with regulatory and pharmacopeial standards.

2. Scope

This SOP applies to all plastic, rubber, elastomeric, and polymer-based packaging systems used for drug products and medical devices analyzed by the Analytical Method Development (AMD) department.

3. Responsibilities

• Analytical Scientist: Designs extraction protocol, develops and validates analytical method.
• QC Analyst: Performs cross-verification and supports during method transfer.
• QA Executive: Reviews validation protocol and approves method suitability for GMP use.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that all extractables testing methods are scientifically justified, validated, and meet regulatory expectations before routine implementation.

5. Procedure

5.1 Selection of Packaging Components

1. Include:
   • Container Closure Systems (CCS) such as vials, stoppers, ampoules
   • Blister packs, caps, liners, plungers, syringes
2. Classify based on material type: LDPE, HDPE, PP, PVC, rubber, glass.

5.2 Design of Extraction Study

1. Use simulated solvents: WFI, 0.9% NaCl, 10% ethanol, hexane.
2. Conduct extractions at 40–70°C for up to 24 hours.
3. Use appropriate surface area-to-volume ratio.

5.3 Analytical Method Development

1. Analyze extracts using:
   • GC-MS: for volatile organics and solvents
   • LC-MS: for semi-volatiles and polymer additives
   • ICP-MS: for elemental impurities (e.g., Al, Zn, Pb)
2. Develop method parameters:
   • Column type, gradient program, injection volume
   • Detector settings (e.g., SIM mode, ion scan range)

5.4 Method Validation

1. Validate for:
   • Specificity and selectivity
   • Limit of Detection (LOD) and Limit of Quantitation (LOQ)
   • Linearity (r ≥ 0.990 over working range)
   • Accuracy (80–120% recovery)
   • Precision (%RSD ≤ 10%)
2. Document validation data in Annexure-2.

5.5 Risk Assessment and Safety

1. Refer to E&L risk thresholds (e.g., 1.5 µg/day per TTC concept).
2. Ensure solvents used for extraction are compatible with material and non-destructive.

5.6 Documentation

1. Compile raw chromatograms, calibration curves, spike recovery logs.
2. Prepare a validation summary report and submit for QA approval.

6. Abbreviations

• SOP: Standard Operating Procedure
• GC-MS: Gas Chromatography-Mass Spectrometry
• LC-MS: Liquid Chromatography-Mass Spectrometry
• ICP-MS: Inductively Coupled Plasma Mass Spectrometry
• E&L: Extractables and Leachables

7. Documents

1. Extractables Study Plan – Annexure-1
2. Validation Data and Recovery Log – Annexure-2
3. Method Summary Report – Annexure-3

8. References

• USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging
• ICH Q3D: Elemental Impurities
• EMA: Guidelines on Plastic Primary Packaging Materials
• FDA: Container Closure Systems for Packaging Human Drugs and Biologics

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Anita Kale	Ravi Thakur	Sunita Reddy
Designation	Analytical Scientist	QA Reviewer	Head – AMD
Department	Analytical Method Development	QA	Analytical Method Development

11. Annexures

Annexure-1: Extractables Study Plan

Component	Material	Solvent	Temperature	Time
Vial Cap	Butyl Rubber	10% Ethanol	50°C	24 hr

Annexure-2: Validation Data Summary

Analyte	LOD (µg/mL)	LOQ (µg/mL)	Recovery (%)	%RSD
Phthalate	0.2	0.6	96.2	4.3

Annexure-3: Method Summary Report

GC-MS method for detection of extractables from butyl rubber vial components was successfully validated. The method met acceptance criteria for specificity, sensitivity, accuracy, and precision. Method ready for regulatory filing and routine QC use.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
21/05/2025	2.0	Updated to include LC-MS and ICP-MS validation requirements	Annual Review and E&L Compliance Update	Sunita Reddy
15/04/2022	1.0	Initial SOP Release	New SOP	QA Head