1、September 2011 Translation by DIN-Sprachendienst.English price group 12No part of this translation may be reproduced without prior permission ofDIN Deutsches Institut fr Normung e. V., Berlin. Beuth Verlag GmbH, 10772 Berlin, Germany,has the exclusive right of sale for German Standards (DIN-Normen).
2、ICS 11.080.01!$tk b) container and closure configuration. 5.2 Following application of the specified lyophilization process it shall be demonstrated that the product meets its specified requirements for safety, quality and performance. 6 Process definitions 6.1 A specification for the lyophilization
3、 process shall be documented. 6.2 The lyophilization process applicable for a defined product shall be established. Process development shall be performed to determine critical process parameters. 6.3 The process parameters, together with their tolerances, shall be established and documented. These
4、shall include, but not be limited to: a) the range of temperatures and pressures; b) the rates of freezing; c) the time at a given temperature and pressure. EN ISO 13408-3:2011 (E) DIN EN ISO 13408-3:2011-09 66.4 During all processes the conditions achieved shall be monitored, maintained within spec
5、ified tolerances, and recorded. 6.5 Where conditioning of the product is required prior to the lyophilization process it shall be defined and documented as part of the lyophilization process. 6.6 The following stages of the lyophilization process shall be evaluated to determine the relevance of maxi
6、mum hold or wait times: a) between the start of filling and the start of the lyophilization cycle; b) between the end of the lyophilization cycle and the start of unloading (where stoppers are not seated into the product containers within the equipment prior to the opening of the lyophilizer chamber
7、); c) between sterilization of the lyophilizer and the start of the lyophilization cycle; d) between sterilization and use of utensils (such as trays, bags, placing devices, tweezers etc). 6.7 Specifications for the Cleaning-in-Place (CIP) and Sterilization in Place (SIP) processes shall be document
8、ed. ISO 13408-4 and ISO 13408-5 shall apply. 7 User requirements 7.1 General 7.1.1 Documentation shall define clearly and precisely the equipment functionality and performance required but without regard as to how that functionality shall be designed or implemented. It shall be reviewed and approved
9、 by the user. 7.1.2 The product/process application shall be developed before designing the lyophilizer. The process conditions/parameters, together with their tolerances, shall be defined so that the use of the lyophilizer and the ancillary equipment will produce a reliable and safe product. 7.2 Eq
10、uipment characterization 7.2.1 Design specifications for equipment to deliver the required processes within defined tolerances shall be established and documented. 7.2.2 The equipment shall be designed, built and located so as to facilitate aseptic processing, cleaning, sterilization and lyophilizat
11、ion. For CIP and SIP, ISO 13408-4 and ISO 13408-5 shall apply. 7.2.3 The design shall address such issues as the internal surfaces and the surrounding environment from the prior processing step through to loading and unloading, with special attention to the position of equipment, personnel and criti
12、cal processing zones. 7.2.4 The design of the lyophilizer shall permit effective cleaning and sterilization of chamber and condenser. 7.2.5 Blocks, cassettes, frames, shelves, trays etc. required for the lyophilization process shall be defined and documented as part of the process. NOTE Flat shelves
13、 are desirable for even product contact for both reasons of temperature uniformity and the distribution of mechanical pressure (e.g. during stoppering in the case of vials with stoppers) and for the prevention of condensate retention. 7.2.6 The maximum permitted leakage of air into the lyophilizer s
14、hall be specified. EN ISO 13408- :2011 (E) DIN EN ISO 13408-3:2011-09 737.2.7 If compressed air, nitrogen or any other gas is admitted into the lyophilizer, its purity and rate of admission shall not impair the integrity of the product. 7.2.8 Equipment controls in the critical processing zone shall
15、be minimized. 7.2.9 The specification for the location in which the equipment and its components are to be installed shall be established and documented and include (but not be limited to): a) the services that are required for the lyophilizer and for the area in which it is installed; b) the materi
16、als of construction for the parts that transport the utilities to and from the lyophilizer. 7.3 Product handling 7.3.1 Transport to, and loading of, the lyophilizer 7.3.1.1 A procedure for loading the lyophilizer, including the loading pattern within the chamber, shall be specified and documented. 7
17、.3.1.2 Transport to the lyophilizer and loading of the filled product, utensils or other equipment into the lyophilizer shall take place in a critical processing zone. Where auxiliary equipment or containers are used for transport, the validated conditions maintained therein shall be equivalent to t
18、he critical processing zone. 7.3.1.3 Airflow patterns resulting from transport devices and venting of the loading zone where the unsealed containers are exposed shall maintain critical processing zone conditions. 7.3.1.4 Utensils used during transfer to, and loading of, the lyophilizer that could co
19、ntaminate the product shall be subjected to a validated sterilization process. 7.3.2 Unloading the lyophilizer 7.3.2.1 A procedure for unloading the lyophilizer shall be specified and documented. NOTE Seating of the stoppers is normally performed within the lyophilizer chamber prior to unloading. 7.
20、3.2.2 Where seating of the stoppers is not completed prior to opening the lyophilizer chamber, product removed from the lyophilizer shall remain in a critical processing zone during subsequent handling. 7.3.2.3 Utensils used during unloading of lyophilizer and transfer shall be subjected to a valida
21、ted disinfection and/or sterilization process. 7.4 Microbiological and particulate environmental monitoring A programme for microbiological and particulate monitoring of the environment during product transfer and lyophilization shall be defined and documented. 7.5 Cleaning and sterilization 7.5.1 C
22、leaning-in-place (CIP) For CIP processes ISO 13408-4 shall apply. 7.5.2 Manual cleaning 7.5.2.1 The cleaning process shall be specified and shall be capable of being validated to provide an adequate challenge that represents the worst-case conditions experienced during routine operation and cleaning
23、 of the equipment. EN ISO 13408-3:2011 (E) DIN EN ISO 13408-3:2011-09 87.5.2.2 The process shall be sufficient to prevent chemical and particulate contamination of the product or material during the lyophilization process, and to remove any residues that would otherwise create a barrier between the
24、sterilizing agent and the equipment surfaces. NOTE An automated process is preferred in order to improve consistency, reliability and personal safety. 7.5.3 Sterilization in place (SIP) 7.5.3.1 For sterilization in place processes, ISO 13408-5 shall apply. 7.5.3.2 The lyophilizer shall be sterilized
25、 before each load or, under defined circumstances, before each campaign. A limit to the number of dryer loads in a campaign should be specified and validated. 7.5.3.3 Conditions protecting the lyophilizer from contamination after sterilization shall be maintained, the efficacy of the protection shal
26、l be validated and the performance documented. 7.5.3.4 In the case of a closing system for pre-plugged vials, sterilization of the ram protruding into the chamber should be addressed where applicable. 7.6 Vent filter system 7.6.1 Bacteria retentive filters shall be used to maintain lyophilizer integ
27、rity when breaking the vacuum. Flow or pressure increase rate shall be specified, documented and justified. 7.6.2 The filter assembly shall be sterilized in conjunction with chamber and condenser, without damaging the filter. NOTE In situ filter sterilization is preferred. 7.6.3 The frequency of the
28、 filter integrity testing shall be specified, justified and documented. 7.7 Lyophilizer leak test 7.7.1 The lyophilizer shall comply with user-defined leak test procedures and limits. 7.7.2 Procedures shall be documented and shall include such aspects as the frequency of routine testing, the targete
29、d vacuum conditions (depth and duration), the maximum permitted leakage of air into the lyophilizer chamber and condenser, as well as the alert limits and rationale behind possible corrective actions. 8 Validation 8.1 General Written protocol(s) shall be established and shall specify how validation
30、is to be conducted. Protocol(s) shall be reviewed and approved and shall specify critical parameters and acceptance criteria. Validation of equipment design, installation, operation, performance and processes shall be performed by qualified personnel in accordance with the approved protocol(s). Any
31、deviation from the protocol(s) shall be documented, investigated and resolved. EN ISO 13408- :2011 (E) DIN EN ISO 13408-3:2011-09 938.2 Design qualification Appropriateness of system design and design of the facilities, utilities, equipment and materials used shall be confirmed to meet the requireme
32、nts for the intended use at the first stage of validation. Design qualification should be emphasised in validation activities as specified in ISO 9001. NOTE Design qualification is documented verification that the proposed design of the facilities, utilities, equipment and system is suitable for the
33、 intended use. 8.3 Installation qualification 8.3.1 General Installation qualification shall be carried out in accordance with a documented procedure that cross-references appropriate equipment and “as installed” specifications. 8.3.2 Installation 8.3.2.1 It shall be documented and verified that the
34、 equipment and its location conform to its specification. 8.3.2.2 It shall be documented and verified that the equipment is installed in accordance with the installation instructions. 8.3.2.3 It shall be documented and verified that the services to the equipment conform to their specification. 8.3.2
35、.4 The calibration of all measuring chains (including any test instruments) used for monitoring, controlling, indicating or recording shall be verified. 8.3.2.5 The operating instructions shall be available and shall reflect the manner in which the equipment is to be operated during operational qual
36、ification. 8.3.2.6 Requirements given in 8.3.2.4 and 8.3.2.5 may be confirmed at the commencement of operational qualification. 8.3.3 Computer and software qualification Computerized control systems and associated software shall be qualified before starting operational tests on the equipment to demo
37、nstrate conformance to the specification. 8.3.4 Alarm systems The alarm system shall be qualified to demonstrate conformance with specifications and to demonstrate that the appropriate control system responses are observed and documented. 8.4 Operational qualification 8.4.1 General Operational quali
38、fication shall be performed in accordance with documented procedures to demonstrate that the installed equipment is capable of delivering the specified processes within defined tolerances. 8.4.2 Leak test A leak test shall be performed to demonstrate conformance with the specification. The leakage o
39、f air into the lyophilizer chamber shall not exceed the specified limits. EN ISO 13408-3:2011 (E) DIN EN ISO 13408-3:2011-09 108.4.3 Thermal control system(s) The system(s) that control temperatures shall be qualified to demonstrate that the rate of thermal control and ultimate temperature capabilit
40、ies of the system conform to the specification(s). NOTE Thermal control system(s) are used to control variables such as shelf temperature, condenser temperature, and jacket temperature. 8.4.4 Vacuum system The vacuum system shall be qualified to demonstrate that the rate of evacuation and the ultima
41、te capabilities of the vacuum system conform to the specification. 8.4.5 Condenser refrigeration The refrigeration system capacity and cooling rate of change shall be qualified to demonstrate conformance with the specification. Operational qualification is the first check of the condenser capacity a
42、nd may be done with a reference solvent such as water. 8.4.6 Defrosting Where a defrost cycle is specified, the sequence of operations shall be performed to demonstrate conformance with the specification. 8.4.7 Lyophilization cycle The sequence of operation of the lyophilization cycle shall be perfo
43、rmed to demonstrate conformance with the specification. 8.4.8 CIP cycle Operational qualification shall be performed in accordance with documented procedures to demonstrate compliance with the requirements of ISO 13408-4. 8.4.9 SIP cycle Operational qualification shall be performed in accordance wit
44、h documented procedures to demonstrate compliance with the requirements of ISO 13408-5. 8.4.10 Stoppering seating system(s) Stoppering seating system(s), where present, shall be qualified to demonstrate conformance to their specification. 8.4.11 Shelf temperature distribution 8.4.11.1 Shelf temperat
45、ure distribution studies shall be performed to identify inter- and intra-shelf variations and shall demonstrate conformance to the specification. Ideally, these studies should be performed with the chamber at atmospheric pressure and include a range of temperatures that take into account both the he
46、ating and cooling phases of the lyophilization cycle. 8.4.11.2 The number of temperature sensors used shall be specified. EN ISO 13408- :2011 (E) DIN EN ISO 13408-3:2011-09 1138.5 Performance qualification 8.5.1 General Data generated during installation qualification and operational qualification s
47、hall be reviewed before performance qualification is started to verify that the requirements of both performance qualification and process validation will be met. Usually, performance qualification is performed with actual product. However, where a well-characterized equivalent placebo is available,
48、 this may be used. 8.5.2 Lyophilization 8.5.2.1 Performance qualification shall be performed to demonstrate the suitability of the equipment for the intended product or process. 8.5.2.2 The lyophilizer shall be loaded with product or placebo, in accordance with documented procedures, and processed t
49、o demonstrate conformance to the predetermined cycle parameters. 8.5.3 SIP Performance qualification shall be performed, in accordance with documented procedures, to demonstrate compliance with the requirements of ISO 13408-5. 8.6 Process validation 8.6.1 General Process validation shall be performed to demonstrate that the lyophilization process leads to the intended product quality and characteristics. NOTE Subparts of process validation are process simulation, cleaning and product qualification simulating routine production. 8.6.2 Cleaning validation Cleaning of the lyophilizer shall be v
