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 fill materials used in capsule formulations. The objective is to achieve the desired particle size distribution to ensure uniformity in capsule filling, dissolution, and bioavailability.

2. Scope

This SOP applies to all capsule fill materials that require particle size reduction. It includes the methods, equipment, and quality checks to ensure that the particle size of the fill materials meets the specifications required for efficient capsule production.

3. Responsibilities

Formulation Development Team: Responsible for determining the required particle size range for the capsule fill materials based on formulation specifications and desired dissolution profiles.
Manufacturing Team: Responsible for carrying out the particle size reduction process using appropriate equipment and ensuring that the materials are processed in compliance with this SOP.
Quality Control (QC) Team: Responsible for testing the particle size distribution of the fill materials to ensure they meet the specified criteria.
Quality Assurance (QA) Team: Ensures that the particle size reduction process adheres to regulatory requirements and company standards, and that all documentation is accurate and complete.

4. Accountability

The Capsule Manufacturing Supervisor is accountable for ensuring that the particle size reduction process is carried out according to the specifications. The QC Manager is responsible for ensuring that the final particle size meets the required specifications.

5. Procedure

5.1 Determining the Required Particle Size

Before beginning the particle size reduction process, determine the appropriate particle size for the fill material based on the following factors:

Formulation Requirements
1. Determine the desired particle size range based on the nature of the active pharmaceutical ingredient (API) and excipients, as well as the intended dissolution profile of the capsule.
2. Generally, a smaller particle size is used for better uniformity in capsule filling and to enhance the bioavailability of poorly soluble APIs.
Equipment Compatibility
1. Ensure that the equipment used for size reduction is capable of achieving the desired particle size without overprocessing or damaging the material.
Regulatory Specifications
1. Confirm that the particle size is compliant with any relevant regulatory guidelines (e.g., USP, ICH) that may apply to the specific material or formulation.

5.2 Methods of Particle Size Reduction

There are several methods available for particle size reduction, each suitable for different types of materials and the desired particle size range:

Mechanical Milling
1. Mechanical milling is a widely used method to reduce particle size. It involves the use of grinding mills, such as ball mills or hammer mills, to reduce the material into smaller particles.
2. Adjust the milling parameters (e.g., milling time, speed, pressure) to achieve the desired particle size distribution.
Jet Milling
1. Jet milling uses high-pressure air to reduce particle size by impact. It is especially effective for materials that are heat-sensitive or require a very fine particle size.
2. This method is commonly used for APIs that need to be reduced to sub-micron sizes to improve bioavailability.
Wet Milling
1. Wet milling involves the use of a liquid medium in the milling process. It is particularly useful for materials that are difficult to mill dry or require dispersion in a liquid for better uniformity.
2. Ensure that the solvent or liquid used is compatible with the material and will not cause degradation of the API.
Ultrasonic Milling
1. Ultrasonic milling uses high-frequency sound waves to create cavitation forces that break down particles. It is suitable for fine dispersions or to reduce particle size in a controlled manner.

5.3 Particle Size Measurement

After performing the particle size reduction process, measure the particle size distribution to ensure the material meets the required specifications:

Laser Diffraction
1. Laser diffraction is a common method for measuring particle size distribution. It works by passing a laser through a sample and measuring the diffraction pattern produced by the particles.
2. Ensure that the measurement is conducted according to the manufacturer’s instructions for accurate results.
Sieving
1. Sieving is used to separate particles into size fractions based on mesh size. This method is more suitable for larger particle sizes but can be used in combination with other methods for more precise control.
Microscopy
1. Microscopy (e.g., optical or electron microscopy) can be used to directly observe the size and shape of particles, especially for very fine or irregularly shaped particles.

5.4 Evaluating the Effectiveness of Particle Size Reduction

After particle size reduction, evaluate the effectiveness of the process by examining the following:

Particle Size Distribution
1. Ensure that the particle size distribution meets the specifications set out in the formulation guidelines, with the majority of the particles falling within the desired size range.
2. Ensure uniformity in the particle size to avoid problems with capsule filling, such as incomplete filling or variation in fill weight.
Flowability
1. Test the flowability of the material using a powder flow tester or other suitable methods. Good flowability is essential for smooth filling and efficient capsule production.
Compression and Tablet Formulation (if applicable)
1. If the fill material is also used in tablet formulation, evaluate its compressibility and binding properties to ensure good tablet formation.

5.5 Documentation and Record-Keeping

Document all steps in the particle size reduction process to ensure traceability and compliance with regulatory requirements:

Process Records
1. Document the equipment used, process parameters (e.g., speed, time, pressure), and the batch number for the material being processed.
2. Ensure that all process records are signed off by the responsible personnel and stored securely for future reference.
Test Results
1. Document the results of all particle size measurements, including particle size distribution, flowability, and any deviations from the expected results.

6. Abbreviations

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

7. Documents

Particle Size Reduction Process Records (Annexure-1)
Particle Size Distribution Test Results (Annexure-2)

8. References

USP <711> – Dissolution Testing
FDA Guidelines on Capsule Fill Materials
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: Particle Size Reduction Process Records

Date	Material	Equipment Used	Process Parameters
02/02/2025	Fill Material A	Ball Mill	Speed: 200 rpm, Time: 30 min

Annexure-2: Particle Size Distribution Test Results

Date	Material	Particle Size Range	Mean Particle Size
02/02/2025	Fill Material A	50-100 µm	75 µm

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 testing procedure	Standardization	QA Head