SOP Guide for Pharma

API Manufacturing: SOP for Hold Time Validation of Intermediates – V 2.0

Auditor

API Manufacturing: SOP for Hold Time Validation of Intermediates – V 2.0

Standard Operating Procedure for Hold Time Validation of Intermediates in API Manufacturing

Department API Manufacturing
SOP No. SOP/API/036/2025
Supersedes SOP/API/036/2022
Page No. Page 1 of 10
Issue Date 13/04/2025
Effective Date 15/04/2025
Review Date 13/04/2026

1. Purpose

To define a validated and standardized procedure for determining and documenting hold times for in-process intermediates during API manufacturing, ensuring that intermediate quality is maintained within defined limits throughout the process.

2. Scope

This SOP applies to all intermediates generated during API production at each defined hold stage, prior to the next processing step such as filtration, drying, crystallization, or purification.

3. Responsibilities

See also  API Manufacturing: SOP for Stock Inventory Management and Cycle Counting - V 2.0

4. Accountability

The QA Head is accountable for the approval of hold time validation protocols and reports. The Production Head is responsible for ensuring adherence during batch execution.

5. Procedure

5.1 Selection of Intermediate Stages

  1. Identify critical intermediate stages where material is held for more than 24 hours before next operation.
  2. Examples include: post-reaction slurry, wet cake post-filtration, filtrate for crystallization, dried intermediate awaiting milling.
  3. Document storage conditions: temperature, humidity, container type, and covered/uncovered status.

5.2 Protocol for Hold Time Validation
  1. Prepare a Hold Time Validation Protocol and obtain QA approval.
  2. Include:
    • Time points for sampling (e.g., 0, 12, 24, 48, 72 hrs)
    • Number of samples per time point
    • Test parameters (e.g., appearance, pH, assay, related substances, microbial load)
  3. Perform testing as per validated analytical methods.
  4. Record all time points and results in the “Hold Time Validation Log” (Annexure-1).

5.3 Acceptance Criteria

  1. Intermediates must meet defined specifications at all time points tested.
  2. Any deviation shall be evaluated through risk assessment and impact on final API quality.
  3. If results at any time point fail, revise the hold time to the previous passing time point.

5.4 Final Report and Implementation

  1. Prepare Hold Time Validation Summary Report after all data is reviewed.
  2. Submit report to QA for approval.
  3. Include validated hold time and conditions in relevant Batch Manufacturing Records (BMRs) and process instructions.

6. Abbreviations

7. Documents

  1. Hold Time Validation Log (Annexure-1)
  2. Hold Time Protocol Template (Annexure-2)
  3. Validation Summary Report Template (Annexure-3)

8. References

9. SOP Version

Version: 2.0

10. Approval Section

Prepared By Checked By Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Hold Time Validation Log

Date Batch No. Intermediate Stage Time Point (hr) Tested Parameter Result Pass/Fail
13/04/2025 API-202504 Post-Reaction Slurry 24 Assay 99.1% Pass

Annexure-2: Hold Time Protocol Template

Intermediate Name Container Type Storage Condition Sampling Points Tests to Perform
Crude API SS Vessel RT (20–25°C) 0, 12, 24, 48, 72 hr pH, RS, Microbial

Annexure-3: Validation Summary Report Template

Intermediate Validated Hold Time Conclusion Approved By
Post-Reaction Slurry 48 hr at 25°C Stable till 48 hrs

Revision History:

Revision Date Revision No. Details Reason Approved By
01/01/2022 1.0 Initial SOP Version New Hold Time Protocol QA Head
13/04/2025 2.0 Enhanced sampling intervals and storage conditions Audit Compliance QA Head
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