Good Manufacturing Practices for Sterile Products, Parenteral Preparations (Small Volume Injectables and Large Volume Parenterals) and Sterile Ophthalmic Preparations

Sterile Products: The manufacture of sterile products, parenteral preparations, and sterile ophthalmic preparations requires adherence to stringent standards. As outlined in Schedule M – GMP Part 1, which covers premises and materials for pharmaceutical products, these general requirements must be complied with when manufacturing sterile products and parenteral preparations. The manufacture of sterile items such as small volume injectables, large volume parenterals, and sterile ophthalmic preparations demands an elevated level of attention to detail and precaution due to their sensitive nature. This document provides specific guidelines and requirements for the manufacture of these products.

General Considerations for Sterile Products

Sterile products, being critical to patient health, require a heightened level of precaution and care. It is essential to maintain a sterile, clean, and controlled environment to prevent contamination. Strict adherence to the recommended standards is crucial, particularly regarding the supply of water, air, active materials, and overall hygienic conditions. Ensuring aseptic conditions is paramount, and environments should avoid dampness, dirt, and darkness to maintain these standards.

Building and Civil Works

The foundation of the manufacturing building is critical to maintaining the integrity of sterile environments. The building should be constructed with standardized materials to avoid cracks and prevent contamination, particularly in areas that handle aseptic solutions, filling, and sealing processes.

• Foundation and Materials: The building must be constructed on a solid foundation, with materials that prevent the formation of cracks. Critical areas, such as aseptic solution preparation rooms, filling rooms, and sealing rooms, should be free of imperfections to avoid contamination risks.
• Service Location: Service systems such as water, steam, and gases should be positioned in such a way that any repair or servicing does not compromise the integrity of the sterile facility. Water lines should be located away from aseptic areas to avoid leakage into these critical spaces.
• Separation of Manufacturing Areas: The manufacturing facility should be divided into support, preparation, change, and aseptic areas. These should be clearly segregated to prevent cross-contamination. For instance, the removal of outer packaging from primary packaging materials should occur in de-cartoning areas, which should be isolated from the washing areas to ensure that no contamination occurs.
• Materials and Cleanliness in Aseptic Areas: Aseptic areas should be constructed with walls, floors, and ceilings that are impervious, non-shedding, non-flaking, and non-cracking. Flooring should be continuous, with coves at the junctions between walls and floors and between walls and ceilings to prevent contaminants from accumulating. Wooden pallets, cardboard, and other materials that shed particles should be excluded from aseptic areas.
• Design of Doors and Windows: Doors to aseptic areas should be made of non-shedding materials like aluminum or stainless steel. Wooden doors should be avoided, and doors must open towards the higher-pressure area to ensure they close automatically due to air pressure. Windows should be flush with the walls and made of materials similar to the doors.
• Furniture: Furniture in aseptic areas should be smooth, non-shedding, and made of materials such as stainless steel to ensure that they do not contribute to contamination.
• Change Rooms and Air-Locks: Change rooms must be located before entry into sterile areas, serving as an air-lock between different cleanliness zones. These rooms should be clearly marked according to cleanliness levels (black, grey, white) to prevent contamination. Additionally, air-locks and interlocking door systems should be used to prevent more than one door from opening at a time.

Air Handling System (Central Air Conditioning)

Maintaining clean air quality is critical in sterile product manufacturing, and the air handling system plays a crucial role in this. Different areas of the manufacturing process require different air grades to maintain the required level of cleanliness.

• Air Handling Units: Air handling units for sterile product areas should be separate from other areas. Critical areas like aseptic filling, sterilized component unloading, and change rooms need individual air handling systems to maintain appropriate air quality.
• Air Quality Standards: Areas that handle aseptic products should meet Grade A conditions under normal operating conditions. For terminally sterilized products, Grade C conditions may suffice. For example, the filling area should meet Grade A conditions when the room is not in use, but Grade B conditions are needed during filling.
• Airflow and HEPA Filters: To maintain appropriate cleanliness levels, the air handling systems should incorporate HEPA filters. The air flow rate in laminar flow workstations should be approximately 0.3 meters per second for vertical air flows and 0.45 meters per second for horizontal air flows.
• Pressure Differentials: To prevent cross-contamination, pressure differentials between areas of different cleanliness levels should be maintained at a minimum of 15 Pascals (0.06 inches or 1.5 mm water gauge). This ensures that air flows from areas of higher cleanliness to lower cleanliness, preventing contamination.
• Temperature and Humidity Control: Temperature and humidity levels in aseptic areas should be carefully controlled. The temperature should not exceed 27°C, and relative humidity should remain below 55% to maintain the desired environmental conditions.

Airborne Particulate Classification

The airborne particulate levels in sterile areas should adhere to specified limits to ensure the absence of contamination. The table below provides the maximum number of allowed airborne particles per cubic meter, categorized by the grade of air in operation and at rest.

Types of Operations in Different Grades

Aseptic Preparations: The following table outlines the types of operations that should be carried out in various grades of sterile environments:

Terminally Sterilized Products: The following table outlines the types of operations for terminally sterilized products:

Environmental Monitoring

To ensure that sterile environments remain within the required standards, continuous monitoring is necessary. Monitoring procedures must be defined and periodically evaluated to ensure compliance.

• Monitoring Parameters: Key parameters such as temperature, humidity, air pressure, air change rates, and particulate count must be continuously measured. Additionally, microbiological monitoring via settle plates and swabs should be carried out daily in aseptic areas.
• Frequency of Monitoring: The following table presents recommended frequencies for monitoring different environmental parameters:

Garments and Personnel Protection

Garments used by personnel in aseptic areas must meet stringent requirements to prevent contamination:

• Material: Garments should be made of non-shedding, tightly woven material that does not release fibers or particulate matter. Cotton is not suitable for use in sterile environments.
• Design and Fit: Garments should be designed to cover the entire body, with no pockets, pleats, or belts. Zippers should be made of plastic, and damaged garments should not be used.
• Changing Procedures: Personnel must change garments before entering aseptic areas, and garments should be sterilized and cleaned after each work session. Gloves, masks, and other protective gear should be changed at the start of every shift.

Sanitation

Proper sanitation procedures must be in place to maintain the cleanliness of sterile processing areas:

• Disinfection and Sanitizing: Different sanitizing agents should be rotated, and the concentration of agents should follow the manufacturer’s guidelines. Disinfectants should be diluted with freshly collected distilled water to maintain their effectiveness.
• Sanitizing Agents: When using alcohol or isopropyl alcohol for disinfection, these should be prepared in the appropriate areas, and the diluted solutions should be filtered and stored in sterile containers.

Equipment

Sterile product manufacturing requires specialized equipment, including washing machines, sterilizers, filling machines, and more. The design, installation, and maintenance of this equipment must adhere to stringent standards to ensure the integrity of the manufacturing process.

• Sterilizers and Filling Machines: All sterilization equipment, including autoclaves and dry heat sterilizers, should be validated through biological inactivation studies and regular thermal mapping.
• Validation and Calibration: All critical equipment, such as filling machines and sterilizers, must undergo regular validation and calibration to ensure their proper functioning and compliance with GMP standards.

Water and Steam Systems:

• Potable Water: Must meet microbiological standards with no more than 500 cfu/ml and absence of pathogens like Escherichia coli, Salmonella, Staphylococcus aureus, and Pseudomonas aeruginosa.
• Purified Water: Prepared by de-mineralization, must meet microbiological criteria (≤100 cfu/ml) and IP specifications for chemical quality. Used for hand washing, container washing, and machine parts.
• Water for Injection (WFI): Made by distilling potable or purified water, it must meet microbiological standards (≤10 cfu/100 ml) and endotoxin levels of ≤0.25 EU/ml. Stored in stainless steel or steam-jacketed stainless steel tanks with bacterial filters.
• Steam: Must be sterile and pyrogen-free when in contact with the product. The steam condensate must meet the WFI microbiological and endotoxin specifications.

Manufacturing Process:

• Sterile Products Manufacturing: Requires defined conditions. The bio-burden of raw materials and bulk solutions must be monitored. The time between preparation and sterilization or filtration should be minimized.
• Filling Process: Products should be filled in continuous operations. If more than one operation is used, sterility tests must be conducted for each batch. Special care is needed when filling powders to avoid contamination.
• Form-Fill-Seal Technology: Machines must be installed in at least Grade C environments. The filling zone should meet Grade A requirements.
• Sterilization:
  • Autoclaving: Sterilization processes must be validated, and bio-burden monitoring should be carried out regularly.
  • Dry Heat: Temperature/time charts should be used for validation, and precautions should be taken to prevent contamination during cooling.
  • Moist Heat: Steam quality must be controlled, and leak tests should be performed during the vacuum phase of the sterilization cycle.

Product Containers and Closures:

• Containers and Closures: All packaging materials must comply with pharmacopeial standards. Glass bottles should be validated for particulate matter and only USP Type-I or Type-II glass should be used. No second-hand containers or closures should be reused.
• Plastic Containers: Pre-formed containers for large volume parenterals should be molded in-house through an automatic machine. Operations should be conducted in controlled clean room environments.
• Rubber Stoppers: Must meet specifications and be tested for quality.

Documentation:

• Manufacturing records must include detailed information on batch numbers, ingredients, sterilization details, inspection records, and operator information.
• Detailed records should include test results for sterility, pyrogens, bacterial endotoxins, and weight/volume of drug-filled containers.
• Records of environmental monitoring, periodic maintenance, and validation activities should be maintained.

Sterility Assurance and Testing:

• Integrity Testing: Membrane filters used for sterilization must be integrity-tested.
• Visual Inspection: All filled containers of parenteral and ophthalmic products must be inspected for contamination under controlled lighting.

Key Recommendations for Compliance:

• Ensure a clear microbiological monitoring program for different water systems.
• Maintain written procedures for water and steam system sanitation.
• Use appropriate sterilization techniques, and regularly validate and document them.
• Follow strict documentation protocols for batch manufacturing, sterilization, and inspection processes.
• Adhere to the specified cleanroom requirements for the production and filling of sterile products.