Capsule: SOP for Granulation Process Optimization for Hard Capsules – V 2.0

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Capsule: SOP for Granulation Process Optimization for Hard Capsules – V 2.0

Standard Operating Procedure for Granulation Process Optimization for Hard Capsules

Department Capsule Manufacturing
SOP No. SOP/CM/071/2025
Supersedes SOP/CM/071/2022
Page No. Page 1 of 6
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 process for optimizing the granulation process in the manufacturing of hard gelatin capsules. Optimizing granulation is essential for ensuring uniformity, stability, and flow properties of the capsule fill material, which are crucial for product quality and efficiency.

2. Scope

This SOP applies to the granulation process involved in the production of hard gelatin capsules. It covers the preparation, equipment setup, granulation process, optimization techniques, and documentation required to ensure consistency and quality of the capsule formulation.

3. Responsibilities

  • Manufacturing Team: Responsible for executing the granulation process according to this SOP and ensuring that all necessary adjustments are made to optimize the process for each batch.
  • Quality Control (QC) Team: Responsible for monitoring the granulation process, taking samples, and testing the granules for quality parameters such as size distribution, moisture content, and flowability.
  • Quality Assurance (QA) Team: Ensures that the granulation process is optimized and adheres to regulatory guidelines. Reviews documentation and process optimization data.
  • Maintenance Team: Ensures that all granulation equipment is properly maintained, calibrated, and functioning as required for optimal operation.

4. Accountability

The Capsule Manufacturing Supervisor is accountable for ensuring the granulation process is properly optimized and executed. The QA Manager is responsible for ensuring that process optimizations are implemented in compliance with GMP and regulatory standards.

5. Procedure

5.1 Granulation Setup and Preparation

Before initiating the granulation process, ensure that the following preparation steps are completed:

  1. Raw Material Inspection

    1. Verify the quality and specifications of all raw materials used in the granulation process, including active pharmaceutical ingredients (APIs), excipients, and binders.
    2. Ensure that all raw materials are approved by QC and meet the required specifications.
  2. Equipment Setup

    1. Ensure that the granulation equipment (e.g., high-shear granulator, fluidized bed dryer) is clean, calibrated, and ready for use. Perform a pre-operation check of the equipment.
    2. Ensure that all auxiliary equipment (e.g., sieves, mixers, drying units) are in proper working condition and set up according to the batch requirements.
  3. Granulation Parameters

    1. Set the granulation parameters, such as mixing speed, granulation time, binder solution flow rate, and drying conditions, based on the batch specifications.
    2. Verify the settings against the batch record and adjust if necessary to achieve the desired granule characteristics.
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5.2 Granulation Process

The granulation process should be followed as outlined below:

  1. Wet Granulation

    1. Blend the dry powders (APIs and excipients) in the granulator according to the batch specifications.
    2. Add the binder solution gradually while maintaining the granulation speed. Ensure uniform distribution of the binder and prevent over-wetting, which can affect granule quality.
  2. Granule Formation

    1. Continue the granulation process until the granules have reached the desired size and moisture content. Monitor the granules regularly to ensure uniformity in size and consistency.
  3. Sieving

    1. After granulation, pass the granules through a sieve to achieve the desired particle size range. Remove any oversized or undersized granules that do not meet specifications.

5.3 Granulation Process Optimization

To optimize the granulation process for consistent granule quality and production efficiency, the following steps should be followed:

  1. Granule Size Distribution

    1. Monitor the granule size distribution during the granulation process. The granules should be uniform in size to ensure consistent fill weight in capsules.
    2. Adjust the sieving process and granulation parameters (e.g., mixing speed, binder flow rate) to achieve the desired granule size distribution.
  2. Moisture Content Control

    1. Measure the moisture content of the granules regularly during the granulation process. Granules should have a moisture content within the specified range to prevent issues with flowability and compressibility.
    2. Adjust drying parameters (e.g., temperature, air flow) if moisture content is outside the acceptable range. Ensure that the granules are dried evenly without causing degradation of the active ingredient.
  3. Flowability Optimization

    1. Ensure that the granules have the required flow properties to facilitate smooth encapsulation. Poor flowability can lead to inconsistent capsule filling and increased rejection rates.
    2. If necessary, modify the binder solution, granulation speed, or drying parameters to improve the flowability of the granules.
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5.4 Sampling and Testing

After the granulation process, samples should be taken and tested for the following quality parameters:

  1. Granule Size Distribution

    1. Sample granules and measure the particle size distribution using sieving methods or automated particle size analyzers. Compare the results with the required specifications.
  2. Moisture Content

    1. Measure the moisture content of the granules using a moisture analyzer. Ensure that the moisture content is within the specified range to prevent issues during encapsulation.
  3. Flowability

    1. Test the flowability of the granules using a flow tester. Granules should have a flow index that meets the requirements for efficient capsule filling.

5.5 Post-Granulation Processing

After the granulation process, ensure the following steps are completed:

  1. Drying

    1. Dry the granules if the moisture content exceeds the specified range. Use a fluidized bed dryer or other drying methods as per the specifications.
    2. Ensure that the drying process does not overheat the granules, as this may lead to the degradation of the active ingredient.
  2. Sieving

    1. After drying, sieve the granules again to remove any oversized particles that may have formed during the drying process.
  3. Storage

    1. Store the granules in a clean, dry, and controlled environment until they are ready for encapsulation. Ensure that the storage conditions preserve the granules’ quality and prevent contamination.

5.6 Documentation and Record-Keeping

All activities related to the granulation process should be documented as follows:

  1. Granulation Batch Record

    1. Document all granulation process parameters, including raw materials, equipment settings, granulation process details, and any adjustments made during production. Include the results of all quality tests, such as granule size, moisture content, and flowability.
  2. Deviation Report

    1. If any deviations from the standard granulation process occur, document the issue and corrective actions taken in a deviation report. Ensure that any changes to the process are justified and recorded.
  3. Maintenance Log

    1. Record any maintenance performed on granulation equipment, including calibration, repairs, and cleaning. Ensure that all equipment is functioning properly before the next production run.
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6. Abbreviations

  • SOP: Standard Operating Procedure
  • GMP: Good Manufacturing Practice
  • QC: Quality Control
  • QA: Quality Assurance
  • BPR: Batch Production Record

7. Documents

  1. Granulation Batch Record (Annexure-1)
  2. Deviation Report (Annexure-2)
  3. Granule Quality Test Results (Annexure-3)
  4. Maintenance Log (Annexure-4)

8. References

  • USP <1163> – Pharmaceutical Dosage Forms: Capsules
  • FDA Guidelines for Capsule Manufacturing
  • International Conference on Harmonization (ICH) Guidelines for Pharmaceutical Manufacturing

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 Batch Record

Batch ID Granulation Date Raw Materials Granulation Parameters Operator Name
Batch 001 01/02/2025 API, Excipients Speed: 300 rpm, Time: 30 min John Doe

Annexure-2: Deviation Report

Deviation ID Description Corrective Action Taken Operator Name
DEV-001 Moisture content exceeded specifications Adjusted drying time John Doe

Annexure-3: Granule Quality Test Results

Batch ID Granule Size (mm) Moisture Content (%) Flowability
Batch 001 0.4 – 0.6 5.2% Good

Annexure-4: Maintenance Log

Equipment ID Maintenance Date Tasks Performed Technician Name
Granulator 1 01/02/2025 Calibrated machine Jane Smith

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 optimization Standardization QA Head
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