Why is the investigation quality system still so challenging for the industry?
The industry spends a significant number of resources dealing with deviation investigations to guarantee that products released to the market are not adulterated based on the cGMP’s definition.
Maintaining stringent regulatory compliance and ensuring product quality is non-negotiable. However, during FDA inspections, one major deficiency that continues to persist is inadequate investigations. The key to averting FDA observations is the quality and depth of internal investigations. Investigations are triggered by deviations or discrepancies in manufacturing or quality control processes and serve as a crucial mechanism for identifying root causes and implementing corrective and preventive actions (CAPAs). The thoroughness of these investigations is pivotal. Superficial or incomplete investigations merely scratch the surface, leaving underlying issues unresolved and increasing the risk of recurring deviations and subsequent FDA observations. Conversely, in-depth investigations delve into root causes, addressing not only what went wrong but why it went wrong, resulting in sustainable corrective actions.
The concept of "Investigation Transparency" is a key element. Inspectors expect all pertinent and critical information to be included in investigation reports. Failing to meet this expectation may prompt inspectors to request additional information, potentially leading to assumptions of information concealment.
To bolster investigation thoroughness and reduce the risk of FDA observations, several essential elements must be integrated into the process. Timeliness is critical, ensuring that investigations commence promptly upon issue identification to prevent escalation. Moreover, involving skilled personnel with expertise in areas such as microbiology, sterility assurance, and process knowledge is imperative.
Comprehensive documentation at every stage captures initial findings, root cause analyses, corrective and preventive measures, and all pertinent details. Additionally, a systematic risk assessment evaluates the potential impact on product quality and patient safety.
Evaluating the potential impact on process and product quality, considering ripple effects on other processes or batches, and justifying the inclusion or exclusion of specific products or batches are central aspects of an investigation. The integration of quality risk management into the investigative process proactively identifies and addresses potential quality issues, incorporating root cause analysis and various causal factors with a sound scientific approach. This encourages continual improvement and facilitates informed decision-making in quality problem management. These principles are aligned with the International Council for Harmonization (ICH) guidance for industry Q10 Pharmaceutical Quality System, emphasizing the importance of identifying and effectively communicating risks within the investigative process. ICH Q9 R1 provides tools in Annex II for the application of risk management in Quality Management Documentation, such as Quality defects, OOS, complaints, trends, deviation, and investigations.
A standardized investigation review approach is recommended where lessons learned and mentoring are provided to enhance knowledge and understanding, underscoring the value of experience-driven insights in strengthening quality and compliance practices.
The perception of “Investigation Transparency” is important for the inspector to feel that all pertinent and critical information is contained in the investigation report. The elements below are not all-inclusive; however, they provide a framework for writing and/or reviewing deviations to strengthen the quality and robustness of the investigation report:
Investigation Title – The title must clearly define the deviation, being concise and straightforward. Some Investigators provide excessive information, which can hinder comprehension and disengage the reader. A well-crafted title is crucial for effective recurrence queries. Another situation observed during investigation review is the existence of different titles for a common deviation or defect, which can lead to complications in query results.
Immediate Actions Taken – It is critical to mention which actions were taken upon the event discovery. These must be clear and concise, leaving no room for speculation. Supporting information must be provided supporting the action taken.
Scope - When evaluating the importance of an incident, a critical consideration is its scope. Investigations often start by pinpointing the problem in one lot or area. Yet, further analysis may reveal that similar issues could impact other areas or other product batches. This means the event might occur elsewhere, involve comparable equipment, and/or affect multiple Quality Systems.
Deviation Assessment – This document sets the base for the deviation impact if further investigation is required to determine the Root Cause. While it is a valuable resource, it may require amendments before the final investigation concludes, as it was conducted during the inception process. The Deviation Assessment and the Final Investigation are linked and must be aligned.
Root Cause – The Root Cause determination will define if the event is a one-time event or if the same departure could be observed in the future. Time must be provided to perform an in-depth analysis and eventually eradicate the deviation cause. There are multiple tools used today for these purposes; however, the basis for their use must be clearly established. Tools such as Control charts, Histograms, Scatter diagrams, Pareto charts, Process mapping, Brainstorming, Fishbone diagrams, 5 Whys, and others are commonly used and are very helpful, but the right tool must be selected and justified. ICH Q9 R1 provides tools guidance.
Corrective and/or Preventive Actions and Effectiveness Check – These are the actions that will avoid the event recurrence. If the Root Cause was correctly assessed, the actions to prevent its recurrence are of utmost importance. These actions will provide the assurance that the existing conditions that allowed the deviation to happen were removed. Effectiveness checks must be verified as soon as possible. The effectiveness must not be extended beyond a reasonable time after the CAPA implementation. Furthermore, predictive analysis can play a vital role in anticipating and mitigating future deviations. These techniques harness historical data and statistical methods to proactively identify potential problems and establish preventive measures. By integrating predictive analysis into the deviation management process, organizations can bolster their ability to uphold product quality and compliance while minimizing the risks associated with recurrent deviations.
Final Impact – The event impact classification must include the rationale for its classification and must be based on a risk analysis. The justification for assessing the impact should not rely solely on product quality attributes. Regulatory considerations must also be considered. Many investigations focus the reader on the quality specifications and attributes and fail to mention if the regulatory elements were met as well, such as CPP’s and CQA’s, stability indicators, and other commitments with the agencies, which were part of the product’s submission and approval. Investigators and the quality unit must be savvy in the regulations and regulatory impact of any deviation reported in the investigation.
Investigation report – The investigation report must be self-sustaining, conclusive, and in verbiage that can be understood by any reader. The report should “flow” in correct sequence of events, actions, and other pertinent information. Investigations that are not well-organized will lead to questions and reader’s interpretation.
Thorough investigations yield multiple benefits, not only preventing issues from reoccurring by identifying and addressing root causes but also driving ongoing process improvement, elevating overall product quality. Furthermore, this approach aligns with regulatory expectations and reduces the likelihood of regulatory actions, preserving a company's reputation as a dedicated guardian of quality and regulatory compliance. In essence, investigations' thoroughness is not merely a procedural step; it is a proactive commitment to quality and compliance that safeguards companies from FDA observations and underscores their dedication to patient safety and product integrity.
In conclusion, the bio-pharmaceutical industry faces stringent regulatory scrutiny, with FDA observations serving as a critical indicator of compliance and product quality. A cornerstone defense against these observations lies in the depth and thoroughness of internal investigations. These investigations, when conducted meticulously and in adherence to established principles, not only pinpoint the root causes of issues but also pave the way for lasting solutions. Timely initiation, expert involvement, comprehensive documentation, systematic risk assessment, and unwavering regulatory compliance underscore the importance of robust investigative processes. These processes not only prevent recurring deviations but also fuel continuous improvement, aligning companies with regulatory expectations and preserving their reputation as stalwarts of quality and compliance. As we navigate this landscape, fostering a culture of transparency and learning through lessons learned, we reinforce the value of experience-driven insights, fortifying our commitment to patient safety, product integrity, and the highest standards of quality.
About the Authors
James Feshold, PE/MBA
High-achieving Operations Executive with proven success in diverse teams across. Biotech, Pharma, and Medical Device industries. Adept in navigating complex, regulated manufacturing environments adhering to FDA, DEA, ISO, and EMA standards. Collaborative leader fostering quality improvement, innovation, and continuous learning. Expertise in manufacturing packaging, product transfer, pharmaceutical/ medical device production, and project management.
Karla González-Bonilla, MS
Microbiologist with Master's in Molecular Biotechnology and extensive QA experience. Expertise in data integrity, change control, CAPA, lab control, equipment validation, deviation investigations, and SOPs. Harmonized standards to Annex-1 requirements. Strong background in DIRA, IQ/OQ/PQ, and QMS. Skilled in document management software.
Elizabeth Plaza, R.PH
Boasts over 35 years in the bio-pharmaceutical field, starting as a PD Scientist and later leading consulting ventures since 1993, focusing on compliance, project management, technology transfer and validation. Overseen 3000+ resources, completed 10000+ projects, including 1000+ in tech transfer & validation life cycle management. Currently leads a Third Party Consultant firm qualified as set forth in 21 CFR 211.34 to help establishments in meeting cGMP requirements. Co-authored PDA Technical Report #60 on Process Validation.