The development of drugs and medical equipment is an undeniably crucial part of the healthcare industry. Being able to count on the pharmaceutical products we take and the medical tools that are used to treat our illnesses is an inextricable part of having faith and confidence in our healthcare providers.
Precisely because of that, current Good Manufacturing Practices (cGMP) exist.
cGMP is a fundamental part of determining how efficient and safe the process of developing a drug is. The majority of companies nowadays implement cGMP in their manufacturing processes to ensure the utmost quality and security of their products.
With that said, even with the quality control imposed by cGMP requirements there can still be deviations in the processes. Thankfully, regulatory bodies have ways to deal with such situations when deviation occurs.
To better understand just how cGMP deviations can be handled, we must first learn a bit more about what cGMP is and how errors in the process can affect the final product.
Introduction to cGMP deviations
At its core, current good manufacturing practices are a way for regulators to monitor drug manufacturers’ products and make sure they are safe and up to quality standards.
cGMP refers to a set of regulations that ensure drug products meet the minimum necessities for the facilities, methods, and controls used in manufacturing. This includes the processing and packing of the product as well.
Even with such strict regulations, deviations can occur. When that happens, having a well-functioning quality control unit is what can make the whole difference between a drug being helpful to patients and one that is recalled.
In the past couple of years, especially, despite the efforts by both the industry and regulatory bodies, the prevalence of quality issues has steadily increased.
There is a notable rise in:
- Product complaints;
- Recalls;
- Drug shortages;
- Product bans;
- Plant closures;
- Regulatory enforcement actions.
This trend is making both industry stakeholders and regulators find a better, more effective solution to any current good manufacturing practice deviation.
Interestingly, many of these solutions can be found within existing deviation management processes and the data they generate. Addressing these growing challenges requires a deep understanding of the fundamental principles of cGMP and aligning strong quality management systems with deviation management as a whole.
Regulatory requirements for cGMP deviations
We have talked a bit about regulatory bodies but now we have to delve deeper into the key regulators on the global scale.
Regulatory institutions such as the Food and Drug Administration (FDA) in the US, the European Medicines Agency (EMA), and other international agencies have very strict requirements for managing cGMP deviations. Being compliant with the regulatory guidelines imposed by these agencies is absolutely non-negotiable. As well it shouldn’t be. Although such deviations don’t seem like anything important, they are a fundamental part of securing drug product safety and efficacy.
In failing to manage deviations properly, companies can receive severe penalties, including product recalls, warning letters, and even manufacturing facility shutdowns. cGMP deviations can play a significant role in drug recalls as well.
At the beginning of 2023, there were 13 recalls that impacted an estimated 11.88 million units of pharmaceutical products due to cGMP deviations.
Some of the more common issues that led to these recalls included:
- Contamination;
- Sterility failures;
- Improper manufacturing protocols.
Additionally, there is the Code of Federal Regulations (CFR). The intention behind the code was to make a comprehensive set of rules covering various aspects of regulatory requirements for different industries.
Title 21 is where the FDA approval comes into play as a part of the CFR. Title 21 provides the legal foundation for regulating food, drugs, cosmetics, and related products. This regulation is established under the Federal Food, Drug, and Cosmetic Act and other related statutes like the Public Health Service Act.
Importance of CFR Title 21
Earlier, we explained the origins of CFR Title 21 but didn’t touch on its crucial role in pharmaceutical regulatory compliance.
This title lays out a clear, structured framework that ensures drug manufacturers follow the necessary steps to produce safe and effective drugs. For pharmaceutical companies, adhering to these regulations isn’t just about following rules—it’s essential for avoiding penalties and sustaining their business operations.
Just like all laws and rules, the regulations within Title 21 are continuously updated to reflect a number of factors, including:
- New scientific knowledge;
- Technological advancements;
- Public health concerns.
This process thoroughly ensures that the standards remain relevant and effective in protecting the public and allow for a better manufacturing process. There is, however, more than one type of cGMP deviation that can occur throughout the production process.
Types of cGMP deviations
When we talk about cGMP deviations, we cannot only mention the institutions that govern them. We must also consider all the different types of what is being governed in the first place.
cGMP deviations represent any departure from approved instructions, procedures, or specifications in pharmaceutical manufacturing.
Historically, these deviations have been categorized as either “unplanned deviations” or “planned deviations,” though regulators are moving away from this terminology. Instead, deviations are generally classified into three main types.
Critical deviations
The first type of deviations that have to be noted are the critical deviations. This type can directly impact patient safety or product quality. These deviations pose a significant risk and must be addressed immediately to prevent harm.
There are three reasons why these deviations can have such a strong negative influence on the products:
- Failure to prevent contamination of sterile products can endanger the final quality of the product. This can occur because of inadequate sterilization processes or breaches in aseptic techniques.
- Product safety and efficacy can be compromised when its established specifications are not met.
- Significant procedure lapses, including errors in the manufacturing operations, can lead to completely defective finished pharmaceuticals.
Major deviations
Major deviations are another type of deviation that is not immediately life-threatening but has the potential to affect product efficacy. These deviations have to be addressed properly in order to maintain product integrity.
A very good example of such a deviation is malfunctions in manufacturing equipment. Failure to adhere to the robust operating procedures of such equipment can lead to deviations from the intended processes.
Furthermore, deviations such as incorrect temperature or humidity levels during manufacturing can impact product stability and quality.
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Minor deviations
The last type of deviation based on their severity is minor deviations. They are less critical than the other two and typically do not impact product quality or patient safety. They still, however, require documentation and review to prevent recurrence.
Examples of minor deviations are:
- Minor documentation errors: These might include incorrect entries in production records that do not affect the final product quality;
- Slight variations in process parameters: These are small deviations within acceptable limits that do not compromise product integrity.
Although these types give enough context on the matter, it is important to note that deviations can be further divided into planned and unplanned deviations.
Planned deviations, or temporary changes, are pre-approved and occur within a specified period or for a certain number of batches. Naturally, in this case, the deviations must be evaluated before execution through an approved change control procedure.
Unplanned deviations, also known as incidents or uncontrolled events, occur unexpectedly and require immediate investigation. These can arise from various sources such as human error, equipment malfunction, or utility and service failures.
Managing these deviations effectively is a requirement under cGMP regulations. The proper capture and documentation of such events is essential for identifying root causes and implementing corrective and preventive actions. This not only ensures compliance but also fosters continuous quality improvement within any organization.
Root Cause Analysis for CGMP deviations
As we mentioned before, production and process control are key to maintaining reliable testing laboratories. Catching product quality deviations in manufacturing facilities is an essential way of carrying out thorough Root Cause Analysis (RCA).
Such analysis is usually conducted to ascertain exactly why a deviation happened. The most useful part of RCA is that it involves identifying the underlying causes of a deviation rather than just addressing the symptoms. There are a couple of different techniques that can be used in the analysis and we will be taking a look at one of them.
The technique to properly analyze cGMP deviations involves an approach to identify, verify, and address the underlying factors leading to nonconformities. This process ensures compliance with the different regulations, prevents the recurrence of faults, and fosters continuous improvement.
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Define the deviation
To begin you must first clearly define the deviation, including its scope, impact, and severity.
There is a need to gather all relevant information, such as:
- Batch records;
- Standard operating procedures (SOPs);
- Test results;
- Observations.
Document the deviation comprehensively in a deviation report, including details like the date, time, affected product, and initial actions taken.
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Identify possible root causes
Next, identify the fundamental reasons for the deviation. For this purpose, you can use tools like the 5 Whys, Fishbone Diagram, or Fault Tree Analysis to explore potential causes, including human error and equipment failure amongst others.
You must consider both direct and indirect causes to ensure a thorough analysis.
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Verify the root cause
After investigating product quality deviations and identifying possible causes, verify the most likely and significant one.
Analyze collected data, test assumptions, and use methods such as Pareto charts, scatter plots, or statistical process control to validate findings. Cross-check conclusions with expert opinions or relevant literature to ensure accuracy.
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Implement corrective actions
Develop and implement corrective actions that address the root cause. Define clear objectives and responsibilities, and document these actions in a plan.
Ensure that the actions are feasible, effective, and compliant with GMP standards. Monitor the implementation and outcomes to confirm their success.
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Prevent similar deviations
To prevent similar cGMP violations from occurring elsewhere, identify potential risks and opportunities for improvement.
Implement preventive actions proactively, document them in an action plan, and share lessons learned with relevant stakeholders.
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Review and improve
Finally, review the entire process to assess its effectiveness. Evaluate the deviation report, action plans, and results to identify any gaps or areas for improvement.
Implement continuous improvement measures to enhance the quality system or quality control unit.
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Additional considerations
This step provides an opportunity to share additional insights, examples, or stories that may not fit into the structured analysis but offer valuable learning points.
This structured approach helps organizations not only to resolve current deviations but also to build a foundation for ongoing quality improvement, aligning with regulatory expectations.
Corrective and preventive actions for cGMP deviations
Regulatory bodies will always provide the specific rules that tell a pharmaceutical company what to do in case of a cGMP deviation. They offer, however, ways to prevent situations like this in the first place as well.
The way this is done is by utilizing Corrective and Preventive Actions (CAPA) as an essential component of managing deviations in the pharmaceutical industry. These actions are designed to address the root causes of deviations and prevent their recurrence, ensuring the continuous production of pharmaceutical products that represent strength, quality, and purity.
Corrective Actions (CA)
Let’s take a look at the first measure in the process of dealing with deviations. Corrective actions are steps taken to address the immediate causes of a cGMP deviation. Their goal is to rectify the issue and prevent it from causing further harm to product quality or patient safety.
The process generally involves:
- Root Cause Analysis: As we mentioned above, RCA involves Identifying the underlying cause of the deviation using techniques, one of the main ones being the 5 Whys.
- Immediate remediation: This step of the process is focused on implementing changes to correct the identified problem. This could include process adjustments, equipment repairs, or giving personnel more cGMP training.
- Documentation: When any type of action is taken in the process of correcting an error in a process or a system, it must be documented. The way this is accomplished is through a CAPA report. This documentation should include details of the deviation, the root cause, the corrective actions taken, and the results of those actions;
- Verification: After implementing the corrective actions, it’s crucial to verify their effectiveness. This involves monitoring the affected process or product to ensure that the deviation does not recur.
Corrective action is an effective way to deal with deviations and is a method used by all manufacturers upon thorough investigation. It is not, however, the only method.
Preventive Actions (PA)
Preventive actions, unlike corrective ones, are more proactive measures designed to eliminate the causes of potential deviations before they even occur. These actions are critical to facilitate operations and ensure proper performance during the manufacture of pharmaceutical products.
The preventive action process typically includes:
- Risk assessment: The first part of preventive actions is evaluating the potential risks associated with processes, equipment, or written procedures that could lead to deviations.
- Process improvements: Additionally, implementing changes is very important to reduce the likelihood of future deviations. This might involve updating SOPs or improving employee training programs;
- Monitoring and control: Monitoring and control is another fundamental step. Establishing monitoring systems to detect early signs of potential deviations can allow for more efficient process validation and data integrity. This allows for quick intervention before a minor issues become significant deviations;
CAPA can be a powerful methodology to apply in your quality assurance process. An even better way to fully utilize it, however, is by integrating it with software. You may wonder how any kind of software can account for all the potential risks and assist us in handling them.
The standardization of CAPA can be easily integrated into software. In this scenario, a Quality Management System (QMS) would be the most logical solution.
When dealing with cGMP deviations, risk assessment involves systematically identifying and evaluating potential hazards that could compromise product quality. A QMS supports this process by offering a structured method to capture, assess, and manage risks throughout all stages of the manufacturing process.
Such a system can also have CAPA integrated into it in order to give relevant options on ways to handle potential deviations.
CAPA processes are vital for maintaining the integrity of pharmaceutical products and ensuring that any deviations from cGMP standards are promptly and effectively managed, safeguarding both the manufacturer and the end-users.
Handling investigations and documentation
One of the most important parts of maintaining regulatory compliance and ensuring product quality is the way documentation is handled. When a deviation occurs, it’s essential to conduct a thorough investigation to determine the root cause. This involves many different processes like gathering relevant data or even interviewing personnel.
The investigators should also review processes and analyze any factors that could have contributed to the error in the first place.
Another invaluable part of dealing with cGMP deviations is their documentation. The process of documentation is irreplaceable. Every step of the investigation must be meticulously recorded, including the nature of the deviation – all the findings from the investigation, the rationale behind identified root causes, and the details of the CAPA.
Proper documentation ensures transparency, allows for effective communication across teams, and is critical for audits and regulatory reviews.
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Conclusion
Implementing current good manufacturing practices in your business can be extremely beneficial despite it being mandatory. Utilizing cGMP at its fullest, however, also means that you have to expect deviations from the practices.
These can be errors or mistakes, not only from the people but also from the equipment and raw materials. This shouldn’t discourage you in any way though. Such issues are a normal thing when developing anything.
In the case of pharmaceutical products deviations like these must be handled with care. Understanding the guidelines that manage these deviations is the first step to making them into just another part of the process that will help us grow.
