Standard Operating Procedure for Seeding Techniques in Crystallization in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/062/2025
Supersedes	SOP/API/062/2022
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 standardized procedure for implementing seeding techniques in crystallization operations to control nucleation, improve crystal size distribution, and ensure batch consistency in API manufacturing.

2. Scope

This SOP is applicable to all API crystallization processes where seeding is used to induce or control crystallization in stirred tank reactors, crystallizers, and batch vessels.

3. Responsibilities

• Production Operators: Prepare, introduce, and monitor seed slurry during crystallization as per batch record.
• Production Supervisor: Ensure appropriate seed type and quantity are used and monitor critical parameters.
• QC Department: Verify particle size and polymorph form of seed material (if applicable).
• QA Department: Review documentation and approve the crystallization step.

4. Accountability

The Production Head is accountable for ensuring proper execution of seeding operations. The QA Head is responsible for validating the process and records.

5. Procedure

5.1 Selection of Seeding Strategy

1. Determine seeding requirement based on prior development reports or validation data.
2. Select seed type:
   • Same API crystal form from previous batch or lab-prepared
   • Dry seed or seed slurry (as applicable)
3. Ensure seed matches desired polymorph and particle size (as per CoA or microscopic check).

5.2 Preparation of Seed Slurry

1. Weigh required quantity of dry seed (typically 0.1–1.0% w/w of theoretical API).
2. Disperse seed in suitable mother liquor or solvent under stirring to form uniform slurry.
3. Ensure temperature of slurry matches the crystallization mass (within ±5°C).
4. Record preparation details in the “Seed Slurry Preparation Log” (Annexure-1).

5.3 Addition of Seed to Crystallizer

1. Ensure crystallization mass has reached the seeding temperature (as per batch record).
2. Add seed slurry slowly through charging port over 10–15 minutes under continuous stirring.
3. Maintain agitation to distribute seed uniformly in the batch.
4. Do not allow sudden cooling during or after seeding to avoid uncontrolled nucleation.

5.4 Post-Seeding Monitoring

1. Monitor temperature, agitation, and crystal formation visually or using online probes (if available).
2. Continue to cool the batch gradually as per the crystallization profile.
3. Collect in-process sample for microscopy and pH, if required.
4. Document entire seeding process in the batch record and “Seeding Process Monitoring Log” (Annexure-2).

6. Abbreviations

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QC: Quality Control
• QA: Quality Assurance
• CoA: Certificate of Analysis

7. Documents

1. Seed Slurry Preparation Log (Annexure-1)
2. Seeding Process Monitoring Log (Annexure-2)
3. Batch Manufacturing Record

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• Internal Crystallization Validation Protocol

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Seed Slurry Preparation Log

Date	Batch No.	Seed Type	Quantity (g)	Solvent	Prepared By
13/04/2025	CRY-20250413	API-A Seed	45	IPA

Annexure-2: Seeding Process Monitoring Log

Date	Batch No.	Seeding Temp (°C)	Time	RPM	Observation	Operator
13/04/2025	CRY-20250413	30	09:30	150	Crystal Initiation Noted

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Release	Process Qualification	QA Head
13/04/2025	2.0	Introduced Annexures for Monitoring and Slurry Prep	Audit Recommendation	QA Head