GMP Failure Investigation: Identifying and Fixing the Root Cause

The Code of Federal Regulations (21 CFR 820) expects the drug manufacturers to conduct an immediate failure investigation when the product is reported in Out-of-Specification (OOS) category. Remember that OOS is not product failure, it is just a deviation from the specified test results. It may occur due to one of the following reasons – laboratory error, non-process related error, process related error. GMP failure investigation is also a fair business practice which reduces the rework and eliminates the recurring quality issues.

Above all, investigating into GMP failure ensures that the patients get an effective and reliable product. The failure investigations are conducted in following stages.

GMP Failure Investigation in three phases

GMP Failure Investigation: Phase 1

As soon as the analyst detects an OOS result, makes a mistake in performing analysis, uses incorrect standards or miscalculate the data, they should immediately inform their supervisor about the issue. The supervisor works with the analyst to conduct an investigation. If no apparent reason for the OOS result was found, the supervisor reports to it to the quality assurance department within a specified period, generally 24-48 hours. This is when begins the formal investigation with an attention to corrective action. The company must have a clearly descried SOP for the area or the process where the incident occurred.

At this stage, a checklist is developed to identify the sources of the error that could have occurred in any place- sampling, handling, method validation, instrument performance, method validation, test procedure, etc.

The level of investigation depends upon complexity of the problem. Sometimes, it may require an in-depth investigation, other times, it’s perfectly fine to go ahead with the simple trend analysis and other acceptable tools. The analyst and supervisor determine whether the out-of-specification results should be assigned to a testing laboratory.

In case, the issue is assigned to a testing laboratory, it performs the test for original samples again. If the results of testing laboratory meet the acceptance criteria, the company invalidates original OOS result. All the procedures and root causes are documented. The quality assurance department comes up with corrective measures to save the batch and prevent such recurrences in future.

GMP Failure Investigation: Phase 2

First phase was based on the condition that testing laboratory successfully identifies the root cause of out-of-specification results reported. What if it couldn’t? All the reasons, justifications, evaluation criteria, SOPs and other protocols are documented. If the cause of the OOS could not be identified, an investigation of the manufacturing process is warranted. If no manufacturing error is reported and the quality assurance department has sufficient data obtained from retests and product history to decide that the original OOS error was due to the unassignable laboratory error, then the department concludes that this OOS result is not representative of the batch.

At this point, other batches, equipments and manufacturing processes are also assessed.

GMP Failure Investigation: Phase 3

Primary objective of the last phase of investigation is to recognize the most probable cause of the OOS result. In case, laboratory testing was identified as the primary cause, the company should consider retraining its employees and/or apparatus maintenance. The final report specifies testing procedures, validated processes and people responsible for taking corrective actions to prevent the recurrence of such events.

Entire failure investigation process must be completed within a predefined time period, usually 20 working days. If completion of failure investigation is not possible within this timeline, FDA requires companies to present a valid justification.