Production of sterile products

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Production of sterile products




Study Points



image The requirements for sterile production


image Grades of clean areas


image Design and operation of clean areas


image Isolators


image Environmental monitoring


image Preparation of aseptic products



Introduction


The production of sterile medicinal products has special requirements. These products must be produced in conditions that ensure that they are pure. They must also be free from viable organisms and pyrogens with limited, or ideally no, particulate contamination. It is thus important that only carefully regulated and tested procedures are used to manufacture sterile products.


Owing to their special manufacturing requirements, sterile medicines are prepared in special facilities known as clean rooms. These rooms are designed to reduce the risk of microbial and particulate contamination at all stages of the manufacturing process.


The clean area used to produce sterile products is commonly designed as a suite of clean rooms. With this system, the operators enter the clean rooms by way of a changing room. Within this area, the operators put on clean room clothing before entering into the clean rooms. The changing room has a lower standard of environmental quality. A clean room with a lower environmental standard is also used to prepare solutions. These solutions are then sterilized by filtration before being transferred into the filling room. The clean room used to fill and seal the product containers is the highest quality of clean room. This will reduce the risk of product contamination.


Sterile products that are marketed in the European Union must be produced in conditions which conform with the conditions given in the revised Annex 1 of Good Manufacturing Practices (Volume IV) of The Rules Governing Medicinal Products in the European Union. This guidance on the procedures for manufacturing sterile products describes the cleanliness of the clean room environment and recommends how pharmaceutical clean rooms should be built and used.



Sterile product production


Production of sterile products should be carried out in a clean environment with a limit for the environmental quality of particulate and microbial contamination. This limit for contamination is necessary to reduce the risk of product contamination. In addition, however, the temperature, humidity and air pressure of the environment should be regulated to suit the clean room processes and the comfort of the operators.


Clean areas for the production of sterile products are classified into grades A, B, C and D. These grades are categorized by the particulate quality of the environmental air when the clean area is operating in both a ‘manned’ and ‘unmanned’ state. In addition, these areas are graded by the microbial monitoring of the environmental air, surfaces and operators when the area is functioning. The standards are shown in Tables 40.1 and 40.2.




There are two common procedures used to manufacture sterile products. The first method involves the preparation of products that will be terminally sterilized. The second method involves the aseptic filling of containers that are not exposed to terminal sterilization. Aseptic filling requires a higher environmental quality for the preparation of solutions and the filling of containers. The qualities of the clean rooms used for these production procedures are detailed in Tables 40.3 and 40.4.





Premises


The sterile production unit must be separated from the general manufacturing area within the hospital pharmacy or factory. This sterile production unit must not be accessible to unauthorized personnel.


The unit is designed to allow each stage of production to be segregated. It should also ensure a safe and organized workflow and reduce the need for personnel to move around the clean rooms. The unit is built and the equipment positioned to protect the product from contamination. The layout must allow efficient cleaning of the area and avoid the build up of dust. Premises are also arranged to decrease the risk of mix up or contamination of one product or material by another.


The filling room is typically serviced from an adjacent preparation room. This allows supporting personnel to assemble and prepare materials. Staff within the filling room area then use these materials. Figure 40.1 shows the layout of rooms for the production of terminally sterilized medicines such as small or large volume injections.






Services


Piped liquids and gases should be filtered before entering the clean room. This will ensure that the liquid or gas at the work position will be as clean as the clean room air. The pipes and ducts must be positioned for easy cleaning. All other fittings such as fuse boxes and switch panels should be positioned outside the clean rooms.


Sinks and drains must be excluded from areas where aseptic procedures are performed in clean room areas. They should be avoided in the whole unit wherever possible. In areas where sinks and drains are installed they must be designed, positioned and maintained to decrease the risk of microbial contamination. They are thus often fitted with easily cleanable traps. The traps may contain electrically heated devices for disinfection.


There should be a limited number of entry doors for personnel and ports for materials. Entry doors should be self-closing and allow the easy movement of personnel.


Airlock doors, wall ports, through-the-wall autoclaves and dry heat sterilizers should be fitted with interlocked doors. This will prevent both doors being opened simultaneously. An alarm system should be fitted to all the doors to prevent the opening of more than one door.


Lights in clean rooms are fitted flush with the ceiling to reduce the collection of dust and avoid disturbing the airflow pattern within the room. Similarly, equipment should be positioned in clean rooms to avoid the distribution and the collection of particles and microbial contaminants.



Environmental control


Potential sources of particles and microbial contaminants occurring within the clean room are:



Each of these possible sources can be minimized as described below.



Air supply


The air supply to a Grade A, B or C clean room must be filtered to ensure the removal of particulate and microbial contamination. This is carried out by filtering the air with high-efficiency particulate air (HEPA) filters. The HEPA filter should be positioned at the inlet to the clean room or close to it. A prefilter may be fitted upstream of the HEPA filter. This will prolong the life of the final filter. A fan is required to pump the air through the filter.


The HEPA filters use pleated fibreglass paper as the filter medium. Parallel pleats of this filter material increase the surface area of the filter and increase the airflow through the filter. This structure allows the filter to retain a compact volume. Aluminium foil is used to form spacers in the traditional type of HEPA filter. Spacers are not used in the more modern ‘mini-pleat’ type of filter design. These mini-pleat filters are now widely used. They have a shallower depth in construction than the traditional HEPA filter. Within the structure of the filter, the filter material is sealed to an aluminium frame (Fig. 40.2). At least one side of the filter is protected with a coated mild steel mesh. HEPA filters exhibit:




HEPA filters remove larger particles from the air by inertial impaction, the medium-sized particles by direct interception and the small particles by Brownian diffusion. The HEPA filters are least efficient at removing particles of about 0.3 μm. However, the efficiency of removing particles is affected by the air velocity and the filter packing. Larger and smaller particles will be removed more efficiently.


With a new HEPA filter fitted in a clean room, the air exits from the filter face at a rate of about 0.45 m/s and has a 99.997% efficiency at removing 0.3 μm particles. The pressure difference across the depth of a new filter is about 130 Pascal (Pa). At the end of the effective life of the filter the pressure drop across the filter will increase to about 490 Pa. To retain the operating efficiency of the filter, the fan forcing air through the filter must be able to maintain this pressure difference. Sensors are fitted upstream and downstream of the filters to indicate the pressure differential across the filter. An automatic alarm system should be fitted to indicate failure in the air supply or filter blockage.


The HEPA filters for clean room use must conform with the British Standard 5295 (1989) aerosol test. The filters may have faulty seals and can be damaged during delivery or installation. It is thus important that they are tested in situ before use.


The filter material possesses a uniform resistance and is constructed with a large number of parallel pleats. This results in the air downstream of the filter face flowing uniformly with a unidirectional configuration.


The number of air changes in clean rooms is affected by:



In practice 25–35 air changes per hour are common. The airflow pattern within the clean room must be carefully regulated to avoid generating particles from the clean room floor and from the operators. Various options for ventilating clean rooms may be categorized by the airflow pattern within the room. These are:




Unidirectional airflow systems


Air enters the room through a complete wall or ceiling of high-efficiency filters. This air will sweep contamination in a single direction to the exhaust system on the opposing wall or floor (Fig. 40.3). In the interests of economy, the exhaust grill may be fitted low down on the wall. The velocity of the air is about 0.3 m/s in downflow air from ceiling filters and 0.45 m/s in crossflow air. These are highly efficient airflow systems. However, one major disadvantage of these rooms for pharmaceutical use is that they are expensive to construct. They also use much more conditioned air than rooms with non-unidirectional airflow. This greatly increases their operating costs. Owing to these factors, unidirectional airflow clean rooms are seldom used for pharmaceutical purposes.




Non-unidirectional airflow systems


Air enters the clean rooms through filters and diffusers that are usually located in the ceiling. It exits through outlet ducts positioned low down on the wall or in the floor at sites remote from the air inlet (Fig. 40.4). With the use of this system, the filtered inlet air mixes with and dilutes the contaminated air within the room. As the clean room air has been previously heated and cleaned, it can be recirculated to save energy, a little fresh air being introduced with each air change cycle.



Various designs of diffuser are used with this ventilation system. These affect the air movement and the cleanliness of the rooms. The perforated plate diffuser produces a jet flow of air directly beneath it. This jet of air will carry contamination at its edges. However, it does produce high-quality air directly under the diffuser. It is thus important that production procedures are located directly below the diffuser. By contrast, the air released from the bladed diffuser will mix with the clean room air. This diffuser thus produces a reasonably constant quality of air throughout the room.



Combination systems


In many pharmaceutical clean rooms, it is common to find that the background area is ventilated by a non-unidirectional airflow system. Meanwhile, the critical areas are supplied with high-quality air from unidirectional airflow units.


The combination airflow system is often selected for pharmaceutical clean room applications as it:



Several types of unidirectional flow workstations or benches are used in this combination-type room. Various vertical unidirectional airflow systems are used in combination clean rooms. With one system, the critical area is surrounded by a plastic curtain with vertical unidirectional downflow air ‘washing’ over the manufacturing process and exiting under the plastic curtains into the general clean room area (Fig. 40.5). An alternative system is often used with the small-scale combination-type clean room in hospital pharmacies. With this system, a horizontal airflow cabinet (Fig. 40.6) is used as the workstation. With these cabinets, a fan forces air through a HEPA filter located at the rear wall of the workstation. The air that exits from the filter first washes over the critical work area before washing over the arms and upper body areas of the operator. Contamination arising from the operator is thus kept downstream of the critical procedures. Grade A environmental conditions are achieved at the critical work area. A similar workstation known as a vertical laminar airflow cabinet (Fig. 40.7) could also be used in the combination room. This cabinet passes air vertically downwards from the ceiling of the cabinet over the critical working area. It produces a Grade A environmental quality. The air exits from the front of the workstation.


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Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Production of sterile products

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