Out of Specification (OOS) Investigation in Pharmaceuticals

Definition

OOS results are test results that fall outside the pre-established acceptance criteria defined in specifications, procedures, or regulatory filings.
They can occur in raw materials, in-process materials, or finished products.

Phases of OOS Investigation

1. Phase I – Laboratory Investigation

Purpose: Rule out laboratory errors before moving to manufacturing investigation.

• Immediate Actions:

  • Stop release of affected batch/material.

  • Inform QA and relevant stakeholders.

• Checks Include:

  • Sample Preparation: Correct sampling, sample integrity, proper homogenization.

  • Instrument Performance: Calibration, system suitability, and maintenance records.

  • Reagents & Standards: Validity, storage, preparation accuracy.

  • Analyst Performance: Training records, adherence to SOPs.

  • Data Review: Raw data, chromatograms, integration, calculations.

• Outcomes:

  • Assignable Laboratory Error Found → Repeat testing with a fresh aliquot of the same sample.

  • No Error Found → Move to Phase II.

2. Phase II – Full-Scale Investigation

Purpose: Identify root cause if the lab process is not the source.

• Checks Include:

  • Review of manufacturing process: batch records, deviations, environmental controls.

  • Review of equipment logs and maintenance.

  • Check for raw material variability.

  • Review of storage, handling, and transportation conditions.

3. Hypothesis Testing (Retesting / Resampling)

• Retesting: Testing a second portion from the original sample.

• Resampling: Taking a new sample from the same batch under controlled conditions.

• Must be justified and documented.

• Not a way to “test into compliance” — original failing data must never be discarded.

4. Conclusion & Documentation

• Identify root cause (assignable or non-assignable).

• Classify result:

  • True OOS (manufacturing or material-related issue)

  • Invalid OOS (confirmed lab error)

• Implement CAPA to prevent recurrence.

• Make batch disposition decision (reject, reprocess, or rework).

Key Principles in OOS Handling

• Follow 21 CFR 211.192 (USFDA) and MHRA OOS Guidance.

• Document every step contemporaneously.

• Maintain data integrity (ALCOA+).

• QA should oversee and approve the entire process.