SOP Title: Out of Specification (OOS) results

OBJECTIVE

To establish a detailed procedure for handling Out of Specification (OOS) results, including thorough investigation to identify root causes, determination of appropriate corrective actions, and comprehensive documentation of all events and their chronology to prevent recurrence and ensure regulatory compliance.

SCOPE

This procedure applies to all analytical test results that fall outside predetermined specifications or acceptance criteria for finished products, intermediate materials, primary packaging materials, stability samples, raw materials, and retained samples, covering both physical and chemical testing.

Note: This OOS procedure excludes:

• In-process checks aimed at process control (e.g., reaction termination, process drift prevention). Failures in these checks post-process require deviation initiation by production.
• Vendor samples received for performance trials or quality evaluation.
• Rejection of raw materials/packaging materials based on vendor Certificates of Analysis (COA).
• Analytical method transfer, validation, or verification phases.
• Analyst qualification testing.

RESPONSIBILITIES

• Analyst (Quality Control):
  Log OOS results by the next working day with all relevant data, assist in investigations, and retain all related samples, solutions, and glassware as per Annexure checklist.
• Section Head / Designee (Quality Control):
  Ensure OOS logging within the next working day. Conduct thorough Phase-I investigations to identify potential laboratory errors, including hypothesis testing and data assessment. Manage additional testing (re-testing, re-sampling) as required and perform risk/impact assessments and CAPA identification.
• Section Head / Designee (Production):
  Oversee extended Phase-II investigations covering manufacturing operations and evaluate trends or deviations throughout the manufacturing cycle. Assess the impact period where relevant.
• Section Head / Designee (Quality Assurance):
  Log the OOS in the appropriate logbook, issue phase-wise investigation forms, oversee scientific conduct of investigations, ensure complete and accurate documentation, and maintain records for tracking root causes and CAPA.
• Head QA / Site Quality Head / Designee:
  Approve investigations, CAPA implementation, hypothesis testing protocols, and risk mitigation plans. Make batch disposition decisions and communicate potential customer impact.
• Head R&D / Designee and Section Heads / Designees (All Departments):
  Provide support in root cause identification and CAPA during investigations. Identify systemic abnormalities contributing to OOS results and implement corrective actions.
• CQA Department:
  Ensure overall implementation and compliance with the OOS procedure.

DEFINITIONS

• Specification:
  A set of tests, analytical procedures, and acceptance criteria that define the required quality standards for drug substances or materials to be deemed acceptable.
• Acceptance Criteria:
  Numerical limits or ranges that analytical results must meet for acceptance.
• Out-of-Specification (OOS) Result:
  A test result failing to meet the specified limits or acceptance criteria.
• Reportable Result:
  The final analytical result from a complete test execution, rounded as per the approved method.
• Hypothesis Testing:
  Laboratory re-analysis steps based on assumptions to investigate potential causes of OOS results, including re-injection, re-fill vial, re-dilution, re-filtration, re-sonication, or re-shaking.
• Re-sample:
  A new sample drawn from original containers when the initial sample is insufficient or compromised, subject to QA approval.
• Re-injection:
  Re-analysis of retained solution to check for equipment or injection errors.
• Re-fill Vial:
  Using retained solution in fresh vials to check for vial or injection-related errors.
• Re-dilution:
  Preparing a fresh dilution from retained stock solution to confirm potential dilution errors.
• Re-filtration:
  Filtering the original preparation again with a fresh filter to check for filtration errors.
• Retained Dilution / Solution:
  Remaining portions of original preparation after use.
• Phase-I Investigation:
  Initial lab investigation focused on identifying clear laboratory errors using checklists and hypothesis testing without exploratory testing.
• Phase-II Investigation:
  Comprehensive investigation including manufacturing, sampling, extended lab testing, and SME/R&D support to identify the assignable root cause.
• Outlier:
  A data point significantly deviating from others but still within specification limits.

PROCEDURE

Upon obtaining an OOS result, the analyst shall immediately complete the “OOS-Intimation-Slip” (Annexure and notify the HOD/Designee on the same day, submitting the raw data sheets. The HOD/Designee shall review and physically verify all data and ensure preservation and labelling of all related samples, glassware, and instruments as “Under OOS investigation.” QA issues Annexure.

QA logs the OOS in the appropriate sub-section of the “OOS Logbook” (Finished Product, Raw Material, Intermediate, Stability, Packaging Material) upon receipt of the OOS intimation slip. Any delays in intimation must be justified and impact assessed in the investigation report.

QA assigns a unique OOS number following this format:

PX-OOS-ZZ-YY-XXX

• PX: Plant identifier
• OOS: Title code
• ZZ: Category (FP = Finished Product, RM = Raw Material, INT = Intermediate, ST = Stability sample, PM = Packaging Material)
• YY: Last two digits of calendar year
• XXX: Serial number for that year

QA issues Annexure “OOS Form-Phase-I Investigation” to QC along with the OOS intimation slip, communicates with production, and labels the batch “Under OOS investigation” referencing the OOS number.

QC conducts the Phase-I investigation using Annexure.

Phase-I Investigation

QC assesses if the OOS arose from obvious errors such as:

• If an obvious error is confirmed, document and invalidate the initial OOS, perform repeat analysis, and close the case if the repeat results meet specifications.
• If no obvious error is found, proceed with further laboratory investigation as per Annexure checklist.

Laboratory Investigation (Phase-I, Continued)

If no obvious laboratory error is identified during the initial Phase-I investigation, the QC analyst/supervisor shall proceed with a detailed laboratory investigation using the checklist provided in Annexure.

This Phase-I investigation includes comprehensive review of data, equipment, analytical procedures, and instrument performance, but is not limited to these aspects.

Hypothesis Testing:
Based on the findings from the laboratory investigation, and with prior approval from QA, hypothesis testing may be initiated to identify the root cause of the OOS result, which is beyond the scope of the Phase-I checklist.

• QA will assign and log a unique hypothesis protocol number in Annexure, following the format:

HYP/P/XX/YY/ZZZ

• • HYP: Hypothesis protocol
  • P: Site/Location
  • XX: OOS category (FP, RM, INT, ST, PM)
  • YY: Last two digits of the calendar year
  • ZZZ: Serial number of the protocol starting from 001 each year

• A separate hypothesis report must be prepared, documenting the protocol, results, and conclusions, and included in the investigation report.

Hypothesis Testing Procedures:
The following tests may be conducted on original prepared solutions as applicable and per Phase-I form:

• Re-Injection (same vial solution)
• Re-Fill Vial (using the original preparation but freshly loaded vial)
• Re-Dilution (from the same stock solution)
• Re-Filtration (same solution filtered with a fresh filter)
• Re-sonication / Re-shaking (if applicable)

If an assignable cause is identified through hypothesis testing, retesting shall be performed.

Retesting Guidelines:

• Retesting is done by the initial or equally qualified analyst.
• Retesting samples shall be taken from the original withdrawn sample in duplicate.
• Both individual and average results must comply with the specification limits.
• If any individual or average retest result fails, the OOS remains valid.

General Guidance for Hypothesis Testing:

• Hypothesis tests must be performed only on original samples unless stability issues justify new stock preparation.
• Hypothesis testing is limited to the above methods and exploratory testing is not permitted at Phase-I.
• Prior QA approval is mandatory before hypothesis testing.

Review of Phase-I Investigation

QA shall review the investigation report and conclude as follows:

1. If the OOS is invalidated:

• Document the root cause, impact assessment, corrective and preventive actions (CAPA), and conclusion.
• Obtain signatures on the OOS investigation form/report.

1. If analyst or instrument error is identified:

• Conduct an impact assessment on previously analyzed data/products.

1. If OOS is valid for Raw Material (RM) or Primary Packaging Material (PM):

• Proceed as per Annexure.
• QA Head/designee will approve the rejection form.
• A copy of Goods Receipt Note (GRN) will be sent to warehouse along with reject label. QC personnel shall affix reject labels under QA supervision.
• Rejected RM/PM shall be blocked in SAP and stored securely in the rejected materials area.
• Commercial/Procurement department will be notified with a GRN copy.
• Procurement will coordinate detailed investigation, root cause, and CAPA with the vendor.

1. If OOS relates to Finished Product (FP), Intermediate (INT), or Stability Sample (ST) and no root cause is found in Phase-I:

• QA will issue Phase-II investigation forms (Annexure) to Production.

Phase-II Investigation

The Phase-II investigation is a comprehensive investigation at the manufacturing/production level.

The primary objective of Phase-II is not to invalidate the initial OOS but to identify the root cause or assignable cause at the manufacturing/production stage, if any.

QA shall provide Annexure (Phase-II investigation form) to the concerned production department.

The Phase-II investigation shall include but not be limited to:

• Root cause analysis using tools such as Fishbone diagrams, 5 Whys, etc.
• Review of batch manufacturing records and logs
• Examination of any deviations linked to the batch
• Interviews with production personnel
• Analysis of quality trends in raw materials and products
• Process parameter trends
• Environmental excursion records
• Review of previous failures and related CAPA
• Recent equipment modifications or changes

If a root cause is identified at manufacturing level, the investigation report must include risk assessment, impact assessment, CAPA, and conclusions, then be submitted to QA.

QA will then evaluate the report for:

• Approval of investigation
• Decision on batch rejection, blocking, reprocessing, or distribution
• Need for product recall as per Recall SOP
• For stability study-related OOS, consideration of product shelf-life revision

If no root cause is found in manufacturing, QA shall initiate a sampling investigation.

Sampling Investigation

Sampling investigation shall be conducted by QC, QA, and cross-functional teams as required. The investigation will verify:

• Sampling procedure adherence
• Training and qualification of personnel performing sampling
• Use and cleaning of sampling tools
• Appropriateness of sampling containers and labeling
• Environmental factors affecting the sample
• Sample storage conditions
• Potential contamination risks
• Sample packaging and transportation integrity
• Sample handling during testing

If sampling errors are identified, a strong justification for resampling must be documented in the investigation report. Resampling shall be performed by trained personnel. Retesting shall be conducted in triplicate by two different analysts as per Standard Test Procedure (STP) after QA approval, with results reported.

If the initial sampling method is found to be inherently inadequate, a new accurate sampling procedure must be developed, documented, reviewed, and approved by QA. Impact assessment should be conducted for other lots sampled using the same method.

• Support from R&D, Product Development (PD), and Subject Matter Experts (SME) can be sought by Production or QA to aid root cause identification.
• If a suspected cause arises from cross-functional recommendations, protocol-based hypothesis testing shall be conducted after QA approval.
• If no root cause is identified after manufacturing and sampling investigations, QA shall instruct QC to perform an extended laboratory investigation with additional testing beyond Phase-I, based on QC recommendation and QA approval.

Additional Laboratory Testing

If root cause remains unidentified after Phase-I and Phase-II investigations, additional laboratory testing shall be performed. This includes retesting from the original sample or retesting after resampling if sampling error is confirmed.

Re-test

Inconclusive OOS cases, upon QA approval, shall be retested in triplicate by two different analysts (excluding the original analyst), resulting in six test results from original or resampled material. QC shall analyze data to determine root cause or most probable root cause.

Both analysts performing retests must be equally or more qualified and experienced than the original analyst.

Retest results must meet method precision criteria (% RSD) and comply with specifications.

• If all six individual results comply and % RSD meets acceptance, the average of all six shall be the final value. QC shall identify the most probable root cause and recommend CAPA with conclusions.
• If any retest result or % RSD fails, the initial OOS is confirmed as valid.
• Site QA Head/Designee shall complete the OOS form accordingly.

For valid OOS, QA shall assess impacts on other batches, stability studies, processes, and testing procedures, documenting findings and CAPA in conclusions.

If the batch has not been supplied to customers and OOS is valid, the batch shall be rejected.

For stability OOS, impacted customers shall be informed via marketing department with necessary support.

For validation batches with valid OOS, retest period shall be revised through change control, with customer updates and possible recall if applicable.

Handling Non-Conforming Batches

Non-conforming batches shall be managed as per specific SOPs for reprocessing or disposal.

OOS Investigation Timeline

OOS investigations shall be completed within 30 working days. QA must communicate with QC before the due date for any extension requests. Extensions require approval from Site Quality Head/Head QA/Designee via Annexure, including interim report with justification and timelines. Delays shall be reported in monthly QMS reviews.

OOS Trending

QA shall prepare a half-yearly trend report classifying OOS root causes (invalid, valid, obvious errors) to identify corrective actions and prevent recurrence.

Trend Outcome

OOS trend outcomes, CAPA effectiveness, and history of similar OOS shall be reviewed and documented in reports. QA shall use Annexure template for trending.

OOS from Contract Testing Laboratories

If OOS arises from external contract labs, QC Head/Designee will coordinate investigation with the lab, then evaluate the data. Valid OOS findings lead to Phase-II manufacturing investigation and batch disposition decisions by Head QA/Designee.

Documentation and Evidence

Before closing OOS investigations, ensure all relevant data is reviewed and attached:

Phase-I Investigation:

• Initial analysis data
• Hypothesis testing data (re-injection, re-fill vial, re-dilution, re-filtration, re-sonication, etc.)
• Investigation report and root cause evidence
• Retesting data (if applicable)
• Additional tests/investigation data
• CAPA evidence
• Final batch disposition documents
• Related records (training, service reports, etc.)

Phase-II Investigation:

• Manufacturing investigation report with root cause evidence
• R&D/PD lab experiment reports (if applicable)
• CAPA evidence and implementation records
• Next-stage analysis and impurity profile comparison for reprocessed batches
• Batch reprocessing data (if applicable)
• Label verification and reconciliation records
• Retest data (if applicable)

Note: All supporting documents shall be photocopied and stamped “For Reference” except hypothesis testing original data, which must be retained with the OOS file.

Overall Summary

QA shall prepare an overall summary of the OOS investigation using Annexure , including:

• OOS description
• Investigation details
• Root cause
• Impact assessment
• Corrective and preventive actions
• Batch disposition decision

REFERENCES

FDA Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, October 2022.
EU GMP Guidelines.

ABBREVIATIONS