原則（PRINCIPLE）
為監測優良製造規範原則之實施與遵 守，應執行自我查核，並就必要的矯正 措施提出建議。
Self inspections should be conducted in order to monitor the implementation and compliance wit(with) Good
Manufacturing Practice principles and to propose necessary corrective measures.
9.1 人事、廠房、設施、設備、文件、生產、
品質管制、藥品的運銷、有關申訴與回 收的安排，以及自我查核，皆應依預先 安排之計畫的間隔時間進行檢查，以便 證實其符合品質保證的原則。
9.1 Personnel matters, premises, equipment, documentation, production, quality control, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self
inspection, should be examined at intervals following a pre-arranged programme in order to verify their conformity with the principles of Quality Assurance.
9.2 自我查核應由公司指定能勝任的人員，
以獨立且詳細的方式執行。外部專家的 獨立稽核可能也是有用的。
9.2 Self inspections should be conducted in an independent and detailed way by designated competent person(s) from the company. Independent audits by external experts may also be useful.
9.3 所有自我查核應予記錄。報告應包含在 檢查期間所執行之所有觀察，合適時，
並含矯正措施的建議。後續採取之行動 的說明亦應予記錄。
9.3 All self inspections should be recorded.
Reports should contain all the
observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken should also be recorded.
附則 1 無菌藥品的製造( MANUFACTURE OF STERILE MEDICINAL PRODUCTS)
* 本附則中關於小瓶之上蓋規定條款於 2010 年 3 月 1 日生效。
*Provisions on capping of vials in this Annex will enter into force on 1 March 2010 only.
原則
（PRINCIPLE）
為使微生物學上之污染，與微粒及熱原污
The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological
contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of
preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.
註：本附則並未規定關於測定空氣、表面 等之微生物及微粒的潔淨度之詳細 方法。請參考其他的規範，例如 EN/ISO 標準。
Note: This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces, etc.
Reference should be made to other documents such as the EN/ISO Standards.
1. The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.
2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories;
firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.
3. 無菌產品之製造，其潔淨區是依要求的環 境特徵分級。為使處理中之產品或原物料 的微粒或微生物污染之風險降到最低，每 一製造作業在操作狀態中，均須有適當的 環境潔淨度等級。
3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment.
Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial
contamination of the product or materials being handled.
為符合「動態」的條件，這些區域應經設
In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the
“at rest” occupancy state. The “at rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.
對於每間潔淨室或每套潔淨室，皆應界定 其「動態」及「靜態」 的狀態。
The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.
無菌藥品的製造區分成四個等級。 For the manufacture of sterile medicinal products 4 grades can be distinguished.
A 級：
高風險作業的局部區域，例如，充填區、
橡皮塞貯盆、開口安瓿、小瓶及執行無 菌連接等區域。通常，此種環境由層流 工作站提供。在開放潔淨室應用（open clean room application）的作業位置，層 流空氣系統應提供每秒 0.36 至 0.54 公尺
（指引值）的均勻空氣流速。
層流性（laminarity）的維持應予以證明並 確效。單向氣流（uni-directional air flow）
及較低速率可使用於密閉的隔離裝置及 手套箱（glove boxes）。
Grade A:
The local zone for high risk operations, e.g.
filling zone, stopper bowls, open ampoules and vials, making aseptic connections.
Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54
m/s(guidance value) at the working position in open clean room applications. The
maintenance of laminarity should be demonstrated and validated. A
uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.
B 級：
對於無菌操作之製備及充填，B 級區為 A 級區的背景環境。
Grade B:
For aseptic preparation and filling, this is the background environment for the grade A zone.
C 級與 D 級：
無菌產品的製造中，C 級與 D 級區係執 行較非關鍵性階段的潔淨區。
Grade C and D:
Clean areas for carrying out less critical stages in the manufacture of sterile products.
潔淨室及潔淨空氣裝置分級
（CLEAN ROOM AND CLEAN AIR DEVICE CLASSIFICATION）
4. 潔淨室及潔淨空氣裝置應依 EN ISO 14644-1 予以分級。分級應與操作過程之 環境監測清楚區分。下表提供每一個等級 所容許的最大浮游微粒濃度：
4. Clean rooms and clean air devices should be classified in accordance with ENISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table:
等 級 每立方公尺等於或大於下述粒徑之微粒的最大容許量
靜態 動態
0.5 µm 5.0 µm 0.5 µm 5.0 µm
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520 000 29,000
D 3,520,000 29,000 未界定 未界定
Grade
Maximum permitted number of particles/m3 equal to or greater than the tabulated size
At rest In operation
0.5 µm 5.0 µm 0.5 µm 5.0 µm
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520 000 29,000
D 3,520,000 29,000 Not defined Not defined
5. 針對 A 級區分級之驗證，每一個取樣位置 應採取最少樣品容量 1m3。A 級之浮游微 粒分級為 ISO 4.8，依≥ 5.0 µm 微粒限量決 定。B 級 (靜態)之浮游微粒分級為 ISO 5，係考慮兩種微粒大小。對於 C 級 (靜 態及動態)，浮游微粒分級分別為 ISO 7 及 ISO 8。對於 D 級 (靜態)，浮游微粒分級 為 ISO 8。針對分級，EN/ISO 14644-1 界 定最低取樣點數及樣品量，考量最大的微 粒大小及所收集的數據之估算方式，作為
5. For classification purposes in Grade A zones, a minimum sample volume of 1m3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles
≥5.0 μm. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8
各分級限量之基礎。 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.
6. 為分級之目的，應使用具短取樣管的手提 式微粒計數器，因具長管線的遙控取樣系 統 ≧5μm 之微粒的沉降速率相對較高。
單向氣流系統中，應使用等速採樣頭
（isokinetic sample heads）。
6. Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles ≥5.0μm in remote sampling systems with long lengths of tubing.
Isokinetic sample heads should be used in unidirectional airflow systems.
7. 「動態」之等級可在正常操作或模擬操作 中確認。當需要模擬最差狀況時，則於培 養基充填期間予以確認。對於確認持續遵 循指定的潔淨度分級，EN ISO 14644-2 提 供關於其測試的資訊。
7. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued
compliance with the assigned cleanliness classifications.
潔淨室及潔淨空氣裝置的監測
（CLEAN ROOM AND CLEAN AIR DEVICE MONITORING）
8. 潔淨室及潔淨空氣裝置應在動態中例行 監測，且監測位置應依正式的風險分析研 究，及在潔淨室及/或潔淨空氣裝置之分級 期間所得結果為基礎。
8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.
9. 對於Ａ級區，應在關鍵操作的全程中監測 微粒，包括設備組裝在內，除非證明製程 中之污染物會損壞微粒計數器或呈現危 害，例如活微生物及放射性的危害；在此 種情況下，設備之例行安裝操作期間的監 測，應在暴露於該風險之前為之。模擬操 作期間之監測亦應執行。Ａ級區應以適當 的頻率及採樣量加以監測，使所有介入、
短暫突發事件及任何系統劣化皆會被偵 測到，且如果超出警戒限量將會啟動警報 器。當進行充填時，在充填點，因產品本 身產生之微粒或小液滴，充填點可能無法 一直維持≥5.0 µm 之微粒的限量是可接受 的。
9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, except where justified by
contaminants in the process that would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk.
Monitoring during simulated operations should also be performed. The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels of ≥5.0 µm particles at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.
10. 針對 B 級區，雖取樣頻率可能會減少，但 仍建議使用類似的系統。微粒監測系統之 重要性應由相鄰之 A 級區及 B 級區間的 隔離效果確定。B 級區應依此頻率及適當 的採樣量加以監測，使得污染程度之變 化，及系統之任何劣化將會被偵測到，且 若超出警戒限量將啟動警報器。
10. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. The importance of the particle monitoring system should be determined by the effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.
11. 浮游微粒監測系統可能包括獨立的微粒
11. Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or
radiopharmaceuticals.
12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.
13. 在 A 級區及 B 級區中，≥ 5.0 µm 微粒濃度 計數的監測具有特別的重要性，因為它對
於失敗之早期檢測是一重要診斷工具。≥
5.0 µm 微粒計數之偶爾顯示，可能係由於 電子雜訊、迷光（stray light）、偶合等所 致之非真實計數（false counts）。然而，連 貫性或規則性的低計數，可能是一污染事 the ≥5.0 µm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of ≥5.0 µm particle counts may be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be
diagnostic of poor practices during machine set-up and routine operation.
14. 在「靜態」表中所示之微粒限量應在作業 完成後的無人狀態中，於 15-20 分鐘(指引 值)之短暫「清除」期間（“clean up” period）
中達成。
14. The particle limits given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations.
15. C 級與 D 級區之動態監測應依品質風險管 理的原則執行。其要求及警戒/行動值將取 決於所執行操作作業之本質，但應於「清 除期間」內達到建議之靜態潔淨區要求。
15. The monitoring of Grade C and D areas in operation should be performed in
accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period”
should be attained.
16. 其他特徵，例如溫度及相對濕度，取決於
16. 其他特徵，例如溫度及相對濕度，取決於