Getting to the Root of the Matter for Bio/Pharma Quality Issues

In government-regulated industries—which include, not only bio/pharmaceutical operations, but aeronautics, automotive, and nuclear power—root-cause analysis (RCA) is integral to effective risk management and mandated by Federal laws. When regulatory failures occur, companies must identify the deepest-seated causes of the non-conformances, commensurate with the significance of those events. If the causes are not properly identified, any corrective actions that are taken will not prevent problems from recurring in the future.

One key to developing an effective approach to corrective and preventive actions (CAPAs) and RCA is having mature quality management systems in place that help reduce the total cost of quality. This requires the right mindset to support effective RCA so that the causes of problems can be identified and addressed. For bio/pharmaceutical facilities, expectations are outlined in the International Council on Harmonisation’s (ICH) Q10 (1), which specifies the use of methods found in ICH Q9 (2).

Although it is less expensive to do something right the first time, the authors continue to see rework, rejects, recurring deviations, and recalls within the bio/pharma sector, which lags other regulated industries in evaluating and targeting improvements in the total cost of quality by getting to the root of issues. The bio/pharmaceutical industry’s approach to RCA has also been fraught with misunderstandings (3). Best practices from the nuclear power industry demonstrate how bio/pharmaceutical manufacturers can leverage lessons learned and apply them to operations to create a stronger, more transparent quality culture.

Relying on administrative controls

One consistent problem in bio/pharmaceutical circles has been an over-reliance on administrative controls to address compliance and quality failures. This was clearly seen in the industry’s response to nitrosamine contamination, including the presence of N-nitrosodimethylamine and N-nitrosodiethylamine, probable human carcinogens, in small-molecule APIs and finished drugs, as well as biopharmaceuticals. A recent report on lessons learned from the contaminations (4) showed that corrective actions proposed by the industry were, in large part, administrative in nature. Although there is no disputing that these actions would have some measurable positive effect, an overabundance of these administrative controls do not address root cause, and instead rely on the following:

• Reminding personnel of their responsibilities
• Encouraging better performance
• Clarifying existing control
• Ensuring that there is clarity
• Considering new requirements
• Considering additional recommendations
• Considering amendments to existing guidance
• Reviewing existing guidance
• Revising existing guidance
• Developing new guidance
• Drafting a new document

• Improving existing strategies
• Providing more training
• Enhancing oversight
• Exchanging more information.

As shown by the Hierarchy of Hazard Controls (Figure 1), administrative controls are among the least effective means to address identified hazards.

Bio/pharmaceutical CAPAs can use this hierarchy to screen corrective actions so that, wherever possible, hazards are eliminated, replaced, or isolated. Other strategies include the following:

• An integrated causal analysis to achieve a deeper understanding of human-centric problems
• Integrating causal analysis into risk management systems
• Developing more advanced methodologies for generating and pursuing lines of inquiry when performing RCAs.
• Improving the bio/pharmaceutical industry’s basic definition of RCA.

A company’s quality management maturity (QMM)—first described in 2019 by the FDA’s Drug Shortage Task Force (5)—is central to the International Society of Pharmaceutical Engineers’ (ISPE’s) January 2021 Advancing Pharmaceutical Quality guide (6) and should be considered.

Companies with low QMM take a reactive rather than a scientific, probing approach to compliance or quality failure events, risks, or hazardous situations. At the senior management level, this culture results in what author and researcher Brené Brown calls “armored leadership,” in which business leaders and subject-matter experts are more concerned with being right than getting it right (7). Even scientists, who have dedicated their careers to discovering the truth, can become zealous defenders of the status quo, as Wharton organizational psychologist Adam Grant has found in his research (8). Where QMM is high, leaders and subject-matter experts (SMEs) take the lead in getting to the root cause of adverse events based on available knowledge, intelligence and analysis.

RCA and the nuclear power industry

All regulated industries struggle to meet regulations that call for effective RCA and CAPA programs. Driven by catastrophic failures—including the Three-Mile Island core meltdown (1979), Chernobyl disaster (1986), and the Fukushima Daishi reactor core damage (2011)—the commercial nuclear power industry leaped ahead of other industries in approaching this challenge. Its survival depended on it.

These and other incidents have driven dramatic improvements in programs, processes, and procedures. Reflecting the industry’s progress is its nuclear power plant capacity factors (CF). A CF is the ratio of actual energy produced by a power plant in a given period to the hypothetical maximum possible (i.e., energy produced from continuous operation at full rated power).

As causal analysis, CAPA, and other programs have improved, so too have nuclear plant CFs (8). In 1980, following the Three Mile Island incident, the US nuclear CF national average was 55%. By 2019, it had risen to 93.5%, reflecting the real benefits that can be gained by continuous improvement.

Beyond human factors

Human-centric problems involve a complex combination of human factors (i.e., human performance issues including at-risk behaviors); equipment/tool/material interface issues because humans design, fabricate, manufacture, transport, install, operate, and maintain equipment, tools, and materials; and latent cultural/organizational and programmatic weaknesses. These factors combine to form a complex, three-dimensional socio-technical set of causes that create unintended consequences.

In the 1980s, the Institute of Nuclear Power Operations (INPO) found that up to 80% of events were caused by human-centric factors (Figure 2), and the majority (approximately 70%) of those human-centric factors were caused by deeper-seated organizational and programmatic weaknesses. The nuclear industry has been learning how to solve these kinds of problems ever since (9).

Traditional root-cause methodologies invoke different tools for analyzing human factors, equipment issues, programmatic weaknesses, and in some cases, default to a process of elimination rather than cause-and-effect analysis. When using a process of elimination, investigators start out by identifying a finite set of possible causes and then test/evaluate each one until they rule out what they can and identify the most probable causes.

One method that is finding use in the nuclear power industry is Hyper-Integrated Causal Analysis (HCA), which works by gathering, organizing, and analyzing available evidence and data on a single chart. This approach integrates traditional methods—human factors analysis, barrier analysis, task analysis, change analysis, comparative timeline analysis, event and causal factors charting, and the fishbone—into one approach that generates focused, evidence-based lines of inquiry (LOI).

Pharma and bio/pharma companies could also benefit by applying two approaches that are widely used in the nuclear power industry: probabilistic risk assessment (PRA), which is used to evaluate and mitigate the consequences of potential nuclear accidents, and the Bowtie model (Figure 3), which is used to analyze and communicate how high-risk scenarios develop (10,11). In both PRA and the Bowtie approach, a finite list of potential risks is created and steps are taken to ensure that defenses are in place to prevent the risks from causing events. In addition, actions and other mitigation strategies are developed to mitigate the consequences if an event were to occur.

In bio/pharma operations, RCA is traditionally used after a consequential event has taken place. In the nuclear industry, however, causal analysis is often used proactively, to analyze lower-level events by tying causal analysis programs to the risk prevention side of the Bowtie model. Using key performance indicators and trending and analysis programs, negative trends of low level events can be identified and analyzed, and their deepest-seated causes can be identified and eliminated before they allow the next hazardous event to occur.

Redefining Biopharma RCA

Traditional definitions of the term “root cause” have been in place for over 50 years in regulated industries, but decades of work in the nuclear industry has shown that RCA efforts often stop prematurely, based on an inadequate definition of the concept.

Using the traditional definition of a “root causes,” organizations often declare victory too soon, and corrective actions often fail to keep problems from recurring because the deepest-seated causes are still active. Traditional root causes are best characterized as the “event root causes,” and the true, deepest-seated causes for any serious compliance or quality event lie much further down cause-and-effect pathways. The deepest-seated causes will not only account for the event or issue being investigated, but also for many other events that have taken place in the past, and will continue to cause events in the future until they are identified and addressed.

One way to get to the deepest-seated causes is by taking focused, evidence-based lines of inquiry. Companies in the nuclear power industry take a rigorous approach that generates lines of inquiry from multiple perspectives, including the following concepts:

• Analysis of defenses (i.e., evaluating applicable regulatory requirements and implementing procedures to determine the effectiveness of existing controls)
• Simultaneous completion of comparative timeline analysis and task and change analyses
• Insights generated from the analysis of additional data, including testing, sampling, and other methods used to evaluate the evidence

Additional reviews that come from a clear understanding of the anatomy of an event, including human factors; other applicable programs, processes, and procedures; other equipment, tools, or materials that were not previously evaluated; the evaluation of error-likely situations that may have set up the organization for failure; and the impact of management and oversight involvement.

Rather than conducting individual interviews, facilitated causal analysis sessions are held with small representative samples or focus groups of SMEs from affected teams or organizations, who are asked to provide their expertise. Instead of taking interview notes, their answers are captured directly on a cause-and-effect chart. In addition, SMEs are guided through cause-and-effect analysis as they answer each question, harnessing their expertise in getting to the root causes. Using this approach, an investigation can harness the expertise of hundreds of SMEs in a very short period of time. In one recent HCA investigation, which looked into recurring procurement program failures at a US nuclear laboratory, 14 facilitated causal analysis sessions were held with more than 120 subject-matter experts in just one week (12).

This advanced approach to conducting interviews is more transparent, it eliminates bias, it prevents those being interviewed from feeling like they are being interrogated, it elicits much more cooperation from all parties, and it reinforces to all participants that the investigators are not seeking someone to blame but are seeking to learn.

Bio/pharmaceutical companies can adopt the nuclear industry’s best practices for RCA and CAPA. In return, they stand to gain the following:

• A better understanding of the fundamentals of causal analysis, continuous improvement, and risk prevention
• A better understanding of how to analyze complex, human-centric problems using more modern, lean, agile, flexible, accurate, and effective RCA methodologies that identify causes with speed and accuracy
• More effective CAPAs that focus on the elimination, replacement, or isolation of hazards, and prevent the recurrence of similar problems or events because they address deepest-seated causes of failure
• A transformation of the organizational culture, from compliance, towards a culture of continuous improvement, proactive problem solving, and learning.

References

1. ICH, ICH Q10, Pharmaceutical Quality Systems (2008).
2. ICH, ICH Q9, Quality Risk Management (2006).
3. ISPE, “Joint ISPE/ PDA Root Cause Analysis Guide,” ispe.org (2019).
4. EMA, “Lessons Learnt from Presence of N-nitrosamine Impurities in Sartan Medicines,” ema.europa.eu (June 23, 2020).
5. FDA, Drug Shortages: Root Causes and Potential Solutions, Report (2019).
6. ISPE, Corrective Actions and Preventive Actions (CAPA) System (2020).
7. B. Brown, Dare to Lead (Ebury Publishing, 2018).
8. A. Grant, Think Again (Penguin, 2020).
9. Nuclear Energy Institute, US Nuclear Industry Capacity Factors, nei.org, accessed April 29. 2021.
10. IAEA, Managing Human Performance to Improve Nuclear Facility Operation (Vienna, Austria, 2014).
11. Many Caps Consulting, “Eight Steps to Using Bow Tie Analysis for Risk Management,” manycaps.com (July 2020).
12. R. De La Espriella, “Critical Thinking: A Modern Practitioner’s Journey of Discovery,” presented at the 40th International Conference on Critical Thinking, September 2020.

About the Authors

Nuala Calnan, PhD, is founder of the Quality Risk Management Institute, CEO of BioPharm Excel Ltd., and research fellow at Technological University Dublin.

Rob De La Espriella, rob.dle@DLE-services.com, is president of DLE Technical Services. A former nuclear submarine officer and expert in root cause analysis (RCA), he has more than 30 years of experience in regulated industries that include nuclear power and defense. He is also the creator of the BlueDragon Hyper-Integrated Causal Analysis methodology, a lean and agile approach to RCA. Rob is a recurring guest lecturer at Princeton University’s Keller Center for Entrepreneurship.

Article Details

BioPharm International
Vol. 34, No. 5
May 2021
Pages: 40–43

Citation

When referring to this article, please cite it as: N. Calnan and R. De La Espriella, “Getting to the Root of the Matter,” BioPharm International 34 (5) 2021.