Standard Operating Procedure (SOP) Determination of Residual Hydrocarbon Content in Pharmaceutical Gases

1. Purpose
The purpose of this Standard Operating Procedure (SOP) is to outline the method for the determination of residual hydrocarbon content in pharmaceutical gases used in manufacturing processes. The accurate quantification of hydrocarbons ensures compliance with regulatory standards and maintains the quality of pharmaceutical products.

2. Scope
This SOP applies to the analysis of residual hydrocarbon content in pharmaceutical gases such as oxygen, nitrogen, carbon dioxide, and compressed air, used in facilities manufacturing pharmaceutical products.

3. Responsibility
3.1 Quality Control Analyst:

• Perform analysis as per this SOP.
• Ensure all equipment is calibrated before use.
• Record and report results accurately.

3.2 Laboratory Manager:

• Verify that the method is performed correctly.
• Approve test results.
• Ensure the laboratory complies with regulatory requirements.

3.3 Quality Assurance (QA) Team:

• Review and approve the SOP and related documents.
• Ensure adherence to the SOP during audits and inspections.

4. References

• [ USP, EP, or BP guidelines]
• Manufacturer’s operation manual for gas chromatography (GC) equipment.
• Relevant regulatory guidelines (e.g., ICH Q3C, FDA, EMA).

5. Definitions
5.1 Residual Hydrocarbon Content: Trace amounts of hydrocarbons present in pharmaceutical gases, usually expressed in parts per million (ppm).
5.2 Pharmaceutical Gases: Gases used in pharmaceutical processes such as oxygen, nitrogen, and carbon dioxide.
5.3 Gas Chromatography (GC): An analytical method for separating and quantifying volatile compounds in a sample.

6. Equipment and Materials

• Gas chromatography (GC) system with flame ionization detector (FID).
• Sampling gas cylinders and gas regulators.
• Certified calibration gas standards (e.g., methane, ethane, propane).
• Syringes and gas-tight connectors.
• Data acquisition and processing software.
• Personal protective equipment (PPE), including gloves, goggles, and lab coats.
• Logbooks for equipment calibration and usage.

7. Procedure

7.1 Safety Precautions:

• Ensure proper ventilation in the laboratory.
• Follow all safety guidelines for handling compressed gases.
• Wear appropriate PPE during the analysis.
• Handle gas cylinders carefully to avoid leaks or accidents.

7.2 Sample Collection:

1. Obtain gas samples from designated sampling points within the facility.
2. Use gas-tight regulators and tubing to prevent sample contamination.
3. Ensure the sampling apparatus is clean and free from hydrocarbon residues.
4. Label the gas samples with identification details, including date, time, and sampling point.

7.3 Equipment Setup:

1. Verify that the GC system is in proper working condition.
2. Calibrate the GC system using certified calibration gas standards.
3. Use a capillary column suitable for hydrocarbon analysis. Typical column specifications include:
   • Stationary phase: Nonpolar (e.g., dimethylpolysiloxane).
   • Column length: 30 m.
   • Internal diameter: 0.25 mm.
   • Film thickness: 0.25 µm.
4. Set up the flame ionization detector (FID) and optimize its settings (e.g., hydrogen and air flow rates).
5. Record all setup details in the GC logbook.

7.4 Calibration of GC:

1. Inject calibration gas standards containing known concentrations of hydrocarbons.
2. Prepare a calibration curve by plotting peak areas versus concentrations for each hydrocarbon.
3. Validate the calibration curve by ensuring linearity (correlation coefficient, R², should be ≥0.99).

7.5 Sample Analysis:

1. Connect the gas sample cylinder to the GC system using gas-tight fittings.
2. Purge the GC system with the sample gas for a minimum of 3 minutes to ensure a representative sample is introduced.
3. Inject the gas sample into the GC system using the programmed injection method.
4. Record the chromatogram and identify hydrocarbon peaks using the calibration curve.
5. Quantify the hydrocarbon content and express the results in ppm.

7.6 Acceptance Criteria:

• The total residual hydrocarbon content must meet the specifications outlined in regulatory guidelines or the facility’s internal quality standards (e.g., ≤50 ppm for residual hydrocarbons).

7.7 System Suitability Test (SST):

1. Perform an SST using a standard gas mixture before analyzing samples.
2. Verify resolution, peak shape, and sensitivity meet predefined criteria.

7.8 Data Documentation:

1. Record all observations and data in the laboratory notebook or electronic data management system (EDMS).
2. Include details such as sample ID, calibration details, chromatograms, and final results.
3. Attach a copy of the calibration curve and system suitability data to the test report.

7.9 Troubleshooting:

• Inconsistent results: Check for leaks in the system, contamination, or equipment malfunction.
• Poor resolution: Optimize GC column temperature or flow rates.
• Detector issues: Verify the FID’s gas supply and flame stability.

8. Quality Control
8.1 Method Validation:

• Validate the GC method to ensure accuracy, precision, linearity, specificity, and robustness.
• Revalidate the method whenever there is a significant change in equipment, method, or gas type.

8.2 Internal Quality Checks:

• Perform periodic QC checks using reference standards to verify system performance.
• Maintain detailed logs of all calibration, validation, and analysis activities.

8.3 Out-of-Specification (OOS) Results:

• Investigate OOS results according to the facility’s OOS investigation procedure.
• Document findings and implement corrective actions as needed.

9. Training

• All personnel performing this procedure must be trained in the operation of GC systems and the handling of pharmaceutical gases.
• Training records must be maintained and updated regularly.

10. Document Control

• This SOP will be reviewed periodically (e.g., annually) or whenever significant changes are made to the procedure.
• All revisions must be approved by the QA team and documented in the revision history