Updated: Mar 1, 2021
A quandary faced by many companies regulated by the Food and Drug Administration (FDA) is how to avoid the dreaded FDA-483. Regulatory sanctions such as FDA-483s, warning letters, and consent decrees often put a strain on these companies as they seek to continue to strive towards the goal of providing safe, effective, and quality products to their consumers. A quick glance at any FDA-483 citation or Warning Letter attests to this fact with repeated violations of:
Failure to conduct effective root cause investigations
Failure to conduct an investigation of each event and evaluate the cause of the event, as required by 21 CFR 803.50(b)(3)
Failure to establish and maintain procedures for implementing corrective and preventive actions (CAPA), as required by 21 CFR § 820.100(a)
Failure to establish procedures to analyze and document quality data to identify and investigate existing or potential causes of nonconforming products or other quality problems,
Failure to establish and maintain procedures to verify, validate and implement corrective and preventive actions and ensure that relevant information is submitted for management review.
Failure to document any CAPA activities and their results.
The regulatory sanctions meted out by FDA are unfortunately too common in an industry that continuously strives to implement best practices that comply with sound investigational practices that support conducting effective root cause investigations, identifying and validating appropriate corrective and preventive actions (CAPAs) to prevent recurrence, and monitoring the data for potential trends.
The product(s) associated with regulatory sanctions are branded by FDA as adulterated within the meaning of section 501(h) of the Act in that the methods used in, or the facilities or controls used for, their manufacture, packaging, storage, or installation are not in conformance with the Current Good Manufacturing Practice (CGMP) requirements.
As many companies struggle to find a balance among various critical factors impacting daily operations such as: meeting customer demands for their products, generic competition, rising cost of research and bringing the product to market; their ability to stay current on GMP requirements and establish a robust Quality System that will ensure that only quality products are placed on the market can sometimes prove deficient.
This deficiency derives from several factors including a thorough understanding of the
What to investigate?
How to investigate and document the findings which supports the root cause of the event?
Investigation of product or process non-conformances helps to ensure:
The safety and efficacy of the products that you distribute to the market
That your products consistently meet internal requirements and external customer expectations
That existing issues of nonconforming product or other quality problems are identified and corrected
The root cause(s) of nonconforming products or other quality problems are effectively identified and eliminated
That with appropriate and relevant trending of data, potential nonconforming products and other quality problems may be immediately identified and subsequently eliminated.
Investigations play an integral part in any manufacturing process and the information that may be obtained when an investigation is carried out according to cGMPs and QS regulations can prove to be invaluable to the company’s bottom line. Investigation into the cause of an identified nonconformance is mandated by both the Good Manufacturing Practice (GMP) regulations —21CFR211 and the Quality Systems regulations—21CFR820.
For drug products:
Drug products are governed by the Good Manufacturing Practices regulations of 21 CFR
210 and 211, with the following sections 211.192, 211.198, 211.204, and 211.208 requiring the manufacturer to conduct an investigation into the root cause of the nonconformity. This evaluation and any subsequent investigation shall be documented and substantiated with supporting evidence that either substantiates or eliminates a potential root cause.
For medical devices:
Medical devices are governed by the Quality Systems regulations, 21CFR 820 with section 820.90 requiring each manufacturer to have established procedures in place to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented and substantiated with supporting evidence that either substantiates or eliminates a potential root cause.
The answer to the question of “why investigate” is multi-faceted: it’s mandated by law; it helps to identify and resolve issues that may drain an organization’s resources; it helps to identify potential issues of non-conformance thereby helping the organization to bring these issues to light before they become major observations in a Warning Letter or FDA-483 observation. But I believe that the most important reason to conduct an effective investigation that clearly identifies the root cause of the nonconformance and implements corrective and preventive actions to prevent its recurrence is ultimately one of responsibility. In purchasing a company’s product, a consumer is placing their utmost trust in the product with the expectation that this product will do what the manufacturer says it does, without any adverse reactions. With that trust the manufacturer has the responsibility to ensure that they deliver on its promise.
What to investigate?
For most companies, the ability to readily identify non-conforming product is relatively
simple—that is, they have established pre-defined standard operating procedures (SOPs) or specifications (i.e. limits) and they test according to those specifications. These procedures must include requirements for:
Investigating the cause of nonconformities relating to product, processes, and the quality system;
Identifying the action (s) needed to correct and prevent recurrence of nonconforming product and other quality problems;
Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;
Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;
Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.
The above identified activities and their results shall be documented.
When a result is obtained that falls outside of a predetermined limit (i.e., release, alert, or action), an investigation usually ensues according to the company’s standard operating procedures. Most companies will investigate that nonconformance in order to determine its root cause and implement corrective actions to correct the problem and prevent its recurrence.
However, there are some companies where it is not readily apparent when it comes to
identifying an issue / event warranting an investigation. This lack of transparency usually
stems from a lack of having established procedures that clearly define what to investigate, thereby relegating a decision to investigate solely at the discretion of an individual with inadequate information to make the call. Oftentimes, a manager or supervisor is making this decision without identifying / analyzing quality data sources from existing products that require corrective action; or, without the benefit of analyzing existing trends that may identify potential product and quality problems requiring preventive actions.
The answer to the question of “what to investigate” is clearly defined in the code of federal regulations which stipulates that a manufacturer is required to “investigate the cause of nonconformities relating to product, process, and the quality system.” Investigating the cause of a nonconformance requires the following:
Strict adherence to all applicable failure investigation procedures
Assuring that the failure investigation commensurate with the significance and risk of the nonconformity
Whenever possible, the failure analyses conducted identifies the root cause,
Appropriate controls are in place to prevent the distribution of nonconforming product to the market
Investigating the nonconformance and identifying the root cause
In any nonconformance investigation, identifying the root cause is an integral part of the
process in that it enables you to:
Implement effective corrective actions
Accurately trend data for process monitoring
Implement effective preventive actions
Develop effective strategies for continuous improvement
One of the more prevalent issues that I find in the companies that I have worked with, in
particular, those with significant compliance violations, is that they often do not delve deep enough into the investigation to identify the root cause of this event; or they fail to identify the much larger process related non-conformance which failed to prevent the issue from occurring in the first place. I call this the “reactive vs. pro-active” approach to quality systems investigations.
Some companies take a “reactive” position when they have a product-related non- conformance. That is, they rush to conduct an investigation and in an effort to meet unrealistic, self-imposed deadlines, they hurriedly close the investigation once they have identified what preliminary indications show to be a “root” cause. Oftentimes, this initial cause is rarely the “root” cause but more likely, a symptom of an underlying systemic issue.
The “pro-active” approach to investigations dictates that in any product/process/quality system-related non-conformance, the investigative team delves deep enough into the investigation to not only identify the true “root cause” (as opposed to a symptom of a much larger issue) but also ask the tougher system-related questions that will enable the team to effectively implement corrective and preventive actions in order to prevent future recurrence.
One of the biggest challenges that various FDA-regulated companies face is that oftentimes, their investigations stop at the first apparent or immediate cause and fails to drill down further to address the larger systemic underlying cause(s). A clear and all too common example of this is the traditional “human error” component of many investigations. There is no dispute that humans make mistakes; afterall, we are fallible beings. But, where many companies fail to capitalize on this cause is in their failure to drill down to the root cause and ask the “why?” question just one more time in their investigation. For example, “why did this individual make this mistake?” “What gaps are there in our process / procedure which failed to prevent this nonconformance?” “Could the nonconformance be a result of poorly defined procedure or a lack of a procedure to govern this activity?”
Investigations that rely solely on human error as the root cause with a proposed corrective action of “awareness training” or “retraining” are doomed to recurring instances of the nonconformance because they have failed to identify the root cause of the nonconformance, but rather, has identified a symptom of a larger systemic issue.