| 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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