What is A GMP Deviation Investigation?

In GMP pharmaceutical production including biologics and cell therapy manufacturing, a GMP Deviation Investigation refers to the systematic process of identifying, documenting, understanding, and correcting any unexpected occurrences that deviate from the established quality standards, methods or procedures. These deviations can encompass a wide range of issues, such as equipment malfunctions, procedural errors, environmental variations, material defects or any other factors that might compromise the quality of the product.

The investigation typically involves a thorough and documented examination of the root cause of the deviation, aiming to understand its origin, potential impact, and possible corrective and preventive actions. This investigation activity is crucial to ensure that the manufacturing process remains compliant with regulatory guidelines and that the product meets the required quality standards.

The findings and outcomes of the investigation play a key role in determining appropriate measures to rectify the issue and prevent its recurrence, thus maintaining the integrity of the production process and the safety of patients who will eventually use these biologics or cell therapy products.

Regulatory Drivers of GMP Deviation Investigation

In the United States, pharmaceutical manufacturing is regulated by the Food and Drug Administration (FDA) under the Code of Federal Regulations (CFR), specifically Title 21 CFR Part 211 for finished pharmaceuticals.

The requirement for deviation investigation is primarily outlined in the following sections:

• 21 CFR 211.100 - Written Procedures: This section mandates that pharmaceutical manufacturers must have written procedures in place for production and process control. Any deviations from these procedures must be recorded and justified.

• 21 CFR 211.192 - Production Record Review: This section requires that production and control records be reviewed and approved by the quality unit to ensure that no errors or discrepancies have occurred during production or testing. Any deviations or discrepancies must be investigated.

• 21 CFR 211.198 - Complaint Files: If a drug product complaint involves a deviation from established specifications or procedures, it must be investigated.

• 21 CFR 211.204 - Reserve Samples: If a reserve sample of a drug product demonstrates a significant deviation from its established specifications, an investigation must be conducted.

• 21 CFR 600-680 - Biological Products: For biologics, the general principles in 21 CFR 211 apply, and additional specific regulations are covered under 21 CFR 600-680. These regulations also emphasize the need for investigating deviations that could impact product safety, purity, or potency.

These sections collectively emphasize the importance of investigating any deviations from established procedures, specifications, or controls in pharmaceutical manufacturing. 

GMP Deviation Investigation Report Contents

A GMP (Good Manufacturing Practice) investigation report is a structured document that outlines the details of a deviation, the investigation process, findings, root cause analysis, and proposed corrective and preventive actions. While the specific sections of the report may vary depending on company practices and the complexity of the deviation, here are the typical sections you might find in a GMP investigation report:

Title and Header Information:

• Title of the Investigation
• Unique Identifier or Investigation Number
• Date of the Investigation
• Investigator(s) Names

Executive Summary:

• Brief overview of the deviation, its impact, and the investigation process.
• Summary of the root cause analysis and proposed corrective actions.
• Summary of any potential impact to product or process

Introduction:

• Background information on the deviation and its context.
• Description of the event or issue that triggered the investigation.
• Key governing documents such as Standard Operating Procedures (SOP)

Scope:

• Clear definition of the scope of the investigation including lots or batches within the scope
• Location and/or system boundaries

Investigation Details:

• Detailed chronological account of the deviation, including any relevant observations, measurements, and data collected.
• Information about the personnel involved, equipment, materials, and processes affected.

   

Root Cause Analysis:

• Detailed analysis of the factors contributing to the deviation.
• Identification of the primary root cause and any contributing factors.
• Description of the use of tools such as the "5 Whys" or fishbone diagrams to analyze causative factors.

Impact Assessment:

• Assessment of process impact
• Evaluation of the potential impact of the deviation on product Safety, Quality, Identity, Purity or Potency (SQUIPP) of the product.
• Assessment of whether the product(s) affected are within acceptable quality limits.

Corrective and Preventive Actions (CAPA):

• Description of proposed actions to address the deviation and prevent its recurrence.
• Clear action items with assigned responsibilities and deadlines.

Explanation of how the proposed actions will mitigate the identified root cause.

Attached or Referenced Documentation and Records:

• List of all documentation reviewed or referenced during the investigation.
• List of any attachments including testing, analysis, or experimentation performed during the investigation.
• Supporting data, charts, diagrams, or photographs related to the investigation.

Conclusion:

• Summary of the investigation's findings and outcomes.
• Confirmation that the corrective actions are appropriate to prevent recurrence.

Remember that the structure and depth of each section can vary based on the complexity of the deviation and the company's documentation practices. The report should be comprehensive, well-organized, and adhere to regulatory and internal quality standards.

Use a Structured Based Problem Solving Approach to Deviation Investigation

Deviation investigation can be a complex undertaking.  Taking a structured-based approach to deviation writing offers a range of valuable benefits that contribute to the overall efficiency, compliance, and quality of the investigation process. 

Over the next few months, we will be exploring how organizations can teach a structured approach to GMP investigation and how that can help GMP Manufacturing teams start-up and scale-up the right way to drive organizational learning and avoid delays and backlogs in investigation work.