原 文
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.
譯 文
3.廠房與設備
3.1 帶比例顯示的現場平面布置圖和生產區描述
如附件A所示，生產活動限制在111-128室。其他支持生產活動的輔助設施，諸如配藥房、在制品（WIP）儲藏區等位于107-109、117和121室。原材料和包裝材料倉庫分別位于W2和W7室。成品倉庫位于W8-W11室。在A1-A22室內分別設有質控實驗室、研發實驗室、行政辦公室、餐廳、以及其他工廠支持性的公用設施。
現階段，工廠還沒有涉及有關無菌制品生產的活動。
3.2. 結構性質和表面裝飾
對樓層和墻壁、天花板、燈具和其他配件、門、窗框、和工作表面等的結構性質和表面裝飾的詳細描述。
工作場所的外部裝修為鋪設帶金屬波紋鋼的瓷磚。所有內部墻壁、地板和天花板均采用硬質、無孔、不脫落材料建造。在原材料和產品需要暴露放置的所有加工室內（參見GMP所定義的潔凈室），其墻壁和天花板由鋁板制成，帶有防靜電環氧表面涂層，且內部填充有蜂窩結構鋁夾層和防火材料。墻壁到地板以及墻壁到天花板的接合處都裝配有半徑最小為25mm的弧形飾。所有接頭都使用了防真菌的密封膠并保持與周邊的墻板齊平。在加工、包裝和倉儲區內的地板都涂有2mm的無縫環氧涂層。燈具安裝在吊頂上方，通過不透明的丙烯塑膠板聚束照射。燈架的安裝與天花板齊平。加工區的所有窗戶均采用透明的鋼化玻璃制成，并且窗框的安裝都與相鄰墻板的防真菌密封膠齊平。在每間加工室里都安裝有涂有環氧樹脂的門，門上有金屬罩面漆，配有圓柱形門插銷、拉手和觀察孔。加工室內的所有工作表面都是由不銹鋼制造。在加工區不使用木質材料。
包裝和其他非生產區的墻壁、地板、門和天花板均采用硬質、無孔、不脫落材料建造。天花板為吊頂，采用防顆粒脫落的隔音板和不透明的丙烯塑膠板進行覆蓋，以便隱蔽照明設備。
3.3 空氣調節系統的描述，指示空氣過濾的質量
空氣處理系統圖紙見附件B。在工作場所安裝有一套HVAC（供暖通風和空調）系統，該系統包括2臺空氣處理裝置（即AHU-1和AHU-2）及其相關部件，以便為生產區提供一個受控的環境。其控制是通過位于各個房間內的大范圍溫度、濕度和壓力傳感器來實現的。這些傳感器都被連接到中央計算機控制的控制器上，并利用直接數字控制（DDC）的控制軟件以及終端控制計算機進行分析。該DDC控制整個HVAC系統。
設計的溫度和相對濕度分別為22?2?C和55?5%RH。通過在各個門之間采用空氣穩定器的方式來維持壓力梯度，以便滿足在開門時保持較小的壓力變化。 溫度、相對濕度和房間壓力如附件C所示。
設計使用AHU-1向GMP潔凈室#103-105、118-123、126-128，和129的一部分（清潔過道）提供經處理的空氣，而使用AHU-2向GMP潔凈室#106-117、124-125，和129的一部分（清潔過道）提供經處理的空氣。所有加工室（造粒、混配和壓片）都被設計成相對于過道呈負壓，以便將加工過程中產生的任何粉末都保持在房間之內。在內包裝室和配藥房內保持正壓，以避免任何來自外部環境的污染。
通過安裝在各個GMP潔凈室天花板上的終端HEPA裝置（高效微�？諝膺^濾器）向受控區域提供預先處理過的新鮮空氣。高效微�？諝膺^濾器配備一個過濾效率為99.995%、能過濾0.3?m顆粒的過濾器，以便將空氣清潔度保持在100,000級。壓力微分開關對過濾器的狀態進行監測，當超過設定值時，就會向開關發出一個“過濾器阻塞”的信號，在計算機上的指示燈就會發亮。
在加工室和內包裝室內放置有獨立的便攜式除塵器（Plymovent-Mobile One），該除塵器裝配有聚酯濾芯，過濾效率為99.99%，主要用來清除掉在加工過程中所產生的粉塵。在每個房間回風管的前面板上安裝有一臺一次性的非毛織品過濾器，以及一臺板式可洗粗鋁過濾器，以捕捉收集可能產生的任何粉塵。
非潔凈室區域，諸如次級包裝區、倉庫、質控、餐廳和公用房間以及走道等處都提供有風機盤管裝置系統。拼合式加熱泵空調機組為行政辦公樓提供空調服務。
3.4 處理高毒性、危險和敏感材料的特殊區域
不適用
3.5 包括衛生設施在內的工藝用水系統的簡要描述，以及該系統的示意圖
生產用水由凈化水生產裝置（參見附件D 中的示意圖）生產。該裝置的設計生產能力為400升/小時，所生產的水符合USP25 / BP2001標準的凈化水規格。該裝置由原水預處理組、雙級反滲透裝置、一個儲槽和一個配水回路構成。為避免水在系統中停滯，該裝置裝配有一個“省水器”，它可以使系統在非生產時間內每隔50分鐘運行5分鐘。
原水的預處理工序如下：通過20?m 的濾芯進行過濾，然后再進行軟化。安裝有兩組軟水器，并完全由控制再生和生產周期的特定編程器進行管理。經軟化的水通過5?m的濾芯進行過濾，然后被送到緩沖罐（break tank）。該緩沖罐裝配有自動加注偏亞硫酸氫鹽溶液的附屬設備（氧化還原控制），以便消除微量的游離氯，以及自動加注NaOH溶液（pH控制）以便消除在水中溶解的CO2。
緩沖罐內的水被送到第一段逆向滲透裝置（R.O.），然后被送進第二段逆向滲透裝置（R.O.）。為便于進行控制和調整，這兩個裝置都裝配有數字電導計以及其他附屬設備，以便對水的電導率和報警設定值進行連續的控制。逆向滲透裝置（R.O.）的滑板配備有清潔裝置，可自動進行化學消毒。
然后，電導率小于2 ?S/cm 的凈化水經噴球被送到一個帶夾套的儲槽。該儲槽配有衛生的額定水位探頭、Pt100探頭以及一個用于當空氣排出時的帶夾套的殺菌過濾器（0.2?m疏水過濾器）。該儲槽實現絕熱保溫，以便提供2小時85?C的熱力滅菌。槽內接觸水的部件全部采用不銹鋼AISI 316L 制造。
配水回路裝備有兩臺離心泵，按備用方式裝配，用于凈化水循環。兩臺泵均執行衛生標準，全部由不銹鋼AISI 316L制造，被設計用來保證備用泵內水循環平穩。該回路裝配有熱交換器，以便保證在水回流到儲槽之前保持18?C的水溫，以及在衛生循環期間將水加熱到85?C。該回路被設計用來向受控生產區內的五個用戶點供水。按照衛生標準執行，各個用戶點和所有取樣點都安裝有手動閥。該回路還裝配有衛生流量計、電導計和Pt100探頭。
在整個裝置內使用的所有管道（采用環縫自動導軌焊接連接）、卡箍連接、膜板閥、和衛生泵都采用AISI 316L制造。安裝有各種取樣點，以便在凈化工藝的各個工序上都能進行取樣分析。在配水回路上安裝有兩個取樣點，以便在水進入用戶點之前以及在回流到儲槽之前都能進行取樣分析。
根據驗證數據，現有的衛生程序包括了更換濾芯（每周更換5?m濾芯以及每月更換20?m濾芯），對逆向滲透裝置（R.O）每6個月進行一次化學衛生處理，對儲槽和配水回路每月進行一次熱力殺菌。根據驗證結果，每天有監測水的電導率，每月有監測水質（化學和微生物指標）。根據標準操作規程（SOP）的規定進行了裝置的操作和監測。監測記錄、衛生記錄、保養和衛生進度計劃均有到位，整個裝置處于受控狀態。
