Standard Operating Procedure for Granulation Development for Hard Gelatin Capsules

Department	Capsule Manufacturing
SOP No.	SOP/CM/035/2025
Supersedes	SOP/CM/035/2022
Page No.	Page 1 of 8
Issue Date	01/02/2025
Effective Date	05/02/2025
Review Date	01/02/2026

1. Purpose

The purpose of this SOP is to define the procedure for granulation development for hard gelatin capsules. Granulation ensures that the active pharmaceutical ingredient (API) and excipients are uniformly distributed in the fill material, improving the flowability, compressibility, and overall quality of the capsule content.

2. Scope

This SOP applies to the granulation process for hard gelatin capsules. It includes methods for preparing wet and dry granules, as well as testing the resulting granules for quality attributes such as particle size distribution, flowability, and uniformity.

3. Responsibilities

• Formulation Development Team: Responsible for determining the formulation requirements for the granulation, including the choice of excipients and the granulation method to be used.
• Manufacturing Team: Responsible for performing the granulation process, ensuring proper equipment setup, and following all process parameters.
• Quality Control (QC) Team: Responsible for testing the granules for particle size distribution, flowability, and other relevant parameters to ensure that the granulation meets the required specifications.
• Quality Assurance (QA) Team: Ensures that the granulation development process complies with GMP standards and company policies, and that all relevant documentation is reviewed and approved.

4. Accountability

The Capsule Manufacturing Supervisor is accountable for ensuring the proper execution of the granulation process, while the QC Manager is responsible for testing the granules and approving them for further use in capsule production.

5. Procedure

5.1 Granulation Process Overview

The granulation process can be divided into two main methods: wet granulation and dry granulation. The method selected depends on the characteristics of the API and excipients, as well as the desired characteristics of the final granules.

1. Wet Granulation
   1. Wet granulation involves mixing the API and excipients with a liquid binder to form granules. The process enhances the uniformity of the fill material and improves its flowability and compressibility.
   2. This method is particularly useful for improving the properties of powders with poor flow or cohesion.
2. Dry Granulation
   1. Dry granulation, also known as slugging, involves compressing the blend of powder into large tablets (slugs) and then breaking them down into granules. This method is typically used for heat-sensitive materials that cannot undergo the wet granulation process.

5.2 Granulation Development Method

Follow these steps to develop the granulation process:

1. Formulation Development
   1. Identify the active ingredient (API), excipients (binders, fillers, lubricants), and other additives (e.g., disintegrants) based on the formulation requirements.
   2. Determine the appropriate binder, granulation method, and other excipient ratios based on the material properties (e.g., flowability, compressibility).
2. Weighing and Mixing
   1. Weigh the excipients and active ingredient accurately using appropriate balances. Ensure that the ingredients are of pharmaceutical grade and meet the specifications.
   2. Mix the ingredients thoroughly to ensure uniform distribution before proceeding to the granulation step.
3. Granulation (Wet or Dry)
   1. If performing wet granulation, add the binder solution to the powder mixture gradually, ensuring uniform mixing. Continue mixing until the granules begin to form.
   2. If performing dry granulation, compress the mixture into slugs using a tablet press, then break the slugs into granules of the desired size.
4. Granule Size Adjustment
   1. Adjust the granule size by sieving the material after granulation. Use appropriate mesh sizes to obtain the desired particle size range for the final granules.
5. Drying
   1. If wet granulation was used, dry the granules using a fluidized bed dryer or tray dryer to remove excess moisture. The moisture content should be controlled to avoid sticking during encapsulation.

5.3 Granule Evaluation and Quality Control

Evaluate the granules for the following quality attributes:

1. Particle Size Distribution
   1. Perform sieve analysis or laser diffraction to measure the particle size distribution of the granules. Ensure that the majority of the granules fall within the specified size range for capsule filling.
2. Flowability
   1. Test the flowability of the granules using a powder flow tester or similar device. Granules should flow easily into the capsule filling machine without causing blockages.
3. Moisture Content
   1. Test the moisture content of the granules to ensure it is within acceptable limits. Excess moisture can cause clumping or difficulties in capsule filling.
4. Uniformity
   1. Ensure that the granules are uniform in size, density, and composition to ensure consistent capsule fill weight and drug release characteristics.

5.4 Adjustments Based on Testing Results

If the granules do not meet the required specifications, make the following adjustments:

1. Particle Size Adjustment
   1. If the granules are too coarse, reprocess them through the granulation equipment or sieve them to achieve the desired size.
   2. If the granules are too fine, adjust the granulation parameters or increase the binder content to achieve the desired particle size.
2. Moisture Content Adjustment
   1. If the moisture content is too high, re-dry the granules until the desired moisture level is reached. If the moisture content is too low, adjust the granulation binder ratio or add more moisture during granulation.
3. Flowability Improvement
   1. If the granules do not flow well, consider adding a flow agent or modifying the granulation process to improve the flowability of the material.

5.5 Documentation and Record-Keeping

Ensure that all aspects of the granulation process are thoroughly documented:

1. Granulation Records
   1. Document the formulation details, granulation parameters (e.g., binder concentration, mixing speed, granulation time), and any deviations from the standard process.
2. Quality Control Reports
   1. Document all test results, including particle size distribution, flowability, moisture content, and uniformity, ensuring that the granules meet the required specifications before use in capsule filling.

6. Abbreviations

• SOP: Standard Operating Procedure
• QC: Quality Control
• API: Active Pharmaceutical Ingredient
• GMP: Good Manufacturing Practice
• USP: United States Pharmacopeia

7. Documents

1. Granulation Process Record (Annexure-1)
2. Granule Testing Report (Annexure-2)

8. References

• USP <701> – Granulation Techniques
• FDA Guidance for Industry: Quality in Drug Product Manufacturing
• International Conference on Harmonization (ICH) Guidelines for Pharmaceutical Development

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Granulation Process Record

Date	Batch Number	Granulation Method	Parameters	Outcome
02/02/2025	Batch A	Wet Granulation	Speed: 100 rpm, Time: 15 min	Pass

Annexure-2: Granule Testing Report

Date	Batch Number	Particle Size Range	Flowability	Moisture Content
02/02/2025	Batch A	50-150 µm	Pass	5%

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 process	Standardization	QA Head