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  Lab Investigations  >  Phase 1 Investigation and Phase 2 Investigation

Phase 1 Investigation and Phase 2 Investigation

phase 1 investigation

Understanding the importance of Phase 1 and Phase 2 Investigations for effective risk management

By transitioning from initial risk identification to comprehensive root cause analysis, organizations can proactively address issues and implement lasting solutions.

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The Current Good Manufacturing Practice for Finished Pharmaceuticals (211.192 production record reviews) requires the Quality Control team to review and approve the production of drug products and control records, including packaging and labelling. This is to ensure compliance with pre-established procedures before the release of a batch.

In case of unexpected discrepancies or in case a batch or any of its components does not meet the specifications outlined at the beginning, it should be thoroughly investigated, even if the batch has been distributed. Other batches of the same drug product or other drug products where a specific failure or discrepancy may have an impact must also be investigated. Even batches that are rejected based on an OOS result need to be investigated to see whether other batches of the same drug product or other products experience the same problems. A thorough, timely, unbiased, well-documented, and scientifically sound investigation needs to be done to identify the root cause and take necessary corrective and preventive action.

Usually, this is done in two phases – Phase I and Phase II.


What are Phase 1 and Phase 2 Investigations?

The investigations happen in two parts.

During an OOS Phase 1 Investigation, laboratory data is assessed, and the analyst and supervisor verify initial test preparation and analytical steps to quickly rule out laboratory-related errors. This review is ideally completed before test preparations or retained samples are discarded, enabling evaluation of potential instrument malfunctions, preparation errors, or data integrity issues before progressing to a broader investigation.

The retained solutions should be examined during laboratory investigation, and the OOS test results should not be attributed to analytical error without the investigation being performed and documented.

An OOS Phase 2 Investigation is initiated when the initial investigation confirms that laboratory error is not the cause of the OOS result. Using a predefined procedure, a comprehensive review of manufacturing processes, sampling activities, and any required laboratory work is conducted to identify the true root cause and initiate appropriate CAPA actions.

phase 1 and phase 2 investigation

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Components of Phase 1 and Phase 2 Investigations Approach

CAPA raised per Year

In Phase I, the retained solutions are examined as part of the laboratory investigation. This helps to ensure that the error is not due to faulty equipment/instrument or testing process and involves:

  • Re-injecting the Solution: This helps to establish whether the error is due to the malfunctioning of the instrument.
  • Re-dilution or Re-pipetting of the Solution: This helps to eliminate dilution or pipetting as the cause for the error.

Documenting the investigation is another important component of Phase I investigation. In case a cause is ascertained for the OOS during the investigation, it must be retested or recalculated. The results of the retest or recalculation must be documented and reported. If the results conform to the specifications the second time, then the initial data must be invalidated.

However, if a retest validates the initial results, then a full-scale OOS investigation should be performed using a predefined procedure.

CAPA raised per Year

In Phase II investigation, the components include:

  • Review of production/manufacturing process: A thorough, timely, and well-documented review of the production, sampling procedures, and additional laboratory testing is conducted to identify the root cause.
  • Testing Hypothesis/Experimentation: A document describing the testing process is readied, and investigational testing is initiated with the approval of the QA team.

The document must describe;

  • The hypothesis for investigating the root cause.
  • The samples to be tested.
  • The execution process.
  • The process of evaluating data.

Hypothesis testing is initiated after completing the Analyst and Supervisor investigation and can include the original working stock solutions but not another preparation from the original sample. The original preparation or working solutions can be re-measured. It can be re-injected where transient equipment is suspected of malfunctioning. This is especially useful in identifying a malfunctioning instrument as the root cause. For dilution error, re-dilution of the original Solution can help. Investigational testing helps to confirm a probable cause rather than eliminate a suspect.

  • Additional laboratory testing: Phase II investigation may include additional laboratory testing that covers
  • Resampling: A new sample is collected from the batch in case the original sample is insufficient for conducting the tests. The procedure to obtain the resample must be discussed and agreed upon by QA/Contract Giver/QA and recorded. The same qualified, validated methods as used for the initial sample must be used.

If the investigation reveals that the original sample was not appropriately prepared and therefore does not represent batch quality, a new and more accurate sampling method must be developed, documented, reviewed, and approved by the QCU.

  • Retesting: Retesting should be performed purely based on sound scientific reasons and with approval. A second aliquot from the same homogeneous material as the original sample is tested by a second, more experienced, and qualified analyst.
Incident Investigation

Different Methods Associated with Incident Investigation and Usage of 5 Why Methodology

Regulatory Guidance for Laboratory Phase 1 and Phase 2 Investigations

Section 211.192 of the US Food and Drug Administration requires that whenever an OOS test result is obtained, an investigation must be conducted to establish the cause, with full documentation of the investigation, conclusions, and follow-up actions taken. Regulatory agencies such as the US Food and Drug Administration emphasize that every investigation in pharmaceutical industry operations must be scientifically sound, unbiased, and thoroughly documented.

Section 211.165 stresses the importance of interpreting investigation results, requiring the outcomes of Phase 1 and Phase 2 investigations to be analyzed and the batch evaluated before a release or rejection decision is made.

Further, 211.165(f) mandates evaluation of batch or lot quality to identify the cause of the OOS result, with confirmed OOS findings providing sufficient grounds for batch rejection if established specifications are not met.

According to 211.192, when the cause of an OOS result is confirmed, investigations must also extend to other batches or products that may be associated with the same failure to prevent recurrence and ensure ongoing compliance.

  • Section 211.192 of the US Food and Drug Administration requires that whenever an OOS test result is obtained, an investigation must be conducted to establish the cause, with full documentation of the investigation, conclusions, and follow-up actions taken. Regulatory agencies such as the US Food and Drug Administration emphasize that every investigation in pharmaceutical industry operations must be scientifically sound, unbiased, and thoroughly documented.

  • Section 211.165 stresses the importance of interpreting investigation results, requiring the outcomes of Phase 1 and Phase 2 investigations to be analyzed and the batch evaluated before a release or rejection decision is made.

  • Further, 211.165(f) mandates evaluation of batch or lot quality to identify the cause of the OOS result, with confirmed OOS findings providing sufficient grounds for batch rejection if established specifications are not met.

  • According to 211.192, when the cause of an OOS result is confirmed, investigations must also extend to other batches or products that may be associated with the same failure to prevent recurrence and ensure ongoing compliance.

Why are Phase 1 and Phase 2 Investigations Required?

Current good manufacturing practice requires finished pharmaceuticals and active pharmaceutical ingredients (APIs) to be manufactured conforming to section 501(a)(2)(B) of the cGMP Act. Some of the key requirements for APIs include: Current good manufacturing practice requires finished pharmaceuticals and active pharmaceutical ingredients (APIs) to be manufactured in conformity with section 501(a)(2)(B) of the cGMP Act. A structured investigation in pharmaceutical industry settings is critical to ensuring patient safety, product quality, and ongoing compliance with cGMP requirements. Key expectations for APIs include:

  • Scientifically sound raw material testing
  • In-process monitoring
  • Release and stability testing
  • Process validation
  • Investigations of any OOS result obtained from such testing

These tests support process validation and analytics. These regulations are encapsulated in CGMP regulations for laboratory operations and reflected in part 211, subparts I (Laboratory Controls) and J (Records and Reports). They enable establishing scientifically sound and appropriate specifications, standards, and test procedures for ensuring the conformance of components, in-process materials, containers and closures, and finished drug products with the established standards. The finished drug products that do not meet these standards, specifications, or other applicable quality control criteria will be rejected.

When an OOS result is obtained, it becomes important to ensure that the result is not a laboratory error, identify the true cause, and eliminate it to prevent future recurrence of non-conformance. In Phase I investigation, the focus is to eliminate laboratory error as a cause. The investigation progresses to Phase II when the cause is not a laboratory error, and a thorough investigation is undertaken to identify the causes in the production/manufacturing process.

phase 1 and phase 2 investigations requirement


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Phase 1 Investigation Steps

  • The analyst performing the test is primarily responsible for obtaining accurate laboratory testing results.
  • He/She should ensure he/she understands the potential problems that could occur during the testing process and keep an eye out for them to prevent inaccurate results.
  • Conforming to the CGMP regulations in section 211.160 (b)(4), the analyst should use only those instruments that conform to the performance specifications.
  • All the instruments should be properly calibrated.
  • Only those analytical methods that meet the system suitability requirements should be identified and used.
  • Identifying and correcting the cause of the malfunction is necessary.
  • Using data from before the suspect period should be based on the outcome.
  • Only after checking data for compliance with test specifications should the test preparations or standard preparations be discarded.
  • If the results do not point to the cause, the test preparations should be retained, and the supervisor informed.
  • The accuracy of the results should be assessed immediately.
  • In case the cause of the error is clear, it should be documented.
phase 1 investigation steps
  • Steps to be followed by the Laboratory Supervisor in Phase 1:

The supervisor should conduct an objective and timely investigation without preconceived assumptions regarding the cause of the OOS result. Assess data to establish whether a laboratory error or a manufacturing process is causing it. The solutions, test units, and glassware used in the original measurements and preparations should be re-examined immediately to establish without doubt that laboratory error is the root cause.

  • The supervisor’s assessment should include the following steps:
  • Begin by discussing the test method with the analyst to confirm that the correct procedure has been followed.
  • The raw data obtained from the analysis should be examined to spot anomalies.
  • The final test result should have been obtained using scientifically sound, appropriate, and correct calculations to convert raw data values. No unauthorized or unvalidated changes should have been made to automate it.
  • Ensure that only calibrated instruments were used.
  • Ensure that the solutions met quality control specifications and that only appropriate reference standards, reagents, solvents, and other solutions were used.
  • The performance of the test method should be evaluated to ensure that its performance is as per the expected standards based on method validation data and historical data.
  • The laboratory assessment should be fully documented and records preserved.
phase 2 investigation steps

Phase 2 Investigation Steps

During Phase 2 investigations, the following steps should be followed:

Production Review: The QCU should investigate in collaboration with other departments that could be implicated, such as manufacturing, process development, maintenance, and engineering. Even offsite manufacturing units should be investigated if there is a potential involvement, and all potential problems identified and investigated. A complete review of records and documentation related to the manufacturing process is necessary. The review process should be recorded, covering the following information:

  • Elucidate the need for the investigation.
  • Summarize the manufacturing processes that could be potentially responsible for the problem.
  • Record the findings of the documentation review, assigning actual or probable cause.
  • Whether the problem has occurred previously.
  • Elaboration of the corrective actions taken.

ComplianceQuest delivers!

I’ve been using ComplianceQuest (CQ) for about 9 months and am extremely pleased with the product, the implementation team, and ongoing support. I selected CQ for several reasons. Functionality and a simple user interface were key requirements. CQ has all the functionality needed in support of a global QMS. Implementation includes: document control, change order, personnel training, NC/CAPA, equipment management, supplier management, audit management, and customer complaints, all on a single platform. As a small biologics company, it was critical to find a single solution to meet our GMP quality system requirements. We wanted a cloud-based system that would be quick to implement, that could be expanded globally and in other languages, all for a reasonable price. The user interface. It is exactly what I was hoping for. I constantly hear the staff saying, “I love CQ, it’s so straightforward to use".

The implementation team has met all my expectations. The CQ product ‘out of the box’ meets the majority of my requirements. With some minor configurations, we have developed QMS workflows that are highly efficient and robust. A risk-based validation plan also allowed us to move quickly through the foundational functions: Controlled Documents, Change Order, and Personnel. The implementation team offers many industry best practices as solutions to questions and is also highly competent in listening to your requirements and doing whatever is necessary to fulfill them. Customer Support is incredibly timely in their responsiveness, addressing most questions or concerns within 24-48 hours, while communicating along the way. We are extremely happy with our selection and highly recommend ComplianceQuest.

Donna Matuizek,
Sr. Director Quality

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Optimizing Lab Operations with Lab Investigation Software Solutions

In today's complex regulatory environment, laboratories require robust software solutions that not only streamline investigative processes but also ensure full compliance with industry regulations. ComplianceQuest's Lab Investigation Software Solutions are designed to address these needs by offering an integrated platform that manages every aspect of laboratory investigations, from initial data capture to final reporting.

    Key Features of Our Lab Investigation Software:

  • Real-Time Data Tracking: Immediate access to lab data and metrics to swiftly identify and address issues.
  • Automated Workflow Management: Streamlines processes for faster response times and reduced manual errors.
  • Comprehensive Compliance Tools: Ensures all processes adhere to global standards like FDA, ISO, and more.


Use Case Scenarios:

  • Enhanced Error Handling:
  • Situation: A pharmaceutical company faced frequent delays due to errors in data recording during drug testing phases.
  • Solution: Implementation of ComplianceQuest's software automated data entry and validation, reducing errors by 45% and improving project timelines.
  • Regulatory Compliance Audit:
  • Situation: A biotech firm was preparing for an upcoming FDA audit and needed to ensure their lab operations complied with all regulations.
  • Solution: By using our software, the company was able to automatically generate compliance reports and quickly identify any non-compliance issues, ensuring a smooth and successful audit process.
Optimizing Lab Operations with Lab Investigation Software Solutions

Navigating Laboratory Compliance and Regulations with Advanced Software Solutions

ComplianceQuest provides state-of-the-art solutions to help laboratories navigate the complex landscape of compliance and regulations efficiently. Our software is designed not just to assist in maintaining compliance but also to optimize lab operations to meet and exceed regulatory standards.

Advantages of Leveraging ComplianceQuest for Laboratory Compliance:

  • Up-to-Date Regulatory Information: Our software continuously updates to reflect the latest changes in laboratory standards and regulations.
  • Document Control and Record Keeping: Streamlined document management ensures that all records are audit-ready and easily accessible.

Real-World Application:

  • Meeting ISO 17025 Standards:
  • Situation: A testing lab needed to upgrade its systems to meet ISO 17025 standards for technical competence in testing and calibration laboratories.
  • Solution: ComplianceQuest’s Lab Investigation Software provided the necessary tools to manage documentation, control quality processes, and maintain records, thus facilitating ISO 17025 compliance.

Real-World Application:

  • Handling CAPA Efficiently:
  • Situation: During routine quality checks, an issue was identified that required corrective and preventive actions (CAPA).
  • Solution: The software’s integrated CAPA module allowed for immediate action, documenting the issue, initiating corrective measures, and monitoring preventive strategies to avoid future occurrences.

Conclusion

Implementing robust lab investigation software solutions not only streamlines laboratory processes but also ensures stringent adherence to laboratory compliance and regulations. ComplianceQuest's software offers a comprehensive suite of tools that empower labs to improve efficiency, enhance compliance, and ultimately drive innovation and success in their scientific endeavors.

Manage your entire Phase 1 and Phase 2 Investigation processes with ComplianceQuest’s Laboratory Investigation Software for the efficient test results

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Quality-centric Companies Rely on CQ QMS

  • Flex
  • continental
  • 3m logo
  • YKK
  • Qorvo
  • Canon
  • Stryker
  • Lam Research
  • Just Evotech
  • Tilray

Frequently Asked Questions

  • When an OOS result is obtained, Phase 1 of the investigation is initiated to thoroughly assess any potential laboratory-related causes. If laboratory error is ruled out, the investigation progresses to an OOS Phase 2 investigation, which involves a more comprehensive evaluation of manufacturing, process, and other contributing factors to determine the true cause of the deviation.

  • Automating the Phase 1 and Phase 2 investigations can improve the efficiency of the test results. It can help ensure the correct procedures are followed to meet regulatory requirements. Further, it also helps with collaboration between different teams, especially in Phase 2, when the QCU works with all relevant stakeholders, even in offsite locations.

    Documentation is another regulatory requirement that can be easily handled with an automation solution such as ComplianceQuest’s cloud-based Laboratory Investigation Software.

    The LIS is integrated with the CQ enterprise-wide quality management system. As a result, pharma companies can also leverage the CAPA solution that can be triggered when the cause is identified. This can help correct the issue and prevent its future recurrence.

    Not only the affected batch, but tests may have to be conducted on other batches of the same product or other batches. The CQ solution helps to have greater visibility and access to data at every step to speed up OOS investigation for accurate results.

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