Key Notes on Revised Schedule M: Sterile products

Last Updated on January 11, 2025 by The Health Master

Sterile products

Key considerations for Sterile products for compliance under revised Schedule M are outlined below.

Continued from: Key Notes on Revised Schedule M: Topical Products (External Preparations)

Specific requirements for Manufacture of following:

• Sterile Products,
• Parenteral Preparations (Small Volume Injectables and Large Volume Parenterals) and
• Sterile Ophthalmic Preparations.

Good Manufacturing Practices for Sterile products

This detailed breakdown provides a comprehensive overview of the requirements for pharmaceutical manufacturers to comply with the Good Manufacturing Practices for Sterile Products outlined in Revised Schedule M.

1. General Considerations

Clean Areas:

• Sterile products must be manufactured in the clean areas with access controlled airlocks.
• Maintain appropriate cleanliness standards and filtered air supply.

Area Separation:

• Separate areas within the clean area for different operations: component prep, product prep, filling, sterilization.

Manufacturing Categories:

• Terminally Sterilized: Products sterilized after filling (e.g., autoclaved).
• Aseptically Processed: Processed without terminal sterilization (e.g., sterile filtration).

2. Quality Control

Sterility Testing:

• Sterility test is the final control measure, not the sole assurance of sterility.
• Validate the sterility test for each product.
• Sample strategically, considering potential contamination risks (e.g., beginning/end of aseptic fills, coolest part of heat-sterilized loads).

Sterility Assurance:

• Terminally sterilized: Validate the sterilization cycle.
• Aseptically processed: Validate through media fills (simulated production with growth media).
• Review batch records and environmental quality records.

Endotoxin Testing:

• Monitor water for injection, intermediates, and finished products for endotoxins.

Rapid Microbiological Methods:

• Consider validated rapid methods for quicker results (water, environment, bioburden), but with comparative assessment to pharmacopoeial methods.

3. Sanitation

Clean Area Sanitation:

• Frequent and thorough cleaning with an approved written program.
• Use multiple types of disinfectants.
• Monitor for contamination and disinfectant effectiveness.
• Validate cleaning procedures to ensure disinfectant removal.

Disinfectant/Detergent Handling:

• Monitor for microbial contamination.
• Store in previously cleaned containers for defined periods.
• Sterilize disinfectants/detergents used in Grade A and B areas before use.

Sporicidal Agents:

• Include sporicidal agents in the disinfectant program.

Fumigation:

• Consider fumigation for reducing microbial contamination in hard-to-reach areas.

4. Manufacture of Sterile Preparations

Clean Area Classification:

• Classify clean areas based on the required environmental characteristics (Grades A-D).
• Use ISO standards for classification (airborne particle concentration).

HEPA Filters:

• Install HEPA filters and conduct leakage tests every 6-12 months.

Clean Room Classification:

• Classify clean rooms and clean-air devices according to ISO standards.
• Differentiate between “at rest” and “in operation” states.
• Define maximum permitted airborne particle concentrations for each grade (Table 1).

Particle Monitoring:

• Routine monitoring of clean areas while in operation.
• Grade A: Frequent monitoring during critical processing.
• Grade B: Monitoring frequency based on segregation from Grade A.
• Use appropriate monitoring systems (independent counters, networks, etc.).
• Demonstrate “clean-up” or “recovery” time after operations.
• Monitor for temperature and relative humidity.

Microbiological Monitoring:

• Monitor clean areas for microbial contamination (settle plates, air sampling, surface sampling).
• Establish alert and action limits for microbial contamination (Table 3).

Grade Selection:

• Select appropriate area grades based on the nature of the process operations and validation runs (media fills).
• Terminally sterilized products: Generally Grade D preparation, Grade C filling.
• Aseptically prepared products: Grade A with Grade B background for critical operations.

5. Processing

Minimize Contamination:

• Take precautions to minimize contamination during all processing stages.

Multi-Product Facilities:

• Justify use of multi-product facilities for live micro-organisms with effective containment and decontamination.

Media Fills:

• Validate aseptic processing through media fills.
• Simulate routine aseptic manufacturing steps.
• Conduct three consecutive successful media fills initially, then repeat at defined intervals and after significant modifications.
• Determine the number of containers for media fills based on batch size.

Water Quality:

• Monitor water sources, treatment equipment, and treated water for chemicals, biological contamination, and endotoxins.

Personnel Control:

• Minimize personnel activity in clean areas, especially during aseptic operations.
• Control personnel movement.

Component Handling:

• Handle components, bulk-product containers, and equipment carefully to avoid re-contamination.

Time Limits:

• Minimize time between washing/drying and sterilization, sterilization and use.
• Minimize time between solution preparation and sterilization/filtration.

Bioburden Monitoring:

• Monitor bioburden before sterilization.
• Set working limits for bioburden before sterilization.

Sterile Equipment Handling:

• Sterilize components, containers, and equipment.
• Pass sterilized items into clean areas through double-ended sterilizers or other validated methods.

Process Validation:

• Validate the efficacy of any new processing procedure.

6. Sterilization

Terminal Sterilization:

• Whenever possible, use terminal sterilization by heat in the final container.

Sterilization Methods:

• Acceptable methods: Moist heat, dry heat, ionizing radiation, ethylene oxide, filtration with aseptic filling.

Sterilization Validation:

• Validate all sterilization processes, especially for complex formulations.

Biological Indicators:

• Use biological indicators as an additional monitoring method.

Sterilization Records:

• Maintain detailed sterilization records for each run.

Terminal Sterilization:

• Record temperature and time accurately.
• Allow sufficient time for the entire load to reach the required temperature.
• Take precautions against contamination during cooling.
• Monitor temperature and pressure independently.
• Validate automated control and monitoring systems.

Please note: This information is for general guidance only and may not be exhaustive. Refer to the official regulations and any applicable guidance documents for specific requirements and interpretations.

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Compiled by:
Rakesh Dahiya, SDCO cum Licensing Authority, FDA Haryana

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Next: Key Notes on Revised Schedule M: Sex Hormones ….coming soon

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