Good Manufacturing Practices (GMP) for Metered-Dose Inhalers (MDI) – Detailed Guidelines

Introduction

Metered-Dose Inhalers: In the pharmaceutical industry, manufacturing practices are of utmost importance to ensure the safety, efficacy, and quality of the products produced. One such product is the Metered-Dose Inhaler (MDI), which is used for delivering a specific amount of medication to the lungs in the form of a mist or aerosol. Ensuring the integrity of MDIs requires adherence to stringent Good Manufacturing Practices (GMP). These GMP guidelines, outlined in Schedule M, Part 6, are designed to prevent contamination, ensure uniformity, and maintain the highest possible standards throughout the manufacturing process.

This detailed guide will explore the specific requirements and best practices involved in the manufacturing of Metered-Dose Inhalers (MDIs), with a particular focus on the infrastructure, cleanliness, personnel, equipment, and documentation required.

General GMP Requirements for MDIs: Metered-Dose Inhalers

The manufacturing of MDIs must be performed under strict conditions that minimize microbial and particulate contamination. This is critical because any contamination can significantly affect the safety and performance of the inhaler. The primary objective is to maintain the quality of both the components and the bulk product. Where the medication is in a suspended form, such as in liquid-based formulations, uniformity must be consistently established to ensure that each dose delivers the proper medication.

In addition to the general GMP guidelines applicable to all pharmaceutical products, the manufacture of MDIs includes certain specific requirements due to the unique nature of these products.

Building and Civil Work for MDI Manufacturing

The building structure where MDIs are produced plays a crucial role in maintaining the required GMP standards. The physical integrity of the building and the design of its components are critical for preventing contamination and ensuring a controlled environment for manufacturing.

1. Foundation and Structural Integrity: The building must be located on a solid foundation to reduce the risk of cracks and other structural issues caused by equipment and machinery movements. Any movement or vibration can lead to the deterioration of the facility’s integrity, compromising its cleanliness and safety.
2. Surfaces and Flooring: All surfaces within the manufacturing area, including walls and floors, should be impervious, smooth, and non-shedding. This is important for preventing contamination from dirt and particles. Additionally, the flooring should be continuous and equipped with a cove between the floor and the walls, as well as between the wall and ceiling, to prevent the accumulation of dust and contaminants.
3. Ceiling and Service Lines: The ceiling of the manufacturing area should be solid and continuous, with all light fixtures and air grills flush with the ceiling. This design reduces the likelihood of particles falling into the workspace. Service lines, such as plumbing and electrical lines, must be installed so that they are accessible for maintenance from outside the production area, thereby reducing contamination risks.
4. Segregated Areas: The manufacturing area should be divided into distinct sections, each dedicated to specific tasks. These areas include:
   • Change Rooms: Separate areas where personnel can change into the appropriate clothing.
   • Container Preparation Area: For preparing containers for the bulk formulation.
   • Bulk Preparation and Filling Area: Where the bulk product is prepared and filled into the inhalers.
   • Quarantine Area: For storing products that are awaiting testing or approval.
   • Spray Testing and Packing Areas: Where testing and final packing of the inhalers occur.
5. Separate De-cartoning Area: Components such as containers and valves should be de-cartoned in a designated area, and these components should be air-washed to remove any contaminants before use.
6. Filtration of Propellants: The propellants used in the MDIs must be filtered through 2µ filters before being introduced into the manufacturing process. Propellant bulk containers should be stored separately from the rest of the production facility, clearly identified and controlled to avoid contamination.

Environmental Conditions

Creating a controlled environment is paramount in the manufacturing of MDIs to ensure the safety and stability of the products.

1. Filtered Air: Areas where products or clean components are exposed should be supplied with filtered air, graded at least to Grade C according to international standards.
2. Temperature and Humidity Control: The temperature and humidity in the manufacturing area must be regulated based on the type of product and the propellants used. The conditions must be monitored daily to maintain consistency. The support areas, such as offices or storage rooms, should maintain comfortable temperature and humidity levels.
3. Room Pressure Differential: There must be a differential in pressure between the manufacturing area and surrounding support areas. This ensures that air does not flow from less controlled environments into the critical manufacturing spaces. The difference should be no less than 15 Pascals (0.06 inches or 1.5mm water gauge).
4. Environmental Monitoring Schedule: A written schedule should be in place to regularly monitor and record environmental conditions, particularly temperature and humidity.

Personnel and Garments

Personnel working in the MDI manufacturing and filling sections must wear appropriate clothing to minimize the risk of contamination.

1. Garments: Workers should wear single-piece garments made from non-shedding, tightly woven materials. These garments must be worn at all times within the manufacturing area. Personnel in support areas should wear clean factory uniforms to prevent contamination of the clean spaces.
2. Gloves: Operators working in the manufacturing and filling sections must wear gloves made from materials that do not react with the propellants used in the inhalers. Preferably, these gloves should be disposable to minimize contamination.
3. Protective Equipment: Other necessary personal protective equipment (PPE), such as footwear and safety glasses, should be provided to workers, particularly where potential hazards exist.

Sanitation Procedures

Proper sanitation is crucial to maintaining a contamination-free environment during the manufacture of MDIs.

1. Sanitation Procedures: There should be documented procedures for cleaning and sanitizing the MDI manufacturing facility. Special care must be taken when handling residues and rinses from the propellants, which may pose specific contamination risks.
2. Control of Water Use: Water should be used sparingly and controlled during cleaning procedures to prevent moisture-related contamination. Routine disinfectants can be used to sanitize various areas in the manufacturing facility.
3. Sanitation Records: A record of all sanitation activities should be maintained for compliance and future reference.

Equipment and Calibration

The equipment used in the MDI manufacturing process must be capable of maintaining GMP standards and ensuring product quality.

1. Closed-System Equipment: Manufacturing equipment should be designed as a closed system to prevent contamination during production. All vessels and supply lines should be made from stainless steel to ensure they are durable and easy to clean.
2. Check Weights and Testing Equipment: Equipment such as check weights, spray testing machines, and labeling machines should be provided in the department to ensure that each batch meets the required standards.
3. Calibration and Validation: All equipment must undergo regular calibration and validation processes. This ensures that the equipment remains accurate and reliable throughout its use. Performance should be validated upon receipt and periodically thereafter.

Manufacturing Process

The manufacturing of Metered-Dose Inhalers must follow strict procedures to ensure product quality.

1. Master Formula Records: A Master Formula Record (MFR) must be approved for the manufacture of each MDI product. This record includes all necessary details on the composition and manufacturing process.
2. Filtering of Propellants and Liquids: All propellants, liquids, and gases used in the production process must be filtered through 2µ filters to remove any particles that could potentially contaminate the product.
3. Air Cleaning of Primary Packaging: The primary packaging materials, such as cans and valves, must be thoroughly cleaned using compressed air, which is filtered through a 0.2µ filter. The humidity of the compressed air should also be controlled.
4. Handling of Valves and Components: Valves should be handled with care to prevent contamination. After de-cartoning, they must be kept in clean, closed containers within the filling room.
5. Suspension Handling: In cases where the MDI contains a suspended medication, the bulk formulation should be continuously stirred to maintain uniformity throughout the filling process.
6. In-Process Controls: Throughout the manufacturing process, in-process controls should be performed. These include periodic checks of the weight of the bulk formulation filled into containers, and in the case of a two-shot filling process (liquid filling followed by gaseous filling), 100% checks should be conducted to ensure proper weight.
7. Quarantine of Filled Containers: After filling, the containers must be quarantined for a designated period. This is done to ensure that any leaking containers can be identified and removed before testing, labeling, and packaging.

Documentation and Records

Maintaining proper documentation is essential for compliance and quality assurance.

1. Environmental Conditions Records: Documentation should include records of the temperature and humidity in the manufacturing area, as well as periodic filled weights of the formulation.
2. Rejection Records: Detailed records should be kept for any rejections that occur during the online check weighing or spray testing processes. These records should be reviewed to identify and correct any potential issues in the manufacturing process.
3. General GMP Documentation: Alongside routine GMP documentation, additional information specific to MDI manufacturing should be recorded, ensuring complete traceability and compliance with regulatory standards.

Conclusion

The manufacture of Metered-Dose Inhalers (MDIs) is a complex process that requires strict adherence to Good Manufacturing Practices (GMP). By following these detailed guidelines—covering building design, environmental conditions, personnel requirements, sanitation, equipment, and documentation—manufacturers can ensure that their MDIs are of the highest quality, free from contamination, and suitable for safe and effective use. Proper documentation, rigorous testing, and a carefully controlled manufacturing environment are essential components of a compliant and successful MDI manufacturing operation