欧盟GMP附录一对冻干机的最新要求

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6.11Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should not be a source of contamination and the integrity of the filter tested before installation and after use. Controls should be in place to prevent condensation formation on the filter (e.g. by heating).

如果WFI储罐配有疏水性除菌过滤器，过滤器不应成为污染的来源，并应在安装前和使用后进行过滤器的完整性测试。应进行控制以防止在过滤器上形成冷凝水（例如通过加热）。

6.19Gases used in aseptic processes should be filtered through a sterilisinggrade filter (with a nominal pore size of a maximum of 0.22 µm) at the point of use. Where the filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity tested and the results reviewed as part of the batch certification/release process. Any transfer pipework or tubing that is located after the final sterilisinggrade filter should be sterilised. When gases are used in the process, microbial monitoring of the gas should be performed periodically at the point of use.

在无菌工艺中使用的气体应在使用时通过除菌级过滤器（标称孔径最大为0.22μm）过滤。如果过滤器是基于批次使用（例如用于过滤无菌灌装产品表层通气用气体）或作为产品容器排气过滤器，则过滤器应进行完整性测试，并将结果作为批次认证/放行的一部分进行审核。位于最终除菌级过滤器后的任何输送管道应进行灭菌。当工艺中使用气体时，应在使用时定期对气体进行微生物监测。

8.87The integrity of the sterilisedfilter assembly should be verified by integrity testing before use (pre-use post sterilisationintegrity test or PUPSIT), to check for damage and loss of integrity caused by the filter preparation prior to use. A sterilisinggrade filter that is used to sterilise a fluid should be subject to a non-destructive integrity test post-use prior to removal of the filter from its housing. The integrity test process should be validated and test results should correlate to the microbial retention capability of the filter established during validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold test. It is recognized that PUPSIT may not always be possible after sterilisation due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an alternative approach may be taken providing that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of a non-integral filtration system. Points to consider in such a risk assessment should include but are not limited to:

应在使用前通过完整性测试（使用前灭菌后完整性测试或PUPSIT）核实无菌过滤器组件的完整性，以检查由于使用前过滤器准备造成的损坏和完整性损失。对液体进行除菌的除菌级过滤器，在使用后将滤器从壳体中取出之前，应进行非破坏性的完整性测试。完整性测试过程应经过验证，测试结果应与验证过程中确定的过滤器的微生物截留能力相关联。所使用的测试例子包括起泡点、扩散流、水侵入法或压力保持测试。 已认识到，由于工艺限制（例如，过滤非常少量的溶液），灭菌后的PUPSIT可能并不总是可行的。在这些情况下，可以采取替代方法，只要已进行了彻底的风险评估，并且通过采取适当的控制以减轻任何非完整过滤系统的风险来实现合规。 风险评估中要考虑的要点应包括但不限于：

8.88 The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product) should be verified by testing after use, with the filter remaining in the filter assembly or housing.

关键无菌气体和空气的排气过滤器（与产品的无菌性直接相关）的完整性应通过使用后测试进行核实，过滤器留在过滤器组件或壳体中。

8.89 The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. Where gas filters are in place for extended periods, integrity testing should be carried out at installation and prior to replacement. The maximum duration of use should be specified and monitored based on risk (e.g. considering the maximum number of uses and heat treatment/ sterilisationcycles permitted as applicable).

非关键空气或气体的排气过滤器的完整性应以适当的时间间隔予以确认和记录。如果气体过滤器需长时间放置，应在安装时和更换之前进行完整性测试。应基于风险规定最长使用时间并进行监测（例如考虑最大使用次数和允许的热处理/灭菌循环，如适用）。

8.90 For gas filtration, unintended moistening or wetting of the filter or filter equipment should be avoided.

对于气体过滤，应避免过滤器或过滤器设备意外润湿或弄湿。

8.92 In a redundant filtration system (where a second redundant sterilisinggrade filter is present as a backup but the sterilisingprocess is validated as only requiring one filter), post-use integrity test of the primary sterilisinggrade filter should be performed and if demonstrated to be integral, then a post- use integrity test of the redundant (backup) filter is not necessary. However, in the event of a failure of the post-use integrity test on the primary filter, post-use integrity test on the secondary (redundant) filter should be performed, in conjunction with an investigation and risk assessment to determine the reason for the primary filter test failure.

对于冗余过滤系统（存在第二个冗余除菌级过滤器作为备用过滤器，但灭菌工艺验证时仅用一个过滤器），应进行主要除菌级过滤器的使用后完整性测试，如果证明是完整的，那么冗余（备用）过滤器的使用后完整性测试不是必需的。但是，如果主过滤器的使用后完整性测试失败，则应对二级（冗余）过滤器进行使用后完整性测试，同时进行调查和风险评估以确定主过滤器测试失败的原因。

6.15 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk.

WFI系统应包括连续监测系统，例如总有机碳（ TOC）和电导率，因为这些参数比离散取样更好地指示整体系统性能。传感器位置应基于风险。

6.20 Where backflow from vacuum or pressure systems poses a potential risk to the product, there should be mechanism(s) to prevent backflow when the vacuum or pressure system is shut off.

如果真空或压力系统的回流会对产品造成潜在风险，应有机制以防止真空系统或压力系统关闭的回流。

6.22 Any leaks from these systems that would present a risk to the product should be detectable (e.g. an indication system for leakage).

对产品造成风险的系统泄漏应是可检出的（例如泄漏指示系统）。

8.15 Aseptic manipulations (including non-intrinsic sterile connection devices) should be minimized through the use of engineering design solutions such as preassembled and sterilisedequipment. Whenever feasible, product contact piping and equipment should be pre-assembled, and sterilised in place.

应通过使用预装配并灭菌的设备等工程设计方案，尽量减少无菌操作（包括非固有无菌连接装置）。在可行情况下，产品接触管道和设备应预装配，并在线灭菌。

8.35 The selection, design and location of the equipment and cycle/programme used for sterilisationshould be based on scientific principles and data which demonstrate repeatability and reliability of the sterilisationprocess. All parameters should be defined, and where critical, these should be controlled, monitored and recorded.

灭菌用设备和循环/程序的选择、设计及位置摆放应基于科学原则以及能证明灭菌工艺的可重复性和可靠性的数据。应定义所有参数，并在关键时对其进行控制、监测和记录。

8.37 Particular attention should be given when the adopted product sterilisationmethod is not described in the current edition of the Pharmacopoeia, or when it is used for a product which is not a simple aqueous solution. Where possible, heat sterilisation is the method of choice.

当采用的产品灭菌方法未纳入现行药典时，或灭菌方法是用于非简单水溶液的产品时，应特别注意。在可能的情况下， 加热灭菌是首选方法。8.51 The position of the temperature probes used for controlling and/or recording should be determined during the validation and selected based on system design and in order to correctly record and represent routine cycle conditions. Validation studies should be designed to demonstrate the suitability of system control and recording probe locations, and should include the verification of the function and location of these probes by the use of an independent monitoring probe located at the same position during validation.

用于控制和/或记录的温度探头的位置应在验证过程中确定，并根据系统设计进行选择，以正确记录和反映常规循环条件。验证研究的设计应证明系统控制和记录探头位置的适用性，并应包括在验证过程中使用位于同一位置的独立监测探头来确认这些探头的功能和位置。

8.58For autoclaves capable of performing prevacuumsterilisationcycles, the temperature should be recorded at the chamber drain throughout the sterilisationperiod. Load probes may also be used where appropriate but the controlling system should remain related to the load validation. For steam in place systems, the temperature should be recorded at appropriate condensate drain locations throughout the sterilisationperiod.

对于能够进行预真空灭菌循环的高压灭菌釜，应在整个灭菌过程中记录腔室排水口的温度。在适当的情况下，也可以使用负载探头，但控制系统应仍与负载验证相关联。对于在线蒸汽灭菌系统，应记录适当的冷凝水排放点在灭菌全过程中的温度。

8.59 Validation of porous cycles should include a calculation of equilibration time, exposure time, correlation of pressure and temperature and the minimum/maximum temperature range during exposure. Validation of fluid cycles should include temperature, time and/or F0. Critical processing parameters should be subject to defined limits (including appropriate tolerances) and be confirmed as part of the sterilisationvalidation and routine cycle acceptance criteria.

多孔循环的验证应包括计算平衡时间、暴露时间、压力与温度的相关性以及暴露期间的最小/最大温度范围。流体循环的验证应包括温度，时间和/或F0。关键操作参数应符合规定的限度（包括适当的公差），并作为灭菌验证和常规循环可接受标准的一部分予以确认。

8.63 Where steam in place systems are used for sterilisation(e.g. for fixed pipework, vessels and lyophilizerchambers), the system should be appropriately designed and validated to assure all parts of the system are subjected to the required treatment. The system should be monitored for temperature, pressure and time at appropriate locations during routine use to ensure all areas are effectively and reproducibly sterilised. These locations should be demonstrated as being representative of, and correlated with, the slowest to heat locations during initial and routine validation. Once a system has been sterilised by steam in place, it should remain integral and where operations require, maintained under positive pressure or otherwise equipped with a sterilising vent filter prior to use.

当采用在线蒸汽灭菌系统进行灭菌时（例如，对于固定管道系统，容器和冻干机箱体） ，系统应经过适当的设计和验证，以确保系统的所有部分都能经受所需的处理。应在日常使用中监测系统适当位置的温度、压力和时间，以确保所有部分都经过有效和可重复的灭菌。初始和例行验证中应证明这些位置能代表升温最慢的位置并与之相关。一旦系统经过在线蒸汽灭菌，应保持完整，并在操作需要时在使用前放置在正压下或配备除菌排气过滤器。

8.122 The sterilisation of the lyophilizer and associated equipment (e.g. trays, vial support rings) should be validated and the holding time between the sterilisationcycle and use appropriately challenged during APS (see paragraph 9.33). The lyophilizershould be sterilisedregularly, based on system design. Re-sterilisationshould be performed following maintenance or cleaning. Sterilisedlyophilizers and associated equipment should be protected from contamination after sterilisation.

冻干机和相关设备（例如托盘，西林瓶支撑环）的灭菌应经过验证，应在APS期间适当挑战灭菌循环和使用之间的放置时间（参见第9.33段）。冻干机应根据系统设计定期灭菌。应在维护或清洁后进行再灭菌。灭菌后的冻干机和相关设备应受到保护，避免污染。

8.124 The integrity of the lyophilizershould be maintained following sterilisation and during lyophilization. The filter used to maintain lyophilizerintegrity should be sterilisedbefore each use of the system and its integrity testing results should be part of the batch certification/release. The frequency of vacuum/leak integrity testing of the chamber should be documented and the maximum permitted leakage of air into the lyophilizershould be specified and checked at the start of every cycle.

灭菌后和冻干过程中应保持冻干机的完整性。用于维持冻干机完整性的过滤器应在系统每次使用前进行灭菌，其完整性测试结果应作为批次认证/放行的一部分。应记录冻干室的真空/检漏测试的频率，应规定最大允许的空气泄漏，并在每个循环开始时进行检查。

5.8 A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).

传送带不应穿越A级或B级区与较低空气洁净度生产区域之间的隔墙，传送带本身能连续灭菌者除外（例如，灭菌隧道内）

8.9 Where possible, the use of equipment such as RABS, isolators or other systems, should be considered in order to reduce the need for critical interventions into grade A and to minimize the risk of contamination. Robotics and automation of processes can also be considered to eliminate direct human critical interventions (e.g. dry heat tunnel, automated lyophilizerloading, sterilisation in place).

在可能的情况下，应考虑使用诸如RABS、隔离器或其它系统之类的设备，以减少对A级的关键干预措施，并将污染风险降至最低。也可考虑机器人和工艺自动化，以消除直接的人为关键干预（例如干热隧道，冻干机自动装载，在线灭菌）。

8.123Lyophilizers and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as far as possible. The frequency of lyophilizersterilisationshould be determined based on the design and risks related to system contamination during use. Lyophilizers that are manually loaded or unloaded with no barrier technology separation should besterilisedbefore each load. For lyophilizersloaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilisationshould be justified and documented as part of the CCS.

冻干机和相关产品转移和装载/卸载区域应经过设计，尽可能减少操作人员的干预。冻干机灭菌的频率应根据设计和使用过程中与系统污染相关的风险来确定。没有屏障技术隔离的手动装载或卸载的冻干机应在每次装载前进行灭菌。对于通过自动化系统装载和卸载或由密闭的屏障系统保护的冻干机，应论证并记录其灭菌频率，作为CCS的一部分。