Standard Operating Procedure for Reference Standard Qualification and Handling in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/131/2025
Supersedes	SOP/API/131/2022
Page No.	Page 1 of 9
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

The purpose of this SOP is to establish a standardized procedure for qualification, handling, storage, and periodic review of reference standards used in the analysis of Active Pharmaceutical Ingredients (APIs). This ensures that all reference standards are reliable, traceable, and meet regulatory and internal quality requirements.

2. Scope

This SOP applies to all reference standards (including working and primary standards) used in API manufacturing, covering their qualification prior to use in analytical testing, proper handling, storage conditions, and periodic requalification or replacement.

3. Responsibilities

• QC Analyst: Prepare and verify reference standards as per the approved protocols.
• QC Supervisor: Ensure that reference standards are properly stored and documented before use.
• QA Officer: Review qualification data and storage conditions, and authorize periodic requalification.
• Production Manager: Ensure that only qualified reference standards are used in the manufacturing process.

4. Accountability

The Head – QC is accountable for the implementation and control of reference standard qualification and handling procedures. The QA Head is responsible for ensuring that all reference standards are maintained in accordance with cGMP guidelines.

5. Procedure

5.1 Qualification of Reference Standards

1. Upon receipt, record all details of the reference standard including:
   • Certificate of Analysis (CoA)
   • Lot number
   • Expiry date
   • Storage conditions
2. Perform initial qualification tests (identity, purity, potency) as per the approved analytical method or pharmacopeial monograph.
3. If the reference standard meets specifications, assign a unique Reference Standard Code (e.g., RS-API-001) and log details in the Reference Standard Logbook (Annexure-1).
4. If deviations are noted, quarantine the standard and initiate an investigation. Do not use unqualified standards for analytical testing.

5.2 Handling and Storage

1. Store qualified reference standards in a dedicated controlled environment:
   • Temperature: As recommended on the CoA (e.g., 2–8°C for sensitive materials, 25°C ± 2°C for stable materials)
   • Humidity: Maintain as per CoA requirements (e.g., less than 60% RH)
2. Ensure the storage area is secure and accessible only to authorized personnel.
3. Periodically inspect storage conditions and update the log accordingly.

5.3 Use of Reference Standards

1. Before use, verify that the reference standard is within its expiry date and storage conditions have not been compromised.
2. Document the usage of the standard in the Reference Standard Usage Log (Annexure-2), noting:
   • Date of use
   • Sample and analysis type
   • Operator details
3. Any observed anomalies during use must be reported immediately to the QC Supervisor.

5.4 Periodic Requalification and Replacement

1. Conduct requalification of reference standards annually or as determined by risk assessment and storage conditions.
2. Reperform critical tests (identity, purity, etc.) and compare results with the original CoA.
3. If the standard fails requalification, remove it from inventory, document the deviation, and replace it with a newly qualified standard.
4. Update the Reference Standard Logbook to reflect requalification outcomes and any changes to stock.

5.5 Documentation and Record Keeping

1. Maintain all documentation relating to reference standard qualification, usage, storage, requalification, and disposal in their respective logs:
   • Reference Standard Logbook (Annexure-1)
   • Reference Standard Usage Log (Annexure-2)
   • Reference Standard Replacement/Disposal Records
2. All records must be reviewed monthly and archived as per company document control policy.

6. Abbreviations

• RS: Reference Standard
• QC: Quality Control
• QA: Quality Assurance
• CoA: Certificate of Analysis
• cGMP: Current Good Manufacturing Practices
• API: Active Pharmaceutical Ingredient

7. Documents

1. Reference Standard Logbook (Annexure-1)
2. Reference Standard Usage Log (Annexure-2)
3. CoA and Qualification Reports
4. Requalification Review Form

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• USP Monographs pertaining to reference standards
• 21 CFR Part 211 – US FDA cGMP
• WHO Guidelines for Reference Standards

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Reference Standard Logbook

Date	Reference Standard Code	Material Name	Lot Number	Expiry Date	Qualification Result	Storage Condition	Remarks
13/04/2025	RS-API-001	Active Ingredient A	LOT12345	12/2026	Qualified	2–8°C	Initial qualification complete

Annexure-2: Reference Standard Usage Log

Date	RS Code	Batch No.	Test Performed	Operator	Remarks
13/04/2025	RS-API-001	API-20250413	Assay & Impurity Profiling	Ravi Kumar	Used without deviation