and Annex 1 of EU GMP.

2. Scope

This SOP applies to all sterile injectable products manufactured at the facility, including vials, ampoules, and prefilled syringes, and covers container closure integrity testing (CCIT) at development, in-process, and finished product stages.

3. Responsibilities

• QC Analyst: Executes container closure integrity tests as per approved protocols.
• QC Supervisor: Reviews test data and ensures compliance with specifications.
• QA Personnel: Verifies that results are recorded and investigated properly.
• Engineering Team: Supports testing by maintaining test instruments.

4. Accountability

The Head of Quality Control is accountable for ensuring implementation of this SOP and compliance with regulatory standards regarding CCS integrity.

5. Procedure

5.1 Types of Container Closure Integrity Tests

1. Deterministic Methods: These include vacuum decay, high-voltage leak detection (HVLD), laser-based headspace analysis, and pressure decay methods. Preferred due to accuracy and reproducibility.
2. Probabilistic Methods: Includes dye ingress and microbial ingress methods. Used as supportive or investigational tools.

5.2 Selection of CCS Integrity Test

1. Choose appropriate test method based on container type (vial, ampoule, syringe), product sensitivity, and critical quality attributes.
2. Validate the method for specificity, sensitivity, repeatability, and detection limit.

5.3 Sample Preparation

1. Collect representative samples from production batches, including edge vials and stress-tested containers.
2. Ensure samples are labeled with batch number, container ID, and date of sampling.
3. Inspect containers for pre-test visual integrity.

5.4 Deterministic Method Procedure – Vacuum Decay

1. Place sealed containers in the vacuum chamber.
2. Evacuate chamber to the validated vacuum level.
3. Monitor pressure changes over time; a stable pressure indicates integrity.
4. Compare results to control sample readings.

5.5 Dye Ingress Test Procedure (if required)

1. Submerge containers in 0.1% methylene blue solution under vacuum conditions.
2. Apply vacuum for 30 minutes followed by atmospheric pressure for another 30 minutes.
3. Remove containers, rinse, and inspect for dye penetration visually and/or spectrophotometrically at 660 nm.

5.6 Acceptance Criteria

• No visible dye ingress or measurable pressure change in deterministic methods.
• Acceptance criteria must align with validation protocol and regulatory guidance.

5.7 Handling of Failures

1. Isolate failed samples and initiate an investigation using SOP/QC/051.
2. Determine potential root causes: improper sealing, glass defects, crimping issues, etc.
3. Document non-conformance and assess impact on batch disposition.

5.8 Documentation

1. Record all observations, data, and instrument settings in Container Closure Integrity Test Log (Annexure-1).
2. Attach instrument printouts and calibration status.
3. Submit records to QA for review and archival.

5.9 Frequency of Testing

• Performed as part of routine quality control of every production batch.
• Stability samples to be tested at each scheduled interval.
• Executed post-process change, machine maintenance, or sealing system validation.

5.10 Equipment Calibration and Maintenance

• Maintain calibration schedule for CCIT equipment (Annexure-2).
• Ensure daily performance checks and quarterly maintenance.

6. Abbreviations

• CCIT: Container Closure Integrity Testing
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• HVLD: High Voltage Leak Detection

7. Documents

1. Container Closure Integrity Test Log – Annexure-1
2. Equipment Calibration Record – Annexure-2
3. CCIT Failure Investigation Form – Annexure-3

8. References

• USP <1207> – Container Closure Integrity Testing
• FDA Guidance for Industry – Container Closure Systems for Packaging Human Drugs and Biologics
• EU GMP Annex 1

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation	QC Analyst	QA Executive	Head QA
Department	Quality Control	Quality Assurance	Quality Assurance

11. Annexures

Annexure-1: Container Closure Integrity Test Log

Date	Batch No.	Container Type	Method	Result	Analyst
22/06/2025	INJ-845	Vial	Vacuum Decay	Pass	Sunita Reddy

Annexure-2: Equipment Calibration Record

Instrument ID	Model	Last Calibration	Next Due	Calibrated By
CCIT-02	Micropress V900	15/04/2025	15/10/2025	Rajesh Kumar

Annexure-3: CCIT Failure Investigation Form

Date	Batch	Issue Observed	Initial Assessment	Corrective Action
20/06/2025	INJ-842	Leak Detected	Improper Sealing	Re-trained Operators

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
15/03/2022	1.0	Initial Release	New Requirement	Head QC
24/06/2025	2.0	Incorporated USP <1207> and Annex 1 references	Annual Review	Head QA