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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.

3. 厂房与设备

3.1 带比例显示的现场平面布置图和生产区描述

如附件A所示,生产活动限制在111-128室。其他支持生产活动的辅助设施,诸如配药房、在制品(WIP)储藏区等位于107-109、117和121室。原材料和包装材料仓库分别位于W2和W7室。成品仓库位于W8-W11室。在A1-A22室内分别设有质控实验室、研发实验室、行政办公室、餐厅、以及其他工厂支持性的公用设施。

现阶段,工厂还没有涉及有关无菌制品生产的活动。

3.2. 结构性质和表面装饰

对楼层和墙壁、天花板、灯具和其他配件、门、窗框、和工作表面等的结构性质和表面装饰的详细描述。

工作场所的外部装修为铺设带金属波纹钢的瓷砖。所有内部墙壁、地板和天花板均采用硬质、无孔、不脱落材料建造。在原材料和产品需要暴露放置的所有加工室内(参见GMP所定义的洁净室),其墙壁和天花板由铝板制成,带有防静电环氧表面涂层,且内部填充有蜂窝结构铝夹层和防火材料。墙壁到地板以及墙壁到天花板的接合处都装配有半径最小为25mm的弧形饰。所有接头都使用了防真菌的密封胶并保持与周边的墙板齐平。在加工、包装和仓储区内的地板都涂有2mm的无缝环氧涂层。灯具安装在吊顶上方,通过不透明的丙烯塑胶板聚束照射。灯架的安装与天花板齐平。加工区的所有窗户均采用透明的钢化玻璃制成,并且窗框的安装都与相邻墙板的防真菌密封胶齐平。在每间加工室里都安装有涂有环氧树脂的门,门上有金属罩面漆,配有圆柱形门插销、拉手和观察孔。加工室内的所有工作表面都是由不锈钢制造。在加工区不使用木质材料。
包装和其他非生产区的墙壁、地板、门和天花板均采用硬质、无孔、不脱落材料建造。天花板为吊顶,采用防颗粒脱落的隔音板和不透明的丙烯塑胶板进行覆盖,以便隐蔽照明设备。

3.3 空气调节系统的描述,指示空气过滤的质量

空气处理系统图纸见附件B。在工作场所安装有一套HVAC(供暖通风和空调)系统,该系统包括2台空气处理装置(即AHU-1和AHU-2)及其相关部件,以便为生产区提供一个受控的环境。其控制是通过位于各个房间内的大范围温度、湿度和压力传感器来实现的。这些传感器都被连接到中央计算机控制的控制器上,并利用直接数字控制(DDC)的控制软件以及终端控制计算机进行分析。该DDC控制整个HVAC系统。

设计的温度和相对湿度分别为22?2?C和55?5%RH。通过在各个门之间采用空气稳定器的方式来维持压力梯度,以便满足在开门时保持较小的压力变化。 温度、相对湿度和房间压力如附件C所示。

设计使用AHU-1向GMP洁净室#103-105、118-123、126-128,和129的一部分(清洁过道)提供经处理的空气,而使用AHU-2向GMP洁净室#106-117、124-125,和129的一部分(清洁过道)提供经处理的空气。所有加工室(造粒、混配和压片)都被设计成相对于过道呈负压,以便将加工过程中产生的任何粉末都保持在房间之内。在内包装室和配药房内保持正压,以避免任何来自外部环境的污染。

通过安装在各个GMP洁净室天花板上的终端HEPA装置(高效微粒空气过滤器)向受控区域提供预先处理过的新鲜空气。高效微粒空气过滤器配备一个过滤效率为99.995%、能过滤0.3?m颗粒的过滤器,以便将空气清洁度保持在100,000级。压力微分开关对过滤器的状态进行监测,当超过设定值时,就会向开关发出一个“过滤器阻塞”的信号,在计算机上的指示灯就会发亮。

在加工室和内包装室内放置有独立的便携式除尘器(Plymovent-Mobile One),该除尘器装配有聚酯滤芯,过滤效率为99.99%,主要用来清除掉在加工过程中所产生的粉尘。在每个房间回风管的前面板上安装有一台一次性的非毛织品过滤器,以及一台板式可洗粗铝过滤器,以捕捉收集可能产生的任何粉尘。

非洁净室区域,诸如次级包装区、仓库、质控、餐厅和公用房间以及走道等处都提供有风机盘管装置系统。拼合式加热泵空调机组为行政办公楼提供空调服务。

3.4 处理高毒性、危险和敏感材料的特殊区域

不适用

3.5 包括卫生设施在内的工艺用水系统的简要描述,以及该系统的示意图

生产用水由净化水生产装置(参见附件D 中的示意图)生产。该装置的设计生产能力为400升/小时,所生产的水符合USP25 / BP2001标准的净化水规格。该装置由原水预处理组、双级反渗透装置、一个储槽和一个配水回路构成。为避免水在系统中停滞,该装置装配有一个“省水器”,它可以使系统在非生产时间内每隔50分钟运行5分钟。
原水的预处理工序如下:通过20?m 的滤芯进行过滤,然后再进行软化。安装有两组软水器,并完全由控制再生和生产周期的特定编程器进行管理。经软化的水通过5?m的滤芯进行过滤,然后被送到缓冲罐(break tank)。该缓冲罐装配有自动加注偏亚硫酸氢盐溶液的附属设备(氧化还原控制),以便消除微量的游离氯,以及自动加注NaOH溶液(pH控制)以便消除在水中溶解的CO2。

缓冲罐内的水被送到第一段逆向渗透装置(R.O.),然后被送进第二段逆向渗透装置(R.O.)。为便于进行控制和调整,这两个装置都装配有数字电导计以及其他附属设备,以便对水的电导率和报警设定值进行连续的控制。逆向渗透装置(R.O.)的滑板配备有清洁装置,可自动进行化学消毒。

然后,电导率小于2 ?S/cm 的净化水经喷球被送到一个带夹套的储槽。该储槽配有卫生的额定水位探头、Pt100探头以及一个用于当空气排出时的带夹套的杀菌过滤器(0.2?m疏水过滤器)。该储槽实现绝热保温,以便提供2小时85?C的热力灭菌。槽内接触水的部件全部采用不锈钢AISI 316L 制造。

配水回路装备有两台离心泵,按备用方式装配,用于净化水循环。两台泵均执行卫生标准,全部由不锈钢AISI 316L制造,被设计用来保证备用泵内水循环平稳。该回路装配有热交换器,以便保证在水回流到储槽之前保持18?C的水温,以及在卫生循环期间将水加热到85?C。该回路被设计用来向受控生产区内的五个用户点供水。按照卫生标准执行,各个用户点和所有取样点都安装有手动阀。该回路还装配有卫生流量计、电导计和Pt100探头。

在整个装置内使用的所有管道(采用环缝自动导轨焊接连接)、卡箍连接、膜板阀、和卫生泵都采用AISI 316L制造。安装有各种取样点,以便在净化工艺的各个工序上都能进行取样分析。在配水回路上安装有两个取样点,以便在水进入用户点之前以及在回流到储槽之前都能进行取样分析。

根据验证数据,现有的卫生程序包括了更换滤芯(每周更换5?m滤芯以及每月更换20?m滤芯),对逆向渗透装置(R.O)每6个月进行一次化学卫生处理,对储槽和配水回路每月进行一次热力杀菌。根据验证结果,每天有监测水的电导率,每月有监测水质(化学和微生物指标)。根据标准操作规程(SOP)的规定进行了装置的操作和监测。监测记录、卫生记录、保养和卫生进度计划均有到位,整个装置处于受控状态。

 

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