Standard Operating Procedure for API Uniformity in Tablet Granules

Department	Tablet
SOP No.	SOP/TAB/055/2025
Supersedes	SOP/TAB/055/2022
Page No.	Page 1 of 6
Issue Date	15/11/2025
Effective Date	20/11/2025
Review Date	15/11/2026

1. Purpose

This Standard Operating Procedure (SOP) defines the steps for ensuring the uniform distribution of Active Pharmaceutical Ingredients (APIs) in tablet granules during the manufacturing process. Achieving uniformity in API content is critical for maintaining consistent drug potency, ensuring patient safety, and meeting regulatory requirements.

2. Scope

This SOP applies to all tablet manufacturing processes where granulation is involved. It focuses on ensuring that the API is uniformly distributed within the granules before compression into tablets.

3. Responsibilities

• Manufacturing Personnel: Responsible for preparing, mixing, and granulating the batch according to the prescribed formula, ensuring API uniformity during the granulation process.
• Quality Control (QC): Responsible for testing granules to confirm uniformity of the API content, conducting sampling, and ensuring that the final granules meet the required specifications.
• Quality Assurance (QA): Ensures the process complies with GMP standards, reviews records, and approves any adjustments to the process or formulation to maintain API uniformity.
• Formulation and R&D Team: Responsible for assisting in the formulation development and adjustments to ensure optimal API distribution during the granulation process.

4. Accountability

The Production Manager is accountable for ensuring the uniform distribution of APIs in tablet granules and for ensuring compliance with this SOP during production. The QA Manager ensures the review and approval of the batch records and any deviations.

5. Procedure

5.1 Pre-Granulation Setup

1. Ensure all raw materials, including the API, excipients, and binders, meet the required specifications and are properly weighed before the granulation process begins.
2. Verify the proper functioning of the granulation equipment and ensure that it is clean and free from any contaminants from previous batches.
3. Ensure the correct formulation is used for the granulation process, and review the batch record to confirm API and excipient specifications.
4. Review and set the required parameters for the granulation process, including binder addition rate, granulation speed, and drying temperature, to achieve optimal API distribution.

5.2 Granulation Process

1. Load the dry ingredients, including the API and excipients, into the granulator, ensuring that the powder is evenly distributed.
2. Start the granulation process and gradually add the binder solution. Ensure the binder is added slowly and uniformly to promote even API distribution throughout the granules.
3. Monitor the granulation process to ensure that the API is thoroughly mixed with the excipients and that the granules form uniformly. If necessary, adjust the mixing speed to achieve the desired consistency.
4. Periodically stop the process to check for uniformity and ensure that the granules exhibit the desired size and texture.

5.3 Sampling for API Uniformity Testing

1. After granulation, take representative samples from different areas of the batch to test for API uniformity.
2. Perform the following tests on the samples:
   • API content uniformity
   • Particle size distribution
   • Moisture content
3. If the API content is found to be uniform and within the specified range, continue with the process. If uniformity is not achieved, adjust the granulation parameters, such as binder addition or granulation speed, and re-test until uniformity is achieved.
4. Document all sampling and testing results in the batch record (Annexure-1).

5.4 Post-Granulation Drying

1. After granulation, transfer the granules to the drying system and ensure that the drying temperature and airflow are set as per the batch specifications to prevent degradation of the API.
2. Monitor the moisture content of the granules during the drying process to ensure it meets the required specifications.
3. If the moisture content is too high, continue drying until the target moisture level is reached. Over-drying should be avoided, as it can affect API distribution and granule integrity.

5.5 Granule Screening and Sieving

1. After drying, sieve the granules using an appropriate mesh size to remove oversized or undersized particles.
2. Ensure that the screened granules exhibit uniform particle size distribution. Granules that are too large or too small can affect API uniformity and tablet performance.
3. Test the flow properties of the granules to ensure that they will flow consistently during the tablet compression process. If necessary, add a lubricant to improve flowability.
4. Record the granule testing results, including particle size distribution and flow properties, in the batch record (Annexure-1).

5.6 Final API Content Uniformity Check

1. Before proceeding to the tablet compression stage, perform a final check of the API content uniformity in the granules.
2. Conduct a series of API content tests on granules from different areas of the batch. The API content should be within the specified limits as per the formulation requirements.
3. If the API content is not uniform, investigate the cause (e.g., improper binder mixing or incomplete granulation) and adjust the process accordingly.
4. Document the results of the final uniformity test in the batch record (Annexure-1) and approve the batch for the next stage of production (tablet compression).

5.7 Documentation and Record-Keeping

1. Ensure all batch records, testing data, and any deviations are documented thoroughly, including any adjustments made to the process to achieve API uniformity.
2. Maintain detailed records of the granulation parameters, API uniformity test results, and corrective actions taken in the batch record (Annexure-1) and deviation report (Annexure-2).
3. Store all records according to the company’s retention policy and ensure they are accessible for future audits or regulatory inspections.

5.8 Equipment Maintenance and Calibration

1. Regularly maintain and calibrate the granulation and drying equipment to ensure consistent performance and uniformity in the API content of granules.
2. Perform routine inspections of equipment such as the granulator, mixer, and sieve to ensure they are functioning properly. Any malfunction or irregularity should be addressed immediately.
3. Document all maintenance activities in the maintenance log (Annexure-3) to ensure traceability and compliance with GMP requirements.

6. Abbreviations

• SOP: Standard Operating Procedure
• GMP: Good Manufacturing Practice
• QC: Quality Control
• QA: Quality Assurance
• API: Active Pharmaceutical Ingredient

7. Documents

1. Batch Record (Annexure-1)
2. Deviation Report (Annexure-2)
3. Maintenance Log (Annexure-3)

8. References

• 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals (US FDA)
• EU GMP Guidelines Part I – Basic Requirements for Medicinal Products
• ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Batch Record

Batch Number	API Type	Granulation Process	API Uniformity Test Results	Comments
Batch 001	Paracetamol	Fluidized Bed	Pass: API content 99.5% – 100.5%	No deviations

Annexure-2: Deviation Report

Deviation Date	Batch Number	Deviation Description	Corrective Action	Responsible Person
20/09/2025	Batch 002	API content variation	Adjusted binder concentration	Jane Smith

Annexure-3: Maintenance Log

Maintenance Date	Equipment Component	Maintenance Performed	Performed By	Comments
15/09/2025	Granulation Mixer	Lubrication, Inspection	John Doe	No issues found, cleaned and calibrated

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
01/01/2024	1.0	Initial Version	New SOP Creation	QA Head
01/02/2025	2.0	Updated Granulation Parameters	Improved API Uniformity	QA Head