RCA Investigation Tools- It's application to Pharmaceutical Industry

“An effective RCA process is the foundation of a robust Pharmaceutical Quality System”  

An RCA is a solution providing tool start from identifying the underlying cause(s) and /or casual factors of defects or problems and results into the corrective and preventative actions. A factor is normally as sub-cause can be considered “root cause” if removal thereof from the problem-fault-sequence prevents the final undesirable event from recurring; whereas a causal factor is one that affects an event's outcome, but is not a root cause. Though removing a causal factor can benefit an outcome, it does not prevent its recurrence with certainty.

An RCA is the first key step in offering an effective solution to prevent the defects/problems, approach used for identifying the underlying cause (s) is to understand the basics on how and why an incident occurred to conclude the real root cause and /or proximate cause (s), and if not at worst to identify the casual factors affecting the outcome of the process.  

RCA is always regarded as plural, namely “Underlying Cause(s)”, which is not merely the singular i.e. there may be several cause(s) responsible for the outcome of the problems/defects. An RCA is a systemic process starts with identifying the underlying cause(s) and /or casual factors, the success rate to find out the right root cause(s) depends on various factors in which use(s) of relevant RCA-tool plays a vital role. 

Why RCA? -

An RCA is typically used when something goes bad (normally negative events /outcome), this can be understood with the three basic questions mentioning below:

? What's the problem? This is a typical/problem statement as an outcome of incidents/failure/OOS/OOT/Nonconformance/Customer Complaints etc.

? Why did it happen?   This can be answered by using the appropriate tools to find out the cause(s) and /or casual factors.

? What will be done to prevent it? This is typically resultant action points, called as CAPA initiated based on the identified root cause analysis. 

RCA TOOLS- AN INTRODUCTION:

A major cornerstone of the commitment to quality improvement prescribed by Deming and the other early quality gurus , who invented several “Quality problem solving tools” to identify the cause(s) of quality problems that are still widely used today, including but not limited to as; process flowcharts, Cause and Effect Diagrams, five-why’s, Cause mapping, brain storming, Fault tree analysis, and failure mode and effects analysis, check sheets, histograms, scatter diagrams, statistical process control charts and cause-and-effect diagrams, Pareto charts etc.

The fig on RCA-Tools lists out the various well-known-RCA tools (including the seven quality tools, also known as magnificent seven) for identifying quality problems and their causes & effects. 

A root cause analysis tool analyzes the underlying factors in any given adverse reaction to identify a problem's source and take corrective measures to fix it. The selection of appropriate RCA-Tool is a unique process as it delves deeper to find answers based on hidden cause(s) and their effects, rather than merely looking at the most apparent or sometimes knows as Symptoms. 

The application of these RCA tools is based on the occurrence of the type of events/problem, type of industrial operations, and experience of individuals. RCA tools can be utilized as discrete or in-combination depending upon the scope and depth of the investigations requirement.

Let’s discuss the RCA-Tools in details to get a deeper understanding about the basic methodology- how it works, it’s application, case study (as applicable) as well as benefits. 

DISCUSSIONS ON VARIOUS RCA- TOOLS AND IT’S USE(S)

Process Flow Chart-

A process flowchart is a diagram of the steps in a job, operation, or process. It enables everyone involved in identifying and solving quality problems to have a clear picture of how a specific process or operation works in a common frame of reference. It also enables a quality/process improvement team to understand the interrelationship of the activities that constitute a process. This helps focus on where problems might occur and if the process itself needs fixing. Development of the flow chart can help identify quality problems by helping the problem solvers better understand the process.

For example, if the in-process results failed at unit operation number 46, then an investigational RCA should focus on what happened from the last step, say the review of process data confirms that process was running within the state of control until operation number 24, then a step by step break down and brain storming of the process from unit operation number 25 to 46 can help to identify the underlying cause(s), while other unit operations can be ruled out from the scope of the investigation. 

CAUSE-AND-EFFECT DIAGRAM (6M/FISH-BONE):

A Cause-and-effect diagram is known as fish-bone or 6M, invented by Dr. Kouro Ishikawa. The tool defines the graphical description of the elements of a specific quality problem and the relationship between those elements. It is used to identify the cause(s) of a quality problem so it can be corrected and prevented in future. Cause-and-effect diagrams are usually developed as part of brainstorming to help cross functional teams in breaking-down the process into the secondary and tertiary sub-branches to reach closer to real and/or proximate cause(s)/ Casual factors. 

The box at the end of each branch (or fishbone) describes the cause category. The diagram starts out in this form with only the major categories at the end of each branch. Individual causes associated with each category are attached as separate lines along the length of the branch during the brainstorming process. Sometimes the causes are rank-ordered along the branches in order to identify those that are most likely to affect the problem. The cause and- effect diagram is a means for thinking through a problem and recording the possible causes in an organized and easily interpretable manner. This is most widely used tool in the manufacturing industry for the identification of cause(s) of OOS/OOT, Customer complaints, deviations/incidents etc.

FIVE-WHY’s:

“ Five-Why’s?” is a pragmatic tool to ask “WHY”? And continue to ask until ascertain the right answer on the “root cause of the problem”. The process involves the discussion usually between the cross functional teams comprises with subject matter expert, process development, Manufacturing, engineering, Quality control, Quality Assurance etc.

CHECK-SHEETS: 

Check sheets, which are frequently used in conjunction with histograms, as well as with Pareto diagrams. A check sheet is a fact-finding tool used to collect data about quality problems. A typical check sheet for quality defects tallies the number of defects for a variety of previously identified problem causes. 

Checklist can identify the number of problems occurred/not occurred for each category and can present into the graphical way, such as in the form of histograms and praetor charts to understand the relationship of the causes v/s effect i.e. majority of problem could be attributed due to some of the items. Refer the Histogram or pareto chart. 

HISTOGRAM: 

Histogram can represent the uniformity/non-uniformity of data distributed across the specified limit.

With the Histogram, one can identify the number of frequency, data skewness either positive or negative side or abnormal distribution which can help further to investigate those data points attributing the non-uniformity

PARETO-CHART:

Pareto chart is a method of identifying the causes of poor quality. The tool was devised in the early 1950s by the quality expert Joseph Juran. He named this method after a nineteenth-century Italian economist, Vilfredo Pareto, who determined that a small percentage of the people accounted for most of the wealth. Pareto analysis is based on Juran’s finding that most quality problems and costs result from only a few causes.

The Pareto chart identifies the major cause of poor quality and correcting the problem will result in the greatest quality improvement. However, the other problems should not be ignored. Continual quality improvement is the long-term goal. The Pareto diagram simply identifies the quality problems that will result in the greatest immediate impact on quality improvement. This can be utilized to determine the frequency of the failures/OOS/OOT by assigning the category such as but not limited to; specific block of manufacturing, vendor, seasonal, equipment, method, man etc. and focus on few cause(s) leading to major failures/problems.

SCATTER DIAGRAMS: 

Scatter diagrams graphically show the relationship between two variables, such as the outcome quality attribute of the material while varying the process parameters-temperature, vacuum, time limits etc. One temperature reading should result in a specific degree of brittleness representing one point on the diagram. Many such points on the diagram visually show a pattern between the two variables and a relationship or lack of one. This diagram could be used to identify a quality problem associated with the manufacturing process, such as different vendor, equipment, manufacturing blocks, seasons etc. 

PROCESS CONTROL CHART:

Control chart is a means for measuring if a process is doing what it is supposed to do, like the behavior of process with respect to it’s quality and yield attributes. This is constructed with a horizontal line through the middle of a chart representing the process average or standard norm. It also has a line below this center line representing a lower control limit and a line above it for the upper control limit. Samples from the process are taken over time and measured according to some attribute.

If the measurement is within the upper and lower control limits, the process is said to be in the state of control and possess with natural variance without any quality problem, but if the measurement is outside the limits, then a problem probably exists and should be investigated and corrected.

For Example; if LCL and UCL is set to be within the three-sigma band, then process should perform within the defined band of three-sigma range and outside data points (either being lower or upper) are unnatural variance. These data points normally subjected to investigation in identifying the random/assignable cause. Normally Cpk > 1.33 process are regarded as very good state of control, <1.33 and >1.00 are in edging state, while < 1.00 is considered as unfavorable band and can be subjected to investigations and assessment. 

POTENTIAL USE(S) OF RCA-TOOLS: 

The applications and utilization of relevant RCA-tool is enriched based on various factors, such as but not limited to; experience/expertise in area of working, type of industrial operations- process /Analytical/engineering, type of event, scope or criticality of event and finally important one is-to Practice. 

RCA-TOOLS- APPLICATIONS AND BENEFITS:

RCA-tools are used to address reactive as well as potential negative-events, such as OOS, OOT, Customer complaints, recall, incidents/deviations, trend detections, risk management and risk detected during the internal and external audits etc. 

Positive Aspects of RCA Tools:

ü Solving real problem/defects will prevent reoccurrence

ü RCA tools provides scientific way of consistent decision making

ü Avoiding generation of waste/dead inventory which will avert recycling /reprocessing/reworking

ü Robust quality process provides assurance to patient safety

ü Faster regulatory approvals will lead to market capitalization

ü Positive outcome of successful regulatory/ Customer audits will build trust

ü Boost-up employee morale and helps in ensuring co-operative working culture

Improved and sustained bottom line

SUMMARY & CONCLUSION:

To summarize the discussions, documenting the RCA process should provide a meaningful insight to reviewer in explicit and understandable manner on how the root cause(s) and/or casual factors were ascertained. Data gathered and compiled as part of investigation process should provide a step-by-step visibility to connect the dots with the conclusion on RCA drawn, which should lead into specific action oriented and /or clear decision making in lieu of be informative as usual. Per the USFDA- guidance on investigation of OOS, the investigation should be “Meaningful” and adhere to the “five-key-elements of good investigation” process i.e. – it must be “Thorough, Timely, Unbiased, Scientifically sound & well-documented”

RCA-tools can be utilized as part of investigational-journey to ensure decision makings are consistent, unambiguous and are based on proven empirical rationales instead of individual experiences, sometimes perceptions and /or preconceived assumptions. RCA tools can be applied in the entire life cycle starts from ““product development, technology transfer to commercial manufacturing through product discontinuation”. The effective use of RCA-tools not just ensures the prevention of existing problems but make sure to prevent the potential problems, which is a prime signal of healthy functioning of Pharmaceutical Quality System in order to serve right-first-time-quality products.

For example, if the in-process results failed at unit operation number 46, then an investigational RCA should focus on what happened from the last step, say the review of process data confirms that process was running within the state of control until operation number 24, then a step by step break down and brain storming of the process from unit operation number 25 to 46 can help to identify the underlying cause(s), while other unit operations can be ruled out from the scope of the investigation.

CAUSE-AND-EFFECT DIAGRAM (6M/FISH-BONE):

A Cause-and-effect diagram is known as fish-bone or 6M, invented by Dr. Kouro Ishikawa as depicted per Fig-4. The tool defines the graphical description of the elements of a specific quality problem and the relationship between those elements. It is used to identify the cause(s) of a quality problem so it can be corrected and prevented in future. Cause-and-effect diagrams are usually developed as part of brainstorming to help cross functional teams in breaking-down the process into the secondary and tertiary sub-branches to reach closer to real and/or proximate cause(s)/ Casual factors.