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In drug manufacturing quality control, a robust, well-defined testing and lab investigation process is critical to ensure that the drug matches the specifications and Is safe to be released to market.

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Regulatory Requirements for Lab Testing

regulatory-requirements-for-lab-testing

CGMP regulations 211.160 and 211.165 mandate laboratory testing to ensure that components, containers and closures, in-process materials, and finished products meet specifications, including stability. Those that deviate are required to be rejected.

Furthermore, finished pharmaceuticals and active pharmaceutical ingredients (APIs) manufacturing should comply with cGMP section 501(a)(2)(B). For APIs, cGMP requires raw materials to be tested to ensure that their performance is scientifically sound. They must be monitored in-process, in addition to the release and stability testing and process validation. In the case of OOS results obtained during the testing and monitoring, adequate investigations need to be conducted to identify the root cause and the errors rectified before they are tested again, validated, and then manufactured.

If a batch is rejected because of an OOS result, the manufacturer will have to ensure that the OOS result is confined to that particular batch of that drug and is not replicated in other batches or other products.

Documenting the investigation process, the conclusions arrived at, and the follow-up action taken is also required by FDA 211.192.

Phase 1 investigation: Finding an Assignable Laboratory cause

An initial assessment is done to ensure that the laboratory’s data is accurate. By ensuring this even before preparing for the test eliminates any errors due to laboratory error or a malfunctioning instrument. Once it is established that the OOS result is not caused by lab errors, an OOS investigation should be undertaken fully. If contract laboratories are involved, the data, findings, and supporting documentation should be shared with the manufacturing firm’s quality unit (QU) by the laboratory. The QU, in turn, should initiate a full-scale OOS investigation called Phase II.

Phase 2 investigation: Production Review

In the Phase II investigation, a predefined procedure should be used to determine the root cause of the OOS result and corrective action and preventive action to rectify the error as well as prevent future recurrence. It should include reviewing production and sampling procedures followed often by laboratory retesting.

The QU should lead the investigations and involve all functions responsible for the production, such as engineering, manufacturing, process development, and maintenance. If manufacturing is outsourced to a contract manufacturer or happens at different manufacturing sites, investigations should include all these sites as well. This is also an opportunity to identify other potential problems and investigate them to proactively prevent the same known issues from causing deviations later.

All records and documents related to the manufacturing process should be investigated thoroughly to determine the possible cause of the OOS result(s) in a timely, detailed, well-documented review. The review document should include:

  1. A well-articulated reason for the investigation
  2. A brief on the various factors of manufacturing that could be responsible for the problem.
  3. The findings of the documentation review, assigning the actual or probable cause.
  4. The findings of a review to identify if this is a recurring problem.
  5. Recording the corrective actions taken.

Based on the findings of the OOS investigation, the product may be rejected or further investigated.

The following three methods are used to find OOT:

  • Calculating the average of previous readings
  • Using 3 Sigma
  • Checking the high and low range of the previous results

Lab Investigation Challenges

OOS and OOT investigations are an essential part of clinical testing and development, but it is a complicated process that requires a “right from the first time” approach. It requires visibility into the investigation processes, documentation, follow-up action, and regulatory submissions. Of course, it also requires ensuring that the product is not pushed into the market before the investigations are completed, and corrective action is taken.

But in a manual system using spreadsheets, the risks of this happening due to the difficulty in tracking and communicating with all stakeholders can be very difficult.

Since collaboration is essential, keeping everybody updated, assigning tasks, and following up to make sure the required action has been taken as specified can add to the complexity.

Lab investigations can also be time-consuming and lack the consistency or thoroughness needed to be compliant with the regulatory standards. It requires instructions and processes to be easy to follow for all key stakeholders. It should be comprehensive and thorough, compliant, well-documented, and right the first time.

Overall, it is also critical that the overall lab investigation process is

  • Efficient: decreases the time needed for investigations with increased quality and process efficiency
  • Insightful: Identify trends for root cause analysis by tracking the results of all your investigations
  • Cost Saving: with decreased cycle time and task automation
  • Compliant: makes sure your investigations adhere to regulatory standards
  • Documented: all steps, assessments, results, checklists and findings are well documented and easily shareable/printable

Automating OOS/OOT Investigations with ComplianceQuest

ComplianceQuest’s Lab Investigation Solution ensures a systematic, efficient, and compliant approach to laboratory investigations. It facilitates seamless collaboration between various teams that can be located in different geographical areas as it is cloud-based. Thorough documentation and identification of the assignable or root cause of every OOS test result are made possible. This helps assign follow-up action and track progress to ensure that corrective and preventive correction is taken.

Being aligned to all relevant regulations, the CQ solution ensures compliant investigations with pre-built checklists to guide investigations and production reviews. It also makes the investigations effective by reducing the time and cost of investigations and increasing quality and process efficiency.

The key features of the CQ Lab Investigation Solution include:

Phased investigation: Lab supervisors and QA have the option to escalate from phase 1 to phase 2 or close the investigation.

Integrated: Ability to launch NCs and actions directly from the investigation record and link records together.

Automated alerts and notifications: Automatic notifications and action requests to people involved in the investigation.

Configurable queues: To configure the workflow and approval matrix queue to fit your needs and processes.

Formatted printouts: With ability to assign parent/child document structure and customize printouts of investigations as needed.

Reports and dashboards: To generate any report or dashboard they need to keep track of lab investigations and identify trends.

Pre-built checklists: Preliminary lab investigations and production reviews can be populated with pre-built and customizable checklists to guide the investigation, ensure consistency and thoroughness.

Field alert assessment: Will automatically show in the lab investigation if the record of the OOS test result is for stability testing, reminding quality teams to send the alert if needed.

Embedded risk assessment: Embedded in-lab investigation so that QAs can determine the risk assessment.

Customer notification: After a lab investigation (phases 1 and 2), quality teams can indicate if notifying customers is needed.

Impacted material/batches: Can be referenced in the lab investigation record.

To know more about how the ComplianceQuest lab investigation solution can help ace your OOS and OOT deviations, contact us now: https://www.compliancequest.com/online-demo/

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