EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL
Consumer goods慈怎么组词
Pharmaceuticals
Brusls, 25 November 2008 (rev.)
EudraLex
The Rules Governing Medicinal Products in the European Union
Volume 4
EU Guidelines to
Good Manufacturing Practice
Medicinal Products for Human and Veterinary U
Annex 1
Manufacture of Sterile Medicinal Products
(corrected version)
Document History
Previous version dated 30 May 2003, in operation since September 2003
Revision to align classification table of clean rooms, to include guidance on media simultations, bioburden monitoring and capping of vials November 2005 to December 2007
莫泊桑式结尾Date for coming into operation and superding 01 March 20091 Plea note correction on the implementation of provisions for capping of vials!
1Note: Provisions on capping of vials should be implemented by 01 March 2010.
Commission Européenne, B-1049 Bruxelles / Europe Commissie, B-1049 Brusl – Belgium. Telephone: (32-2) 299 11 11
ANNEX 1
MANUFACTURE OF STERILE MEDICINAL PRODUCTS
Principle
The manufacture of sterile products is subject to special requirements in order to minimize 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.
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.
General
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 pasd through filters of an appropriate efficiency.
2. The various operations of component preparation, product preparation and filling should be carried out in parate areas within the clean area. Manufacturing operations are divided into two categories; firstly tho where the product is terminally sterilid, and condly tho which are conducted aptically at some or all stages.马蹄的功效与作用禁忌
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 minimi the risks of particulate or microbial contamination of the product or materials being handled.
In order to meet “in operation” conditions the 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 pers
onnel prent. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.
The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.
For the manufacture of sterile medicinal products 4 grades can be distinguished.
Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aptic 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 ud in clod isolators and glove boxes.
Grade B: For aptic preparation and filling, this is the background environment for the grade
A zone.
Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.
Clean room and clean air device classification
4. Clean rooms and clean air devices should be classified in accordance with EN ISO 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.
Maximum permitted number of particles per m 3 equal to or greater than the tabulated size
At rest In operation Grade
0.5 µm 5.0µm 0.5 µm 5.0µm 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
阐扬3 520 000 29 000 Not defined Not defined 5. For classification purpos in Grade A zones, a minimum sample volume of 1m 3 should be taken per sample location. For Grade A the airborne part
icle 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 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purpos EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size bad on the class limit of the largest considered particle size and the method of evaluation of the data collected.
6. Portable particle counters with a short length of sample tubing should be ud for classification purpos becau of the relatively higher rate of precipitation of particles ≥5.0µm in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be ud in unidirectional airflow systems.
7. “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-ca simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.
Clean room and clean air device monitoring
8. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations bad on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.
9. For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment asmbly, except where justified by contaminants in the
process that would damage the particle counter or prent a hazard, e.g. live organisms and radiological hazards. In such cas monitoring during routine equipment t 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 itlf. 10. It is recommended that a similar system be ud for Grade B zones although the sample frequency may be decread. The importance of the particle monitoring system should be determined by the effectiveness of the gregation 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. Airborne particle monitoring systems may consist of independent particle counters; a network of quentially accesd sampling points connected by manifold to a single particle counter; or a combination of the two. The system lected must be appropriate for the particle size considered. Where remote sampling systems are ud, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle loss in the tubing. The lection of the monitoring system should take account of any risk prented by the materials ud in the manufacturing operation, for example tho involving live organisms or radiopharmaceuticals.
12. The sample sizes taken for monitoring purpos using automated systems will usually be a function of the sampling rate of the system ud. It is not necessary for the sample volume to be the same as that ud for formal classification of clean rooms and clean air devices.
13. In Grade A and B zones, the monitoring of 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 fal counts due to electronic noi, stray lig
ht, coincidence, etc. However concutive 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 t-up and routine operation.
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. 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. Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. The parameters should not interfere with the defined cleanliness standard.
17. Examples of operations to be carried out in the various grades are given in the table below (e also paragraphs 28 to 35):
Grade Examples of operations for terminally sterilid products. (e paragraphs 28-
30)
A Filling of products, when unusually at risk
C Preparation of solutions, when unusually at risk. Filling of products
D Preparation of solutions and components for subquent filling
Grade Examples of operations for aptic preparations. (e paragraphs. 31-35)
A Aptic preparation and filling.
C Preparation
of注塑车间
solutions to be filtered.
D Handling of components after washing.
18. Where aptic operations are performed monitoring should be frequent using methods such as s
ettle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods ud in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product relea. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.
19. Recommended limits for microbiological monitoring of clean areas during operation:
Recommended limits for microbial contamination (a)
Grade air sample走出校门
cfu/m3ttle plates
(diameter 90 mm)开心的一件事
cfu/4 hours (b)
contact plates
(diameter 55 mm)
cfu/plate
glove print
5 fingers
cfu/glove
A < 1 < 1 < 1 < 1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -积食发烧怎么办
Notes
(a) The are average values.
(b) Individual ttle plates may be expod for less than 4 hours.
20. Appropriate alert and action limits should be t for the results of particulate and microbiological monitoring. If the limits are exceeded operating procedures should prescribe corrective action.
Isolator technology
21. The utilisation of isolator technology to minimize human interventions in processing areas may result in a significant decrea in the risk of microbiological contamination of aptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be designed so that the required air quality for the respective zones can be realid. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully aled systems incorporating sterilisation mechanisms.
