Premises, Equipment & Finishing of sterile products as per WHO TRS 961-Annex 6
It is highly recommended that all premises are designed in a way that minimizes the unnecessary entry of supervisory or control personnel. Specifically, Grade A and B areas should be constructed in a manner that allows for complete observation of all operations from the outside.
In areas that require cleanliness, all surfaces that are exposed should be smooth, impermeable, and free of any breaks or cracks. This is to ensure that there is minimal shedding or accumulation of particles or microorganisms, and to allow for the repeated application of cleaning agents and disinfectants, if necessary.
To prevent the accumulation of dust and to make cleaning easier, it is important to avoid any recesses that cannot be cleaned and to minimize the presence of ledges, shelves, cupboards, and equipment that project out. When it comes to doors, they should be designed carefully to avoid any recesses that cannot be cleaned. Sliding doors may not be ideal for this reason. Swing doors, on the other hand, should open towards the high-pressure side and should have self-closing mechanisms. However, exceptions can be made based on egress and site environmental, health, and safety containment requirements.
False ceilings should be sealed properly to prevent any contamination from the space above them.
When installing pipes, ducts, and other utilities, it is important to ensure that they do not create any recesses, unsealed openings, or surfaces that are difficult to clean. Sanitary pipes and fittings should be used, and threaded pipe connections should be avoided.
Ideally, sinks and drains should be avoided whenever possible, especially in Grade A and B areas where aseptic operations are performed. However, if they are necessary, they should be designed, located, and maintained in a way that minimizes the risk of microbial contamination. They should also be equipped with effective and easily cleanable traps, as well as air breaks to prevent backflow. If there are any floor channels, they should be open and easily cleanable, and should be connected to drains located outside the area in a manner that prevents the entry of microbial contaminants.
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Changing rooms should be designed as airlocks to ensure physical separation between different stages of changing, thereby minimizing the risk of microbial and particulate contamination on protective clothing. It is crucial to effectively flush these rooms with filtered air. The final stage of the changing room should match the same cleanliness level as the area it leads to when not in use. In some cases, it may be beneficial to have separate changing rooms for entering and exiting clean areas.
Hand-washing facilities should generally be provided only in the initial stage of the changing rooms. It is important to maintain a consistent cleanliness grade throughout the transition from airlocks or passages to changing rooms. For example, a Grade D passage should lead to a Grade C airlock, which then leads to a Grade B changing room, and finally to a Grade B clean room. Changing rooms should be spacious enough to facilitate easy changing. Additionally, mirrors should be installed in these rooms to allow personnel to verify the proper fit of garments before leaving.
Airlock doors should not be opened simultaneously. An interlocking system and a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time.
A filtered air supply should be used to maintain a positive pressure and an airflow relative to surrounding areas of a lower grade under all operational conditions, it should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of approximately 10–15 Pascal’s (guidance value). Particular attention should be paid to the protection of the zone of greatest risk, i.e. the immediate environment to which the product and the cleaned components in contact with it are exposed.
The recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain certain materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. The decontamination of the facilities and the treatment of air leaving a clean area may be necessary for some operations.
It should be demonstrated that airflow patterns do not present a contamination risk, for example, care should be taken to ensure that particles from a particle-generating person, operation or machine are not conveyed to a zone of higher product risk.
A warning system should be operated to indicate failure in the air supply. Indicators of pressure differentials should be fitted between areas where this difference is important, and the pressure differentials should be regularly recorded and failure alarmed.
Consideration should be given to restricting unnecessary access to critical filling areas, e.g. Grade A filling zones, by means of a physical barrier.
Equipment
A partition between a Grade A or B clean area and a processing area of lower air cleanliness should not have a conveyor belt passing through it, unless the belt is continuously sterilized (e.g. in a sterilizing tunnel).
Whenever possible, equipment used for processing sterile products should be selected in a way that allows effective sterilization using steam, dry heat, or other suitable methods.
To the greatest extent possible, equipment fittings and services should be designed and installed in a manner that allows operations, maintenance, and repairs to be conducted outside the clean area. If equipment needs to be disassembled for maintenance, it should be re-sterilized after complete reassembly, whenever feasible.
If equipment maintenance is performed within a clean area, clean instruments and tools should be utilized, and the area should be appropriately cleaned and disinfected before processing resumes, if the required cleanliness and asepsis standards were not maintained during the maintenance work.
All equipment, including sterilizers, air-handling and filtration systems, air vent and gas filters, water treatment, generation, storage, and distribution systems, should undergo validation and planned maintenance, and their return to use should be approved.
Water-treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Consideration should be given to including a testing programmed in the maintenance of a water system. Water for injection should be produced, stored and distributed in a manner which prevents the growth of microorganisms, e.g. by constant circulation at a temperature above 70 °C or not more than 4 °C.
Finishing of sterile products
Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules, should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures.
The container closure system for aseptically filled vials is not fully integral until the aluminum cap has been crimped into place on the stoppered vial. Crimping of the cap should, therefore, be performed as soon as possible after stopper insertion.
As the equipment used to crimp vial caps can generate large quantities of non-viable particulates, the equipment should be located at a separate station equipped with adequate air extraction.
Vial capping can be performed in two ways: as an aseptic process using sterilized caps or as a clean process outside the aseptic core. In the latter case, it is important to ensure that vials are kept under Grade A conditions until they leave the aseptic processing area. Once the vials are stoppered, they should continue to be protected by a Grade A air supply until the cap is crimped.
Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimize microbial contamination.
Restricted access barriers and isolators may be beneficial in assuring the required conditions and minimizing direct human interventions into the capping operation.
Containers sealed under vacuum should be tested for maintenance of that vacuum after an appropriate, predetermined period.
Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is carried out visually this should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eyesight checks, using personal corrective lenses (e.g. spectacles or contact lenses) as required, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded.
Reference : WHO good manufacturing practices for sterile pharmaceutical products (WHO TRS 961-Annex 6)
