container closure systems into pharmaceutical products under storage or stress conditions.

2. Scope

This procedure applies to container closure systems such as rubber stoppers, plastic caps, ampoules, vials, blisters, and prefilled syringes used with liquid, lyophilized, or inhalation products in the Analytical Method Development (AMD) department.

3. Responsibilities

• Analytical Scientist: Develops and validates the leachables detection method using appropriate analytical tools.
• QC Analyst: Supports comparative studies and transfer of validated methods.
• QA Executive: Reviews and approves method validation protocols and ensures compliance with GMP guidelines.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring scientifically justified and validated leachables methods are available and implemented for all critical container closure systems.

5. Procedure

5.1 Leachables Study Design

1. Select products and packaging systems for leachables study based on extractables risk assessment.
2. Conduct real-time and accelerated stability studies using product-filled containers stored at 25°C/60% RH and 40°C/75% RH up to 6 months.
3. Collect samples at intervals (0, 1, 3, and 6 months) for analytical evaluation.

5.2 Analytical Technique Selection

1. Use orthogonal techniques for broad coverage:
   • GC-MS: for volatile organic leachables (e.g., plasticizers, solvents)
   • LC-MS/MS: for semi-volatiles and non-volatile organics (e.g., antioxidants, UV stabilizers)
   • ICP-MS: for trace metals and elemental leachables (e.g., Al, Zn, Cr)

5.3 Sample Preparation

1. Use direct injection for liquid formulations and SPE or LLE for concentration and cleanup.
2. Ensure sample filtration does not introduce artifacts; use low-adsorption PTFE or PVDF filters.

5.4 Method Development and Optimization

1. Establish retention time, MS ionization parameters, and quantifier/qualifier ions.
2. Select surrogate standards and internal standards for quantification where reference leachable is unavailable.

5.5 Method Validation Parameters

1. Validate for:
   • Specificity (no interference from placebo or matrix)
   • LOD/LOQ (typically < 1 ppm or as per TTC limit)
   • Linearity (r ≥ 0.995)
   • Accuracy (80–120%)
   • Precision (%RSD ≤ 10%)

5.6 Data Documentation

1. Compile chromatograms, calibration curves, peak identification, and validation summary in Annexures.
2. Prepare a final Leachables Method Development and Validation Report (Annexure-3).

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
• TTC: Threshold of Toxicological Concern
• RSD: Relative Standard Deviation

7. Documents

1. Leachables Study Design Protocol – Annexure-1
2. Method Validation Summary Sheet – Annexure-2
3. Leachables Method Validation Report – Annexure-3

8. References

• USP <1664> Assessment of Drug Product Leachables
• ICH Q3D: Guideline for Elemental Impurities
• FDA Guidance: Container Closure Systems
• PQRI Best Practices for Leachables and Extractables Testing

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Ananya Shekhar	Rahul Jaiswal	Sunita Reddy
Designation	Analytical Scientist	QA Reviewer	Head – AMD
Department	Analytical Method Development	QA	Analytical Method Development

11. Annexures

Annexure-1: Leachables Study Design Protocol

Product	Packaging Type	Storage Condition	Time Points
Injection X	Glass Vial + Rubber Stopper	25°C/60% RH	0, 1, 3, 6 Months

Annexure-2: Method Validation Summary Sheet

Analyte	LOD (ppm)	LOQ (ppm)	Recovery (%)	RSD (%)
Butylated Hydroxy Toluene (BHT)	0.05	0.15	98.2	4.5

Annexure-3: Leachables Method Validation Report

LC-MS method developed for BHT and other extractable-related leachables from prefilled syringe components. Method validation confirmed specificity, linearity (r=0.997), and precision (RSD < 5%). All test results met acceptance criteria and method is approved for regulatory submission.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
21/05/2025	2.0	Updated to include LC-MS/MS validation and PQRI guidelines	Annual Review and E&L Expansion	Sunita Reddy
10/05/2022	1.0	Initial SOP Release	New SOP	QA Head