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

• Production Chemist: Collect hold time samples and record hold durations.
• QA Officer: Review hold time data and ensure adherence to hold conditions.
• QC Analyst: Analyze intermediate samples at different time intervals as per protocol.

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

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record

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

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – GMP for Finished Pharmaceuticals
• WHO Technical Report Series 986, Annex 2

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