DECODING BULGING PROBLEM IN TABLET STRIPS (PICTORIAL)

1.0 Objective:

To describe the procedure for analyzing and identifying gases formed in the blister cavities of Amoxicillin and Potassium Clavulanate tablets using Gas Chromatography (GC).

2.0 Scope:

This SOP applies to the analysis of gases collected from bulged or swollen blister packs suspected to contain trapped gases due to degradation or leakage.

3.0 Responsibility:

• QC Analyst: Perform the test and record results.
• QC Reviewer: Verify chromatograms and calculations.
• QA Officer: Review and approve the final report.

4.0 References:

• USP–NF: Amoxicillin and Potassium Clavulanate Tablets
• ICH Q1A (R2): Stability Testing of New Drug Products
• ASTM F1929: Packaging Integrity Test Methods

5.0 Apparatus & Materials:

• Gas Chromatograph with Thermal Conductivity Detector (TCD)
• Columns: Molecular Sieve 5A and/or Porapak Q
• Gas-tight syringe (250–500 µL, Hamilton type)
• Helium (carrier gas, high purity)
• Certified gas standards (CO₂, O₂, N₂)
• Crimp vials (10–20 mL) with butyl/PTFE septa
• Micro-needle and piercing assembly
• Isopropyl alcohol wipes

6.0 Procedure:

6.1 Sample Collection:

1. Select representative bulged blister packs.
2. Clean surface with isopropyl alcohol and allow to dry.
3. Insert a fine needle through the bulged cavity without damaging the tablet.
4. Using a gas-tight syringe, withdraw 200–500 µL of headspace gas.
5. Immediately inject into GC or transfer into a sealed GC vial for short-term storage (<30 min).

6.2 Instrument Setup:

Parameter	Setting
Detector	TCD
Carrier Gas	Helium or Nitrogen, 20–30 mL/min
Column	Molsieve 5A / Porapak Q
Injector Temp	100–150 °C
Oven Temp	40–60 °C (isothermal)
Detector Temp	150–200 °C
Injection Mode	Splitless

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6.3 Calibration:

1. Inject standard gas mixtures (low, medium, high) containing CO₂, O₂, N₂.
2. Plot calibration curves for each gas (Area vs % concentration).
3. Verify correlation coefficient (R² ≥ 0.995).
4. Run a mid-level calibration verification after every 10 samples.

6.4 Sample Injection:

1. Purge syringe once with sample gas before final draw.
2. Inject 100–500 µL of sample directly into the GC inlet.
3. Record chromatogram and note retention times for CO₂, O₂, N₂.

6.5 Calculations:

• Determine gas concentration using the external calibration curve.
• For air ingress:
  • Expected ratio: N₂:O₂ ≈ 79:21.
  • Excess CO₂ indicates possible chemical degradation (clavulanate hydrolysis).
• Report values in % v/v or ppm.

6.6 Acceptance Criteria:

Parameter	Expected Range	Interpretation
CO₂	≤0.04%	Normal (ambient)
CO₂ >0.5%	Product degradation / moisture ingress
O₂:N₂ ratio ≈ 21:79	Air ingress (seal failure)
Other gases (H₂, CH₄, etc.)	Not detected	Contamination if present

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7.0 Quality Control:

• Run blank and standard before and after each batch.
• Duplicate injection RPD ≤ 10%.
• Maintain all chromatograms and raw data with sample ID and date.

8.0 Precautions:

• Avoid contact between the needle and the tablet.
• Perform all gas handling in a ventilated enclosure.
• Do not reuse syringes between samples without purging.

9.0 Documentation:

Attach chromatograms, calibration curves, calculation sheets, and investigation reports to the final record.

10.0 Interpretation and Reporting:

Based on gas composition:

• High CO₂ → degradation due to moisture.
• O₂/N₂ presence → seal leakage or packaging defect.
• Other gases detected → further investigation needed.