By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero
In drug development, the production of clinical products is heavily regulated by a strict set of standards known as Current Good Manufacturing Practices (cGMP). These standards ensure that drugs are produced consistently and controlled according to quality standards, upholding patient safety. Despite rigorous planning and execution, deviations from established standards and procedures can still occur during production of your clinical product. As a Sponsor, it’s important to know what to expect and how to handle these situations. To meet regulatory requirements, any deviation must be documented within a quality system and investigated to identify the root cause if not immediately known. Deviation investigations are integral to continuous quality improvement, helping to eliminate recurrence in future production and, most importantly, ensuring the reliability of drugs for patient health and safety. This article discusses the different types of deviations, their potential consequences to the Sponsor, and establishes a framework Sponsors can follow to effectively manage deviations.
What is a Deviation?
In a cGMP environment, a deviation describes any departure from established Standard Operating Procedures (SOPs), protocols, specifications, manufacturing batch record instructions, or other pre-approved quality documents. They can be planned or unplanned, depending on the level of foresight and control over the occurrence. Planned deviations typically require a temporary change in an established process and must be recognized, assessed for impact, and approved by the quality unit before they occur. In contrast, unplanned deviations happen unexpectedly without prior approval and are generally considered to have greater regulatory implications, requiring more intensive investigation to assess risks to product quality, purity, potency, integrity, and safety. Deviations are typically assigned a severity rating based on their potential impact. The three severity levels listed in ascending order of severity are:
1. Minor
Deviations classified as Minor have little to no impact on product quality, safety or compliance, and are easily addressed without the need for immediate corrective action.
2. Major
A Major deviation is one that may affect product quality or regulatory compliance and requires a formal Corrective and Preventive Action Plan (CAPA) to prevent recurrence.
3. Critical
Critical deviations pose a significant risk to patient safety or product quality. They require immediate action to mitigate harm and ensure compliance with regulations. Like Major deviations, they require a formal CAPA to prevent recurrence.
"Addressing deviations may require time consuming investigations and corrective actions, extending the overall drug development timeline."
Implications of Deviations
Deviations occurring during the scope of a cGMP production run of clinical products can significantly impact a Sponsor’s program in a variety of ways. The major areas of concern are outlined below.
1. Regulatory Consequences
Frequent or major deviations can lead to increased scrutiny by regulatory agencies and may result in regulatory holds until corrective actions are implemented.
2. Quality & Safety Concerns
Inconsistencies in the manufacturing process can jeopardize the quality and efficacy of investigational drugs, potentially leading to adverse clinical outcomes and compromising patient safety and the reliability of clinical trial results.
3. Financial Impacts
Investigating and resolving major deviations can often incur unexpected costs from additional testing, reprocessing or remanufacturing of batches - or even product recalls - all putting strain on the Sponsor's budget. Delays and complications may also undermine investor confidence due to increased perceived risks, leading to withdrawal of funding or demands for higher returns.
4. Timeline Delays
Addressing deviations may require time-consuming investigations and corrective actions, extending the overall drug development timeline. Critical milestones such as drug production, clinical trials, and market launch may be delayed resulting in opportunity loss and increasing the risk of falling behind competitors developing similar drugs.
5. Damaged Reputation
For Sponsors, especially smaller or newer companies, a reputation for poor quality control can be detrimental. A history of deviations can lead to negative publicity and harm relationships with regulators and investors. Perceptions of unreliability in product quality can erode trust among clinical trial participants, healthcare professionals, and future patients once the drug reaches commercialization.
"When a deviation occurs, it’s essential for the Sponsor to address the situation systematically to maintain product integrity and regulatory compliance."
Effective Deviation Management to Minimize Risk
Sponsor companies play a crucial role in managing deviations that arise during the production of their clinical products at their Contract Development and Manufacturing Organization (CDMO). When a deviation occurs, it’s essential for the Sponsor to address the situation systematically to maintain product integrity and regulatory compliance. The following stepwise approach ensures deviations are managed effectively. Upon identification or notification that a deviation has occurred the sponsor should:
1. Establish Communication
Promptly communicate with the CDMO to receive details about the deviation and an understanding who the primary contacts are from both sides for future communications.
2. Obtain Documentation
Request detailed documentation from the CDMO regarding the deviation, including when and how it was detected, initial assessments, and any immediate actions taken. This documentation will serve as the basis for further investigation.
3. Assess Impact Together
Collaborate with your CDMO to assess the potential impact of the deviation on product quality, safety, and compliance. This may include evaluating for other affected batches and determining if actions like product quarantine or recall are necessary.
4. Initiate a Collaborative Investigation
Facilitate a joint investigation with the CDMO to determine the root cause of the deviation. This should include a cross-functional team from both the sponsor and the CDMO to ensure a comprehensive investigation.
5. Implement Corrective Actions
Work with the CDMO to develop and implement CAPAs based on the investigation's findings. It’s important that the CAPA addresses the immediate issue and all systemic factors that contributed to the deviation.
6. Monitor Progress
Establish regular check-ins with the CDMO to track the progress of the investigation and the implementation of CAPA, ensuring timely resolution and prevention of recurrence.
7. Evaluate for Regulatory Implications
Assess any potential regulatory implications arising from the deviation. Determine whether it must be reported to regulatory authorities and ensure all required communications are made according to relevant regulations.
8. Review Quality Agreements
Ensure that the CDMO adheres to the quality agreements and SOPs outlined in the contract with the Sponsor. This may involve reviewing performance metrics and compliance history.
9. Document Everything
Maintain thorough records of all actions taken in response to the deviation. This documentation is crucial for internal audits, regulatory inspections, and future reference.
"effectively managing deviations and their CAPAs are crucial for ensuring compliance and maintaining product quality in clinical product manufacturing."
In conclusion, effectively managing deviations and their CAPAs are crucial for ensuring compliance and maintaining product quality in clinical product manufacturing. By understanding and promptly addressing deviations, Sponsors can safeguard patient safety and the integrity of clinical trials. Following a systematic approach to deviation management that promotes collaboration with their CDMOs, emphasizes documentation, and facilitates clear communication that reduce delays, mitigates risks, and protect the Sponsor's reputation.
BrevisRefero Corporation is a collection of biologics drug development CMC experts utilizing its collective 100+ years of experience in advancing our clients outsourcing objectives through its RFP>Navigator® portal to accelerate drug candidates efficiently into clinical trials.
If you would like a free, no-obligation consultation to talk about your biologic or CGT drug development outsourcing, planning, quality & compliance, budgeting, or execution then please reach out to us at:
contact@brevisrefero.com or call us at (905) 636 - 6559.
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By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero
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