Capsule: SOP for Particle Size Reduction for Capsule Fill Materials – V 2.0

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Capsule: SOP for Particle Size Reduction for Capsule Fill Materials – V 2.0

Standard Operating Procedure for Particle Size Reduction for Capsule Fill Materials

Department Capsule Manufacturing
SOP No. SOP/CM/034/2025
Supersedes SOP/CM/034/2022
Page No. Page 1 of 7
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 particle size reduction of capsule fill materials to ensure uniformity in particle size distribution, improve flow properties, and enhance the overall quality of the final capsule product.

2. Scope

This SOP applies to the process of particle size reduction for all types of fill materials used in soft gelatin capsules, including powders, granules, and other solid excipients or active pharmaceutical ingredients (APIs) that require size reduction before encapsulation.

3. Responsibilities

  • Formulation Development Team: Responsible for determining the desired particle size range for each fill material and ensuring that the particle size reduction process meets the formulation requirements.
  • Quality Control (QC) Team: Responsible for verifying that the particle size reduction process achieves the specified size range and evaluating the flow and handling properties of the reduced particles.
  • Manufacturing Team: Responsible for executing the particle size reduction process as per this SOP, ensuring the equipment is used correctly and that all safety and quality procedures are followed.
  • Quality Assurance (QA) Team: Ensures compliance with this SOP, reviews records, and verifies that the process meets regulatory requirements for consistency and quality.

4. Accountability

The Capsule Manufacturing Supervisor is accountable for ensuring that the particle size reduction process is followed correctly and that the process meets the necessary standards for capsule production. The QC Manager is responsible for reviewing particle size results and approving the fill material for further processing.

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5. Procedure

5.1 Particle Size Reduction Methods

Several methods can be used for particle size reduction, depending on the characteristics of the fill material:

  1. Milling

    1. Milling is a common method for reducing particle size, typically using a ball mill, hammer mill, or jet mill. This method involves grinding the material to achieve the desired particle size distribution.
    2. Ensure that the milling equipment is calibrated and cleaned regularly to prevent contamination of the fill material.
  2. Granulation

    1. Granulation may be used to form aggregates or larger particles from powders, often by adding a liquid binder. This process is used when fine powder is not suitable for capsule filling.
    2. Granules should be sized to meet specific flowability and encapsulation requirements while ensuring uniformity in size and content.
  3. Sieving

    1. Sieving is used after milling or granulation to ensure uniform particle size by separating the desired particle size range from oversized or undersized particles.
    2. Ensure that sieves are clean and calibrated before use, and that the mesh size is appropriate for the target particle size range.
  4. Drying

    1. If the material is in a wet state post-granulation or milling, ensure that drying is carried out before further processing to achieve the desired moisture content and prevent particle agglomeration.

5.2 Preparation of Equipment

Ensure that the equipment used for particle size reduction is prepared and calibrated according to the following steps:

  1. Clean and Calibrate Equipment

    1. Inspect all equipment before use, ensuring it is clean, free from contaminants, and in good working condition.
    2. Calibrate the equipment (e.g., milling machine, sieving apparatus) to ensure that particle size reduction is achieved accurately and within the specified range.
  2. Check Material Compatibility

    1. Ensure that the equipment is compatible with the fill material being processed. For instance, some materials may require specialized equipment or settings to avoid damage or inefficiency.

5.3 Performing Particle Size Reduction

Follow these steps to perform particle size reduction on the fill materials:

  1. Set Parameters

    1. Set the milling or granulation parameters based on the target particle size range, ensuring that the speed, time, and other settings are optimized for the material.
    2. If sieving is required, select the appropriate mesh size for the desired particle size distribution.
  2. Reduce Particle Size

    1. Begin the particle size reduction process, ensuring that all steps are monitored to prevent over-processing or under-processing.
    2. If using milling, regularly check the particle size distribution to ensure that the target size range is being achieved.
  3. Monitor Process

    1. Monitor the process to ensure consistent particle size reduction, checking parameters such as temperature, pressure, and milling time.
    2. Perform intermediate checks if necessary to ensure that the material is not becoming too coarse or too fine.
  4. Sieving and Screening

    1. After milling or granulation, sieve the material to remove oversized or undersized particles. The remaining particles should be uniform in size and meet the specifications.
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5.4 Testing and Quality Control

After the particle size reduction process, the following tests should be performed:

  1. Particle Size Distribution

    1. Perform particle size analysis using appropriate techniques such as laser diffraction or sieve analysis to ensure that the reduced particles meet the required specifications.
  2. Flowability Test

    1. Test the flowability of the reduced particles, ensuring that they are suitable for capsule filling. This can be done using a flowability test such as the Hausner ratio or the angle of repose.
  3. Moisture Content Test

    1. If granulation or milling involved the use of liquids, test the moisture content of the reduced material to ensure it is within the acceptable range for capsule filling.

5.5 Documentation and Record-Keeping

Ensure proper documentation of the particle size reduction process:

  1. Process Records

    1. Document all steps taken during the particle size reduction process, including equipment settings, material properties, and any deviations from the standard process.
    2. Ensure that all records are signed by the personnel responsible for the process and reviewed by the supervisor or manager.
  2. Test Results

    1. Document the results of all quality control tests, including particle size distribution, flowability, and moisture content. Ensure that the material meets the required specifications before proceeding with capsule production.
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5.6 Adjustments Based on Testing Results

If the particle size distribution or other properties do not meet the required specifications, make the necessary adjustments:

  1. Adjust Milling Parameters

    1. If the particle size is too large or too fine, adjust the milling parameters, such as time, speed, or the mesh size used for sieving, and re-test the material.
  2. Modify Formulation

    1. If necessary, adjust the formulation (e.g., increase binder or use a different excipient) to achieve the desired particle size and flow properties.

6. Abbreviations

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

7. Documents

  1. Particle Size Reduction Process Record (Annexure-1)
  2. Flowability Test Report (Annexure-2)

8. References

  • USP <701> – Particle Size Analysis
  • FDA Guidance for Industry: Quality in Drug Product Manufacturing
  • ISO 9001:2015 – Quality Management Systems

9. SOP Version

Version: 2.0

10. Approval Section

Prepared By Checked By Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Particle Size Reduction Process Record

Date Material Equipment Used Settings Outcome
02/02/2025 API X Ball Mill Speed: 200 rpm, Time: 30 min Pass

Annexure-2: Flowability Test Report

Date Material Flowability Test Result Remarks
02/02/2025 API X Pass Flow rate: 25 g/sec

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 particle size reduction process Standardization QA Head
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