. Some industry experts believe that there should be a change in the way organizations view human error. The current way is to identify an employees inaccurate assessments, wrong decisions and bad judgment, assessing blame to the employee. A new vision calls for a new approach to human error as a symptom of a deeper problem inside a system. Human error should be less about the person and more about why that person made the error. Manufacturers should identify how people assess tasks and decisions that make sense at the time given the circumstances that surrounded them, and they will likely find out the real reason for the human error. This can be done with RCA.

For example, complaints often constitute an area that should be regularly addressed, even if some of those are not particularly important, because they deal directly with patients a high-risk area. Statistical Methodologies It is important to use tried and true statistical techniques when evaluating products and assessing risk. Some of the statistical methodologies include Pareto charts, run charts and control charts. Pareto charts summarize and display the relative importance of the differences between groups of data. Control charts focus on the variation in a process. Run charts, which are similar to control charts, focus more on time patterns, displaying process performance over time. The FDA and the International Organization for Standardization (ISO) have several regulations regarding trending, including the following:

Trending Should Focus on Items With Major Impact to Company

It isnt always easy to decide what to trend and when. The tendency among drug manufacturers is to rank issues or areas from major to minor. Companies identify what they believe are important and not-so-important trends and those things that might not be trends. It is important to select items with major impact to the company, especially product- and process-related items. The FDA tends to focus on three areas of risk: patient risk, product risk and process risk. The level of risk associated with an issue and its impact on a business are the ways to evaluate and determine how frequently trending should be done and whether an area makes it to the top of the list. The things that offer insight into major risks should be trended first and most often.

21 CFR Part 820.100(a)(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, and or other quality problems This regulation provides an extensive list of what should be trended. For pharmaceuticals, although the word trending is not explicitly used, as it is in the medical device area, the FDA considers it to be required by this portion of the regulations:

21 CFR Part 211.180(e): Written records required by this part shall be maintained so that data therein can be (See Trending, Page 8)

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March 2011

Trending, from Page 7 used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Trending should be done as often as necessary. For most products and processes, an annual review of trends is not enough, according to experts. Most companies do a good job of trending complaints and monitoring results, but many of the other corrective and preventive actions sources are not trended often enough or are entirely missed.

shall include determination of applicable methods, including statistical techniques, and the extent of their use. Reviewing Trends Management must review all data trends. Trends should be reported so that management hears first about those trends that are occurring most frequently, as well as those that pose the greatest risk to the company, the products and the processes, but first and foremost, to the patients. Management review should be conducted at a level of frequency based on the kinds of problems being detected. As time goes by and the problems are better controlled and the level of risk falls, the reviews may be conducted less often. In other words, manufacturers should look at the array of products being produced, and as products age and new products are introduced, consider the correct frequency. Management must assure that each corrective or preventive action that is taken is implemented and verified or validated. The process should include identifying problems, recommending solutions and verifying that those solutions are successfully fixing the problems. All of these procedures must be properly documented for internal recording purposes and in the event of an FDA inspection.

ISO 9001:2000 8.4: The organization shall determine, collect and analyze appropriate data to demonstrate the suitability and effectiveness of the quality management system and to evaluate where continual improvement of the effectiveness of the quality management system can be made. This shall include data generated as a result of monitoring and measurement and from other relevant sources characteristics and trends of processes and products ISO 9001: 2000 8.1: In regards to measurement, analysis and improvement, this requirement states, The organization shall plan and implement the monitoring, measurement, analysis and improvement processes needed

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