Out of Specification (OOS) and Out of Trend (OOT) guideline was published by MHRA (Medicines and Healthcare Products Regulatory Agency in October 2017 which is complementary to FDA guidance on investigating OOS Test results in Pharmaceutical Production October 2006.
Investigations of “Out of Specification (OOS) / Out of Trend (OOT)/ Atypical results” have to be done in cases of:
-Batch release testing and testing of starting materials.
-In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis.
-Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests)
-Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results.
-Batches for clinical trials.
Out of Specification (OOS) and Out of Trend (OOT) results necessitate a thorough investigation process in the pharmaceutical industry to ensure product quality and safety. These investigations are divided into 3 distinct phases: Phase Ia, Phase Ib, Phase II, and Phase III. Each phase has specific objectives and processes to identify the root cause of deviations and implement corrective actions.
Phase Ia – Laboratory Investigation: Initial Analysis
Objective: The primary goal is to identify any obvious laboratory errors that might have led to the OOS or OOT results.
Process:
- Initial Review by Analyst:
- Immediate assessment of the test procedure, calculations, and raw data for apparent errors.
- Identification of obvious errors like incorrect sample preparations or instrument malfunctions.
- Documentation:
- Detailed documentation of all findings and corrective actions taken.
Outcome: If an obvious error is found, corrective actions are implemented, and no further investigation is needed. If not, the process moves to Phase Ib.
Flow Diagram:
Initial Review by Analyst -> Identify Obvious Errors? -> Yes -> Implement Corrective Actions| If No | Proceed to Phase Ib
Phase Ib – Laboratory Investigation: In-Depth Analysis
Objective: To conduct a detailed investigation to identify less apparent laboratory errors.
Process:
- Hypothesis Testing:
- Detailed examination of the test environment, reagent quality, and analyst competency.
- Use of a laboratory investigation checklist to ensure all possible errors are considered.
- Additional Testing:
- Retesting the sample, if necessary, to verify the results.
- Conducting parallel testing with control samples.
- Documentation:
- Recording all findings and actions taken during the investigation.
Outcome: If no assignable cause is found, the investigation proceeds to Phase II.
Flow Diagram:
Detailed Examination -> Retesting Required? -> Yes -> Conduct Retesting -> Document Results| If No | Proceed to Phase II
Phase II – Manufacturing Investigation
Objective: To identify any manufacturing process errors that could explain the OOS or OOT results.
Process:
- Review of Production Records:
- Examination of batch records, production logs, and environmental monitoring data.
- Verification of raw material quality, equipment calibration, and adherence to SOPs.
- Hypothesis Testing:
- Identification of potential root causes related to the manufacturing environment.
- Testing and validation to confirm or refute the hypothesized causes.
- Corrective and Preventive Actions (CAPA):
- Implementation of measures to correct identified issues and prevent recurrence.
- Documentation of all findings, actions, and final conclusions.
Outcome: Identification of manufacturing process errors and implementation of CAPA.
Flow Diagram:
Review Production Records -> Identify Potential Root Causes? -> Yes -> Test and Validate Causes -> Implement CAPA -> Document Results | If No | Document Findings
Phase III – Full-Scale Investigation
Objective: To conduct a comprehensive investigation involving all relevant departments to resolve persistent or critical OOS/OOT issues.
Process:
- Cross-Functional Team Involvement:
- Collaboration between production, quality assurance, engineering, and other relevant departments.
- Systematic Investigation:
- Detailed examination of the entire production and quality control process.
- Identification of systemic issues affecting multiple batches or products.
- Implementation of Systemic CAPA:
- Development and implementation of long-term corrective actions.
- Monitoring and verification of the effectiveness of CAPA.
Outcome: Resolution of complex OOS/OOT issues and enhancement of overall quality systems.
Flow Diagram:
Cross-Functional Team Meeting -> Conduct Systematic Investigation -> Identify Systemic Issues? -> Yes -> Develop and Implement Systemic CAPA -> Monitor Effectiveness -> End | If No | Document Findings
Conclusion
Each phase in the OOS and OOT investigation process serves a critical function, from identifying laboratory errors to uncovering manufacturing issues and implementing systemic corrective actions. By following these structured phases, pharmaceutical companies can ensure the quality and safety of their products, comply with regulatory standards, and maintain the integrity of their manufacturing processes. Explore the comprehensive phases of Out of Specification (OOS) and Out of Trend (OOT) investigations in pharmaceuticals. Learn about Phase Ia, Phase Ib, Phase II, and Phase III investigations, their processes, objectives, and outcomes. Ensure pharmaceutical quality assurance and regulatory compliance through structured investigations and effective Corrective and Preventive Actions (CAPA).
Reference links : https://mhrainspectorate.blog.gov.uk/2018/03/02/out-of-specification-guidance/
