📝 Case Study: OOS Investigation – Tablet Dissolution

📍 Background

A marketed immediate-release tablet showed dissolution failure during routine quality control testing.

• Specification: NLT (Not Less Than) 80% drug release in 30 minutes.

• Observed result: 60–65% release in multiple tablets.

• Immediate assumption: possible analyst error or instrumental issue.

🔎 Investigation Process (as per FDA Guidance on OOS and ICH Q7/Q10)

1. Phase I – Laboratory Investigation

• Checks performed:

  • Calibration of dissolution apparatus (RPM, temperature, basket/paddle alignment).

  • Medium preparation (pH, volume, deaeration).

  • Analyst competency review.

  • Chromatography/data integrity review.

• Findings:

  • All instruments were calibrated and working properly.

  • No analyst errors or deviations in procedure.

  • OOS confirmed by retesting (per protocol).

✅ Conclusion: Lab error ruled out → move to Phase II.

2. Phase II – Full-Scale Investigation

• Cross-functional team: QA, QC, Production, and R&D involved.

• Batch review:

  • Batch Manufacturing Record (BMR) checked for deviations.

  • In-process controls (granule moisture content, compression force, hardness, friability).

  • Environmental conditions during compression.

• Key Observations:

  • Tablets had higher hardness than specified.

  • Granulation parameters (binder solution volume and mixing time) deviated slightly during compression shift.

  • Harder tablets slowed the disintegration and drug release.

✅ Root Cause Identified: Improper granulation parameters → excessive tablet hardness → dissolution failure.

3. Risk Assessment

• Stability batches checked → borderline dissolution results.

• Market complaint history reviewed → no patient complaints yet.

• Regulatory risk: Since batch was already released, QA initiated recall decision assessment.

4. Corrective and Preventive Actions (CAPA)

• Immediate CAPA (Corrective):

  • Batch was rejected (if not released) OR subjected to regulatory reporting (if already in market).

  • Investigation report documented as per OOS SOP.

• Preventive Actions:

  • Updated granulation SOP with tighter control ranges.

  • Introduced in-process tablet hardness monitoring during compression.

  • Conducted operator retraining on granulation and compression parameters.

  • Implemented QbD approach for critical quality attributes (CQA: dissolution, hardness).

📊 Outcome

• Future batches met dissolution criteria.

• No recurrence reported in subsequent annual product reviews (APR/PQR).

• Company avoided potential warning letter by demonstrating robust investigation + CAPA.

📚 Key Learnings

1. OOS investigations must follow a scientific and phased approach — never assume lab error without proof.

2. True root cause often lies in manufacturing processes, not testing.

3. Cross-functional collaboration (QC + Production + QA) is essential.

4. Regulatory bodies expect documented evidence of root cause, risk assessment, and CAPA.

5. QbD and PAT tools (Process Analytical Technology) can help prevent such issues.