Root Cause Analysis via 1m to 10M in Pharmaceutical Industry for Implementation of Effective Corrective and Preventive Action

Root cause analysis uses multiple investigation tools to identify problems and their contributing factors. Root cause analysis Involves various Tools of Investigation Viz. Why- Why Analysis, Ishikawa Approaches (6 M Analysis), Pareto Analysis, Failure Mode and Effect Analysis (FMEA), Fault Tree Analysis etc. Root Cause Analysis (RCA) is a structured, team-driven process designed to uncover the fundamental causes of events that lead to undesired outcomes. By systematically examining contributing factors, RCA identifies breakdowns in processes and systems—not just surface-level symptoms—and guides the development of targeted corrective actions. The ultimate goal of RCA is to prevent recurrence by addressing the true source of the problem, ensuring long-term improvement and resilience in operations. Root Cause Analysis (RCA) is a critical Methodology for ensuring quality across all organizations, including those in the pharmaceutical industry (1,2). It focuses on identifying the initial action or condition that triggers a chain of events leading to a problem. By tracing issues back to their origin, RCA enables organizations to implement effective solutions that address the true source of the problem—rather than just its symptoms—thereby improving overall quality and preventing recurrence. Auditors & Investigators play a critical role in identifying and understanding deviations (3,4). They must examine each deviation in the context of past events or interventions to determine how specific actions may have contributed to the issue. This requires a thorough analysis of cause-and-effect relationships. To support this process, Root Cause Analysis (RCA) tools are employed to uncover the underlying reasons behind deviations or poor outcomes. These tools help auditors move beyond surface-level symptoms and pinpoint the true source of the problem, enabling effective corrective and preventive actions.

Key Aspects of Root Cause Analysis (RCA) in Regulatory

Root Cause Analysis (RCA) plays a critical role in maintaining compliance and driving quality improvements across regulated industries. Its application ensures that organizations not only resolve issues but also prevent their recurrence (5). Some of Key Functions which are involved in Root cause analysis are mentioned below to understand the basic Role and Fundamentals in Pharmaceutical Industry (6).

• Systematic Process: - RCA employs structured methodologies to uncover the fundamental causes of problems, focusing on systemic breakdowns rather than superficial symptoms.
• Integration with CAPA Systems: - RCA is a cornerstone of the Corrective and Preventive Action (CAPA) framework. It ensures that both corrective measures (to fix current issues) and preventive strategies (to avoid future ones) are effectively implemented.
• Regulatory Compliance: - Regulatory authorities often mandate thorough investigations into Deviations, adverse events, or non-conformances. RCA supports compliance with these requirements, helping organizations avoid penalties and maintain operational integrity.
• Risk Mitigation: - By identifying and eliminating root causes, RCA enables proactive risk management. This reduces exposure to future compliance failures and enhances overall system reliability.
• Continuous Improvement: - RCA strengthens Quality systems by promoting data-driven decision-making and operational efficiency. It fosters a culture of learning and ongoing improvement.
• Broad Applicability: - While widely used in pharmaceutical and life sciences sectors, RCA is equally valuable in other regulated domains such as Finance, Healthcare, and Manufacturing—where compliance and process integrity are paramount.

Further to Assess the Problem and Identification of Root cause the Pharmaceutical and Biotechnological industries used many Tools which is part of Different Regulatory bodies and Guidelines. As per Current Regulations and their Strategic process 6M Analysis are commonly used to determine the causes for Implementation of Effective CAPAs. The commonly used 6M elements are explained and determined here to assess the Probability of Non-Conformance Report (7).

Fig 1: An Ishikawa fishbone diagram could possibly be used to discover root causes (6M Analysis for Implementation of Effective CAPAs).

As mentioned above, The Fishbone diagrams visually identify potential Problem causes by categorizing factors into six main branches. These branches represent the Men, Machine, Material, Method, Measurement, and Mother Nature as cause categories. Furthermore, these tool helps the teams in brainstorming for identification of root causes, prioritize actions, and improve quality systematically (8).

1. Men: - These factor influence the Human error factor where causes to be determine with respect to skills, trainings, and Physical and Mental state of the person, Experience level and Human Error Potential. Along with fatigue, competency, attention to detail, and adherence to procedures.
2. Machine: - These include Equipment/ Instrument related factor which is involved in the Objective. These contributing factors covers Equipment/ Instrument age, Calibration/ Maintenance History, any adjustments etc.
3. Material: - In the RCA analysis of Material category, it included, input/ output phenomenon of Material, Storage Condition of Material, any type of Handling issues which can be impactful on any kind of error/ Laboratory errors.
4. Method: - This category is play a vital role in any kind of Laboratory error. It includes analytical Methodology, Work instructions, Process Parameters, work flow design and other Possible Factors which is responsible for Method Related Errors.
5. Measurement: - Measurement is the Parameter which influence the results accuracy which directly impactful of any kind of Laboratory errors. It includes Instrument Accuracy, Statistical Process Control, and Quality Control Parameters etc.
6. Mother Nature (Environment): - Mother Nature factor involves Temperature/Humidity Conditions of the area, Workplace Lightening, Cleanliness, Layouts and weather Conditions also.

Limitations of 6M elements on Core Investigation:

The 6M Analysis, while widely used in manufacturing investigations, has notable limitations. Its scope is primarily designed for manufacturing processes, making it less relevant for service-based industries without significant adaptation. The approach often oversimplifies complex issues and may overlook systemic causes. Although the “Man” element addresses operator-related factors, it fails to capture broader human aspects such as organizational culture, leadership, and Psychological influences. Furthermore, the framework does not account for dynamic changes in processes, technology, or external factors like market conditions and regulatory requirements. In practice, the analysis can devolve into a brainstorming exercise without integrating actual process data, reducing its accuracy and effectiveness.

Expanded Factors of Root Cause Analysis:

Based upon the formal discussion with the contributing team and leaders, it is find out that 6M factors are not always impactful for assessment of problem causing and implementation of effective CAPA. Hence to address the Psychological Factors and Industrial Factors, the additional 4M Analysis expands in the traditional 6M framework specifically relevant to Pharmaceutical Investigations. This enhanced approach ensures systematic coverage of potential causes, addressing gaps in the original model. By including these factors as the framework provides a more holistic view of process variability and Risks. It supports both Proactive and Reactive Problem-Solving, enabling organizations to identify Root causes more effectively and implement robust corrective and preventive actions (CAPA).

Fig 2: Proposed expansion of 4M Analysis in the traditional 6M framework to Pharmaceutical Investigations

1. Money: - Many time all possible factors as mentioned above are not contributing factors of Problems Statement. Hence to eliminate and identify the cause along with 6M Analysis “Money” are also a Contributing factor of any problems. It includes financial aspects i.e. Budget constraints, unavailability of resources, Cost cutting impacts etc.
2. Management: - Management factors includes Leadership and sponsorship are also a part of Problem causing. It includes Decision-making processes, Communication channels, Policy implementation, Resources planning & Leadership style etc.
3. Maintenance: - These factor includes upkeep and preservation activities i.e. Preventive maintenance schedules, Repair procedures, Spare parts management, Equipment Lifecycle, Maintenance training etc.
4. Motivation: - This factor the final layer of examining Psychological and Cultural factors which includes Work Culture, Team Morale, Incentive Programme, Job Satisfaction etc.

Case Study:

On the basis of Aforesaid Factors, a formal/Predicted Investigation/Contributing factor assessment are performed to addressed the Role of Each Contributing Factor in the Investigation Outcome to Facilitates the Problem Causing Statement, which is mentioned below as: -

Problem Statement: -

On 04-April-2024,There is a failure to throughly review any unexplained discrpancy whether or not batch has been already distributed.

Specifically,

After analysis of samples of Abcd Batch (Batch No. XXXX) for the test of Assay, analyst observed that results of Content for Batch No. XXXX does not conform to Specification (Specification No.SPE-0025).

The samples of Abcd Batch were received from your other unit for analysis on 02-Apr-2025. The analysis was performed on 04-Apr-2025 using HPLC instrument No. HPLC-001 located in Laboratory of your esteemed firm. Results of the analysis are tabulated in the table No: 01 are as follows:

Scope of Investigation:

Investigation carried out by verifying Analyst Qualification Record, Raw Data, Instrument Calibration status, Instrument Malfunctioning verification, used Chemical status, Sample and Standard preparations, used Glassware (Plastic ware), Environmental condition, interaction with Analyst, verification of method validation data, verification with previously analyzed batch. Preliminary investigation was performed.

Details of Investigation:

Preliminary Investigation:

• Phase-I investigation initiated through preliminary investigation. During Preliminary investigation, verification performed with Analyst Qualification record of Mr. Ram Kumar and found analyst is trained on particular instrumental technique.
• Mobile Phase, standard and sample preparation details along with volumetric used for solution preparation were verified and no error has been identified.
• Details of chemicals and standards used for analysis were verified and found satisfactory. All materials were within validity period.
• Sample set was found as per the procedure and all the details of vial position, injection volume, Instrument method selected for analysis etc. were found correct.
• Re-verified the instrument method parameters used for the analysis and found correct. Also, Instrument method was reviewed by reviewer before starting of the analysis.
• Column used for analysis was found same as mentioned under Methodology.
• Calibration details were verified before starting the analysis. Instrument calibration status for HPLC instrument No. HPLC-001 was verified and instrument was found with calibration period (next calibration due on 20/05/2025).
• Also no instrument malfunctioning or error has been observed during analysis. System suitability details were verified and found well within acceptance criteria. Obtained system suitability data for theoretical plate and %RSD for six replicate injections for peak area of Sodium Chlorite are as tabulated in table 1:
• Data of all the analyte peaks found satisfactory in SST-SOL and STD-SOL and was comparable with historical data Table 1.
• Laboratory environmental conditions, sample and standard storage were verified and no any abnormality was found. No any deviation related to temperature excursion has been reported Laboratory during storage and on day of analysis.
• After receiving the samples from Site, all the samples were stored at 2-8°C in Refrigerator (REFR-005) & no temperature excursion observed in the refrigerator.
• Verified all the results and calculations for Assay and no error has been identified.
• Result for Assay was found out of specification Limit.

Inference from Preliminary Investigation:

• No issue w.r.t. Analyst performance, Instrument performance, Material Storage, Method of Analysis, Measurement and Impact of environment was identified during preliminary investigation.
• No other laboratory error has been identified.

Extended Investigation through 1M to 10M Technique:

• Investigation was further extended by using the 1M TO 10M technique to find any laboratory error (if any) or other contributory factor.
• During extended investigation, review of trend data, experiment testing and other contributing factor were evaluated.

1. Man:

Analysis of Sample ABCD Batch No. XXXX was performed by analyst Mr. Ram Kumar on HPLC instrument No. HPLC-001 by using column ID C-253 against sample set ID:   ABCD_ASSAY. Analyst qualification records verified and found that analyst is trained and qualified to perform test by HPLC. Details of analyst qualification is given in table 1. During preliminary investigation check point are verified like raw data, used chemical status, SST-SOL, Standard and Sample preparations details, used plastic ware during analytical activity, followed analytical procedure by analyst with respect of STP (STP-0025). No any obvious error is identified. All the plastic ware used for sample preparation were properly cleaned and same were rinsed with diluent before taking sample for sample solution preparation. Further, Methodology used in analytical activity was verified with respect of applicable STP (STP No. STP-0025) and No discrepancy was observed.  Instrument method parameters as defined in Standard test procedure are verified and  No any error was observed in methodology. The weight taken for preparation of system suitability solution, Standard Solution and sample solution are verified and found in line with requirement. Further interaction has been done with Analyst and analyst followed written procedure as mentioned in STP (STP-0025) with all necessary precautions. Hence no any error was identified during interaction with analyst.

Inference:

• Analyst performed the analysis as per the STP and same was verified from TDS No. TDS-0118, 1.0. Based on the above investigation & discussion with analyst no any abnormality identified. Hence the error due to analyst (Man) has been ruled out.

2. Machine:

Instrument calibration details & Preventive maintenance details were verified and found that all the respective instruments were calibrated and used within calibration validity period also the preventive maintenance of instrument was done as per schedule. Details of calibration tabulated in table 1. Results of system suitability were found satisfactory during analysis. No pressure fluctuation, instrument malfunction or any other error related to instrument performance were observed during analysis.

Inference:

•  Based on the above investigation, the chances of error due instrument functioning were ruled out.

3. Material:

Sampling of material was done at xyz unit. Samples were packed as per the recommended packaging conditions. Chemical and reagent used in analysis were verified and found within validity period & used as per STP (Table 1).

Inference:                

• Based on the above investigation, chances of error due to use of invalid standard, invalid or improper chemicals has been ruled out.

4. Method of Analysis:

Analytical Method was already Validated at Validation Laboratory (VR-0400). Retention time and area counts of all the analytes in SST-SOL and Standard Solution found satisfactory. System Suitability found meeting the acceptance criteria throughout the sample set. Analytical method was successfully transferred to manufacturing site. Refer analytical method transfer report No.: AMT-095. No discrepancy w.r.t. method performance was identified during Validation Method Transfer and routine analysis. 

Inference:

• Based on the above investigation, issue related to method performance has been ruled out.

5. Measurement:

Test Data Sheet (TDS-0118) was verified and compared with procedure defined in Standard Test Procedure (STP-0025). Found observations are following: The weights taken for analysis were as per standard test procedure. System Suitability Solution, Standard Solution and Test Sample prepared as per defined methodology. Hence weighing and dilution error can be ruled out. Area of Analyte peak in Standard Solution found satisfactory and comparable with the previous Trend data, hence the error related to standard preparation and material used for standard preparation has been ruled out. Same column (C-253) used for the analysis as mentioned in the Standard Test Procedure. Retention time and peak shape of all the analyte found satisfactory and also all the system suitability parameter found within the acceptance criteria. Hence error related to column performance has been ruled out. All the calculations and formulas used to calculate the results were verified. This calculation was performed by using validated calculator (CAL-012), Requalification date: 23-Feb-2027).

Inference:

• Based on above investigation and observations, the chances of measurement error were ruled out.

6. Environment:

The subjected samples of batch no. XXXX were received from XYZ Unit. Sample were kept in a box containing ice packs. After receiving the sample at Validation Laboratory, samples were kept inside the Refrigerator (REFR-005) to maintain 2-8°C temperature. Samples were kept at room temperature for about 30 minutes to attain the room temperature before weighing. While weighing the sample for analysis, utmost care was taken to minimize the exposure to the environment. After preparation, samples solution was stored inside sample compartment of instrument at controlled temperature. Analytical Laboratory functions under controlled temperature conditions and no deviation related to temperature excursion was reported from date of receipt (23-Apr-2025) to date of analysis (25-Apr-2025).

Inference:

• Based on the investigation with related to environment, no abnormality observed. Hence impact of environment has been ruled out.

7. Money:

All Financial aspects i.e. budgeting of Laboratory, Resources availability verified and there is no concern was observed. In the Last Financial Year -2024 (April-2024 to March-2025), Consumption of Chemical Inventory Record verified and found that All Chemicals related to analysis execution are available in sufficient quantity. Further, Interaction with all Laboratory Analysts/Reviewers was initiated to confirm the communication regarding cost reduction concerns and no anomaly observed. In the Financial Year -2024 (April-2024 to March-2025), Total Laboratory Budget are approved in suffice amount.

Inference:

• Based on the investigation with related Money, no abnormality observed. Hence impact of Money related factor has been ruled out.

8. Management:

Daily Work Allocation Log was verified and found that Group Leader Plan the activity before a day ago and analyst accept the Planning on same day. Organogram of the respective team was verified and found that Analyst report directly to the group leader regarding daily work allocation. There are No multiple channels are included for follow-ups. Further analyst interview were placed to confirm the same and analyst confirmed that he was report to group leader directly. There is no multiple channel are included for follow-ups and assigning the task. All Laboratory Polices, Standard operating procedures verified and there are no any understanding gap was observed.

Inference:

• Based on the investigation with related to Management, no abnormality observed. Hence impact of Management related factor has been ruled out.

9. Maintenance: -

Calibration and Preventive maintenance schedulers has been verified and found that all the Calibration and Preventive maintenance activity was executed and completed within schedule date. Breakdown Checklist and Service Record of instruments/equipment’s has been verified and found that no any major repairing activity was performed in between the Calibration and Analysis time period. Record of available spare parts was verified and found that Spare part which is used during preventive maintenance activity are available in stock. Further indent record of all available part and replaced part was verified and found that all Spare parts are quality product and matches with the instrument make/model. Instrument master lists was verified to confirm the instrument age and found that all the instruments are not older than expected and working in smooth condition (Details mentioned in table no.1). Training Record on Operation, Calibration and Preventive Maintenance for Instruments/ Equipment’s verified and found that respective analyst are qualified on following SOPs. Training Record of Service Engineers verified and found that Service Engineer are trained to perform the PM activity for respective Instruments/ Equipment’s. Technical Agreements of Service Providers are verified and found that Service Provider follows all the guidelines and term/Conditions mentioned in agreement.

Inference:

• Based on the investigation with related to Maintenance, no abnormality observed. Hence impact of Maintenance related factor has been ruled out.

10. Motivation:

Psychological Factor of the respective analyst was evaluated w.r.t following attributes Employee Portal was verified from Human Resources Department to confirm the resignation of the employee and found that Employee was not initiated any Resignation till date. Communication with near/dear colleagues of the respective analyst was initiated to verifying the “Low Motivation” i.e. reduced Attention/Delay Response with Group Leader and found that Analyst was fully motivated with the Group Leader and their sub ordinates. There are No understanding gap was observed behind them. Any momentary distraction w.r.t Hooter alarm, specific urgency of EHS, loud noise at work station was verified and No anomaly observed. Previous History of Laboratory Incidents are evaluated with the analyst and found satisfactory. Analyst was more vigilantly involved in their regular activities. Further there are No major incidence are logged due to Human error. Further, incentive programme of the respective analyst were evaluated from joining to till date. Analyst are well satisfied from their yearly incentives and promotions. 

Inference:

• Based on the investigation with related to Motivation, no abnormality observed. Hence impact of Motivation related factor has been ruled out.

Table 1: Analytical study details including analysis date and analyst qualification status.