| 3. Premises and Equipment
3.1 Site plan and description of manufacturing areas with indication of scale
As shown in Attachment A, manufacturing activities are confined in Rooms 111-128. Other complimentary facilities to support the manufacturing activities such as dispensing room, Work-In-Process (WIP) storage areas are located in room 107-109, 117 and 121. Raw materials and Packaging materials warehouses are located in rooms W2 and W7, respectively. Finished Goods Warehouses are located in rooms W8-W11. Located in Room A1-A22 are QC laboratory, R & D Lab, Admin offices, Canteen, and other rooms for plant support utilities.
There is no activity relating to sterile product production in this facility at the present time.
3.2. Nature of construction and finishes
Detailed description of the nature of construction and finishes of floors and walls, ceilings, lights and other fittings, doors, windows, window frame, work surfaces etc.
The exterior finish of the premises is ceramic tiles covered brick with metal corrugated steel. All interior walls, floors and ceiling are constructed with hard, nonporous, non-shedding materials. In all processing rooms (referred to as GMP cleanrooms) where raw materials and products are exposed, walls and ceilings are made of aluminum sheet with anti-static epoxy surface finishes and in-filled with aluminum honeycomb and fire retardant materials. Wall to floor, wall to ceiling junctions are fitted with a minimum radius of 25mm profits (coving). All joints are fitted with anti-fungus sealant and flushed with the surrounding panel. Floorings in processing, packaging and warehouses are coated with 2mm seamless epoxy coating. Lights are installed above the suspended ceiling beaming through the opaque acrylic panels. Light frames are flush mounted to ceiling. All windows in the processing areas are made of clear, tempered glass and the window frames are flush mounted by anti-fungus sealant to the adjacent wall panel. Epoxy painted doors with metal steel finishes, complete with cylinder latch, pull handle and viewing window, are installed in each processing room. All work surfaces in processing rooms are made of stainless steel. No wooden materials are used in the processing area.
Walls, floors, windows, doors and ceiling of packaging and other non-production areas are constructed with hard, nonporous, non-shedding materials. Ceilings are suspended and covered with non-particle shedding acoustical tiles and opaque acrylic panels to conceal the lighting.
3.3 A description of the air control system, indicating the quality of air filtration.
Drawing of air handling system is attached in Attachment B. Installed in the premises is an HVAC System consisting of 2 units of Air Handling Units (namely AHU-1 and AHU-2) and its associated components, to provide a controlled environment to the production area. Its control is functioned by a wide range of temperature and humidity and pressure sensors located in each room. These sensors are connected to the central computerized controllers, and interpreted with Direct Digital Control (DDC) control software and a terminal control computer. The DDC controls the entire HVAC system.
The designed temperature and relative humidity are 22 ? 2?C and 55?5%RH. Pressure gradient is maintained by means of air stabilizers among the rooms to cater for the minor change in pressure during the opening of the door. Temperature, relative humidity, and room pressurization are shown in Attachment C.
AHU-1 is designed to supply treated air to GMP cleanrooms #103-105, 118-123, 126-128 and part of 129 (cleaned corridor), while AHU-2 is designed to supply treated air to GMP cleanrooms #106-117, 124-125 and part of 129 (cleaned corridor). All processing rooms (granulation, blending and tabletting) are designed with negative pressure with respect to the corridor, in order to contain within the room any powders generated during processing. Positive pressure is created in primary packaging rooms and dispensing room to avoid any contamination from the external environment.
Pre-treated fresh air is supplied to controlled areas via a terminal HEPA unit mounted on the ceiling of each GMP cleanroom. The HEPA filter has a filter has an efficiency of 99.995% for 0.3?m particle to maintain the air cleanliness at Class 100,000. Pressure differential switch monitors the status of the filter, when the set point is exceeded, a signal will be given to switch on “filter clogged” indicating lamp on the computer.
An independent portable deduster (Plymovent-Mobile One) equipped with polyester filter cartridge with 99.99% efficiency, is placed in processing rooms and primary packaging rooms, to vacuum the dusts that are generated in the course of processing. A disposable non-woolen filter, and a panel type washable coarse aluminum filter are installed in the front panel of return air duct of each room, to trap powder generated, if any.
Non-cleanroom areas such as secondary packaging area, warehouses, QC, canteen and utility rooms, and corridors are served by fan coil unit system. Split type heat pump air conditioning units served the administrative offices.
3.4 Special areas for handling of highly toxic, hazardous and sensitizing materials
Not applicable
3.5 Brief description of the process water system including sanitation, schematic drawings of the system
Water for use in production is generated from a Purified Water Production Plant (see Attachment D for schematic drawing). The plant is designed to produce 400L/hr and the water produced complies with Purified Water Specification of USP25 / BP2001 monograph. The plant consists of a raw water pretreatment group, a double stages reverse osmosis, a storage tank and a distribution loop. To avoid water stagnation on the system, the plant is equipped with an “economizer” that allows the system to run for 5 minutes for each 50 minutes of non-production time.
Raw water is pre-treated as follows: filtration through 20?m filter cartridge, followed by softening. Two units of water softeners are installed and are completely managed by a specific programmer that controls the regeneration and production cycle. The softened water is then filtered through 5?m filter cartridge and then sent to the break tank. The break tank is equipped with accessories for automatic dosing of metabisulfite solution (Redox control) to eliminate traces of free chlorine, and for automatic dosing of NaOH solution (pH control) to eliminate the dissolved CO2 in the water.
The water in the break tank is then sent to the 1st stage Reverse Osmosis (R.O.) unit and then fed into the 2nd stage Reverse Osmosis (R.O.) unit. For control and adjustment, both units are equipped digital conductivity meter and other accessories for continuous control of water conductivity and alarm set points. The R.O. skid is equipped with a cleaning service for automatic chemical sanitation.
Purified water with a conductivity of less than 2 ?S/cm is then sent to a jacketed storage tank via spray balls. The storage tank is equipped with sanitary capacity level probe, Pt100 probe and with a jacketed sterilizing filter for the air vent (0.2?m hydrophobic filter). A thermal insulation is executed in the tank to afford thermal sterilization at 85?C for 2 hours. Water contact parts inside the tank are all in stainless steel AISI 316L execution.
The distribution loop is equipped with two centrifugal pumps assembled in stand-by system, for purified water circulation. Both pumps are in sanitary execution, fully made in stainless steel AISI 316L, and designed to guarantee water circulation even in the stand-by pump. The loop is equipped with a heat exchanger to keep the water at 18?C before returning to the storage tank and to heat the water to 85?C during sanitation cycle. The loop is designed to supply five user points inside the controlled production areas. Manual valves, in sanitary execution, are installed in each user points and all sampling points. The loop is equipped with flow sanitary meter, conductivity meter and Pt100 probe.
All piping (connected with orbital welding), clamp connections, diaphragm valves, sanitary pumps used in the whole plant is in AISI 316L. Various sampling points are installed to enable sampling at every step of the purification process. Two sampling points are installed in the distribution loop to enable sampling of the water before going user points and before going back to the storage tank.
Based on the validation data, the sanitation program that is in-place includes replacement of filter cartridge (5 ?m weekly and 20?m monthly), chemical sanitation of the R.O. Plant every 6 months, and thermal sterilization of the storage tank and distribution loop every month. Daily monitoring of water conductivity and monthly monitoring of water quality (chemical and microbiological) is in-place, based on validation results. Operation and monitoring of the plant are done in accordance with SOPs. Monitoring logs, Sanitation logs, Preventive Maintenance and Sanitation Schedule are currently in-place to maintain the plant in control.
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