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蒸汽灭菌柜验证的10大注意事项(中英文)
White PaperTop 10 considerations when validating an autoclaveValidating an autoclave is a daunting and time-consuming task. This white paper details the tricks, tips and traps to such a validation project from how to choose your Control to which load configuration to use for your validation runs.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 1 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 1 Choosing the right sterilisation cycle to implementThere are three basic types of sterilisation cycles. Choose the right one according to the type of goods to be sterilised:Hard Goods (Vacuum)Suitable for items that are easy to sterilise, because air removal and steam penetration are highly effective on these items. e.g., open glassware and large diameter piping A typical hard goods cycle may draw one vacuum prior to introducing steam to reach the desired sterilisation temperature.Wrapped Goods (Vacuum)Utilized for items that are difficult to sterilise, because air removal and steam penetration are harder to achieve on these items than on hard goods. e.g., empty bottles (glass or plastic) with lids, gowns, long hoses/tubes, vent filters, portable vessels with small inlet/outlet ports A typical wrapped goods cycle may draw three or more vacuums prior to reaching sterilisation. A post-sterilisation vacuum draws the steam from the load items.Liquids (Non-vacuum)Items that contain liquids generally cannot have a deep vacuum pulled or the liquid will be drawn out of them. Autoclave cycles for liquids generally heat up and cool down without a vacuum. Steam, introduced into the top of the chamber, displaces the air. The air is pushed to the bottom of the chamber and is removed.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 2 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveThe steps involved in choosing the right sterilisation cycle.A lower SET temp means a longer sterilization time (ideal for temperature sensitive items) and a higher SET temp means a shorter sterilization time and a faster cycle (ideal for Hard goods).Determine the SET temperature (usually 121.1 °C)Is the cycle timedependent?NoThe cycle is controlled via a liquid CONTROL and the sterilization time is determined by the accumulated F0 of the CONTROL. This is ideal for heat-sensitive samplesYesThe cycle is determined by TIME at 121.1 °C and is controlled via the Drain Decide which liquid CONTROL to use and ensure ongoing consistency with the amount of liquid present during the validation runs and all subsequent processing runs.Usually need F0 & 15. However, to achieve a minimum SAL (at the end of the cycle) 10-6 you need to incdrease the F0 to 20 (to be certain you get F0 & 15 at all points in the load)Minimum requirement is an SAL of 10-6. Is an OVERKILL cycle required?NoMin. 6 log reduction required and SAL of 10-6YesAssume worst-case conditions, i.e. 12 log reduction and a min SAL of 10-6In an OVERKILL approach you avoid collecting bioburden and D-value data by assuming worstcase conditions. A bioburden of 106 of a highly heat-resistant spore-forming bacteria (Bacillus stearothermophillus) is utilized. The D-value at 121.1 °C for these bacteria is generally 1.5 to 2 minutes. Therefore, using 2 minutes is a good worst-case value. Under ideal conditions, an OVERKILL sterilization cycle at 121.1 °C is thus 12 log x 2 min/log = 24 minutes For items that are more difficult to sterilize (eg. some Wrapped Goods such as empty bottles with lids) it will be necessary to increase the time to 40-45 minutes to achieve a min SAL of 10-6 and equilibrium at 121.1 °C: +2 °C/-1 °C for at least 21 minutes.An “ideal” sterilization cycle can be determined with three variables: bioburden, D-value and required SAL. With prior knowledge of the bioburden and D-value you can determine the “ideal” cycle TIME for a min. SAL of 10-6: eg. Bioburden = 100 and D=1.5 min/log then: Log (Bioburden) = Log (100) = 2 Log Reduction = 2 log + 6 log = 8 log, and Ideal Cycle TIME = Log Reduction x D = 8 log x 1.5 min/log = 12 minutes To achieve a minimum 6 log reduction temperatures need to be at 121.1 °C for 15 minutes. Therefore, setting a time of 20 minutes at 121.1 °C should meet criteria.Factors not taken into account here but should be considered are as follows (usually in consultation with the autoclave manufacturer): the number of pre vacuums required the amount of post vacuum drying cycles needed whether the items being sterilized can withstand the vacuum(s) Note: Some pharmaceutical companies divide c porous (Hard goods, Wrapped goods) and liquids (i.e. non-porous).?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 3 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 2 Which load configurations to use?A variable to consider is whether to use fixed load or variable load configurations. There’s a trade-off here between validation effort and operational flexibility C do you want to validate a wide range of load configurations to increase Production’s flexibility in loading the autoclave? Here are some typical load configurations to consider: A fixed load/fixed position configuration means that any load to be sterilised will be placed inside the chamber in exactly the same way for every processing run. A diagram of the load configuration should appear in the Standard Operating Procedure (SOP) so that operators can reproduce the load for every processing run. This situation requires the fewest validation runs (3), but offers no flexibility in load configurations. A fixed load/variable position configuration means that the location of the load items in the autoclave can vary. Only a list of the items that can be in a load is required for the SOP. The validation runs must demonstrate positional equivalence by rotating the items from location to location during the test runs. If positional equivalence is proven after three validation runs, then you can stop. A fixed load/variable position configuration gives operators flexibility in loading the autoclave. This saves time when loading large loads of numerous items of different types. A variable load configuration means that different combinations of items and/or numbers of any item(s) can be placed into the chamber. The validation runs must demonstrate that the cycle is adequate for both a maximum and minimum load configuration. The minimum load tests are done with only one item in the autoclave, that item being the load item demonstrated as being the most difficult to sterilise .Consideration 3 Choosing the right Control for liquid cyclesThe choice of the Control used when sterilising liquids determines whether the load you are sterilising will pass all the acceptance criteria. More than one liquid Control may be needed to validate all the different types of bottles and liquids requiring sterilisation. Consider the following when choosing the Control for liquid cycles: ? ? ? The size of the bottle and its fill volume C the larger the bottle and the greater its volume, the harder it is to sterilise. The thickness of the glass Cthicker glass is more difficult to sterilise than thinner glass.The viscosity of the liquid C the greater the viscosity, the slower the heat-up time, and the harder it is to sterilise. The liquid Control will ideally be the one that is the most difficult to sterilise (worst-case) and will be located at the coldest spot in the chamber (lower level near the front door or directly above the drain). Don’t be tempted to use a Control that is dramatically different from the composition of the load. If the liquid Control takes too long to reach the sterilisation temperature, then the protein composition of the media in the rest of the load (which may have exceeded the desired temperature by the time the Control reaches the sterilisation temperature) may be denatured.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 4 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveIf in doubt, perform preliminary studies using different liquid Controls to obtain information on the load's heat-up times and F0-values. The number of validation runs required for different types of liquids and bottles can be reduced by grouping liquids with similar viscosities, bottle sizes and fill volumes. Each liquid Control will have a unique maximum and minimum load configuration associated with it. Use procedural controls to ensure that the choice of liquid, bottle size and fill volume used for each Control, and its location in the chamber, are maintained during the validation runs and subsequent processing runs.1.1.1.Case study of load configurations and choice of Control:Let’s assume that a laboratory prepares four different media types in three different bottle sizes in the following configurations:Table 1. Media types and bottles sizes for loads in the autoclaveMedia Media A Media A Media B Media C Media DMax/Min Load1 fixed at 50 Max: 160 Min: 40 Max: 144 Min: 9 Max: 144 Min: 9 Max: 144 Min: 9100 mL bottle500 mL bottle 400 mL fill600 mL bottle NA (not applicable) NA 500 mL & 600 mL fill NA NA50 mL fill NA NA NANA 400 mL & 500 mL fill 400 mL & 500 mL fill 400 mL & 500 mLMedia A is the most viscous fluid of those listed. It is prepared in two very different bottle sizes: 500 mL (with a fixed load of 50 bottles in the autoclave) and 100 mL (with a variable load of 40160 bottles in the autoclave). This means that Control 1 is a 500 mL bottle filled with Media A (400 mL) for the fixed load (three studies); and Control 2 is a 100 mL bottle filled with Media A (50 mL) for the variable load (six studies: three at maximum load and three at minimum load). All remaining media types (also known as Broths) have similar viscosities and are in similar bottle sizes with fill volumes ranging from 400 mL to 600 mL. This means that Control 3 is a 600 mL bottle filled with Media B (600 mL)2 for the variable load covering the three different Broths, i.e., six studies: 3 x 144 (max) and 3 x 9 (min) using 600 mL bottles.3 Note: Each validation load consisted of the relevant media type only in the locations where thermocouples, Biological Indicators (BI) and Chemical Indicators (CI) were to be placed. The rest of the load was the same sized bottles filled with the required volume of water.Consideration 412Max/Min Load is the number of these bottles that can be loaded into the autoclave per run. The choice of Control in this case was based on the largest bottle with the largest fill volume. 3 To complete the study, a mixture of Media B and Media D was spread evenly across the load to capture data across the two different media types and, therefore, show compatibility between the two. ?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 5 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveDetermining which load items are the most difficult to sterilise and which location(s) within the items represents the worst-case conditionsWith a large load containing a wide variety of different types of items, the number of possible test locations within items seems to approach infinity. It also can be difficult to get the thermocouple and indicators (BI & CI) into the item without affecting the item’s ability to be sterilised and/or ruining the item (a concern with expensive items). We must evaluate each item on a case-by-case basis and determine how to best challenge the item. Often the item must be sealed somehow to return it to a state that represents equivalency with respect to steam penetration.Some examples:Q. What is the most difficult point to sterilise in a hose of uniform diameter? A. In the centre of the length of hose. Q. How do you get a 3 m length of thermocouple into the middle of a 20 m hose? A. By cutting a slot in the middle of the hose and inserting the thermocouple through the slot, making sure to seal the slot with silicon. If you don’t seal it, you will not be challenging the hose properly. Alternatively, get two 10 m lengths of hose (if available) and join them with a connector, after inserting the thermocouple through the connector. Using this method doesn’t ruin a 20 m length of hose. Q. What is the worst-case location within a bottle, flask or cylinder? A. In the centre near the bottom (but not touching the floor). Q. How do you hold a thermocouple in position inside a sealed bottle? A. Choose a piece of Silastic tubing with an internal diameter (ID) that is narrow enough to hold the thermocouple probe without letting it slip through. Drill a hole in the bottle's lid the same size as the outer diameter (OD) of the tubing. Push the tubing through the hole, into the bottle. Now push the probe into the tubing. Slide the probe through the tubing until it reaches the desired position in the bottle. Make sure it is not touching the wall of the bottle. For bottles with rubber stoppers, make a small hole in the centre of the stopper, sufficient to push the thermocouple through.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 6 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 5 Wired temperature thermocouples are cumbersome and don’t always give accurate dataThe list below highlights some considerations when using wired thermocouples: ? ? Some loss of steam (leakage) will occur when the wire's outer plastic protector has been cut and air or steam can pass through it. This may result in a failed leak test. Validator thermocouples inside the chamber will draw condensate and will need a slice/cut made in their outer protective layer, to ensure that any fluid is released. If condensate passes through the wires and into the electronics, the thermocouples will be destroyed. The thermocouple may be difficult to place into the item without adversely affecting the item’s ability to be sterilised and/or ruining the item (a concern with expensive items). Wires can get caught (and be damaged) under the autoclave's wheels when moving loads into and out of the chamber. It is difficult to place wires inside sealed bottles without (i) touching the inside wall, and (ii) compromising the bottle’s ability to be sterilised. You may be limited by the number of wires you can place through the autoclave's inlet. The resistance of the thermocouple in some locations in the chamber can change, leading to inaccurate and/or unreliable data even though the pre/post calibration verifications meet specifications.? ? ? ? ?Case StudyThis example looks at nine thermocouples placed into a loaded chamber. They were evenly spaced from one another at the top, middle and bottom levels and at the front, centre and rear of the chamber. All were in the chamber and subject to Phase II heat distribution requirements. The study used wired thermocouples in a loaded chamber for a 40-minute cycle at 121.1 °C. The chamber's maximum pressure of 2.16 bar (at any time) was equivalent to 122.7 °C. One probe (top front LHS) constantly reached temperatures between 123.3 °C and 123.5 °C. All other probes were within the required limit of 120.1 °C +2 °C/-1 °C at temperatures from 122.4 °C to 122.7 °C. The temperature differential started during heat-up and remained during the sterilisation and post vacuum cooling phases. The Equipment Engineer and the Manufacturer agreed that the temperature reading at this position was inaccurate and unreliable. The thermocouple reading was inconsistent with the steam pressure indication and the other thermocouple readings. Consequently, no useful data were collected at that point.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 7 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 6 Determining the acceptance criteriaAn example: You run your validation studies, only to realise that you cannot meet one of the acceptance criteria. But, was it really needed in the first place? It’s important to understand the aim of the autoclave cycle and what its parameters are. For example, is it for sterilisation or decontamination? Is the load heat sensitive, or can it be subjected to an overkill cycle? Is it a porous load (hard/wrapped goods), or is it a liquid? Most Validation departments have a Standard Operating Procedure (SOP) detailing the validation requirements for sterilisation processes. Included in that is a complete list of all the acceptance criteria. Each phase of the autoclave cycle is likely to have different acceptance criteria: Phase I C Heat distribution (empty chamber) Phase II C Heat distribution (loaded) Phase III C Heat distribution (loaded) cold spot determination within Phase IV C Heat penetration There may also be different requirements for Phases III and IV if you are sterilising liquids (nonvacuum) vs. porous items (vacuum), e.g., F0 & 15 at the end of sterilisation (liquids only). Typical acceptance criteria are as follows: ? All porous cycles require min SAL 10-6 at the end of sterilisation. All porous items are subject to at least one post-vacuum cycle which removes steam from the chamber (Phases III & IV). All liquid cycles require a min SAL 10-6 and a min F0 & 15 at the end of the cycle, because they do not use vacuum and are subject to natural cooling (Phases III & IV). Throughout the sterilisation phase all temperatures are within a 3 °C range (Phases II, III & IV)?, e.g., 121.1 °C -1 °C/+2 °C. Throughout the sterilisation phase all temperatures in the chamber are within 1.0 °C of the chamber's mean temperature (Phase II). The steam's temperature corresponds to its vapour pressure (Phases II, III & IV).4 Timed measurements are to be controlled to an accuracy of ±1%.? Required pre-certification and post-certification of the data logger ensures that the temperature measurement system is accurate to within ±0.5 °C. The load is visually dry at the end of the cycle (porous cycles only). All autoclaved Biological Indicators (BIs) are negative and the control is positive following incubation (Phase IV).?? ? ? ? ? ? ?4Sterilisation of Medical Devices C Validation and Routine Control of Sterilisation by Moist Heat: European Standard EN 554 (1994).?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 8 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 7 Adequately documenting the validation test runsDocumenting what was done during the validation test runs is all about knowing what needs to be documented and how to present it. This documentation must be clear, consistent between runs and transparent, and must conform to all GMP requirements. It must be complete and must include the following items: ? ? ? ? ? ? a diagram showing the location of all load items within the autoclave chamber the precise location/number of each thermocouple, BI and CI within each item the printout from the data recorder the printout or chart from the autoclave the time the sterilisation period began and finished (per the data recorder time) the time difference between the autoclave controller and the validation temperature monitoring device? the results of each BI and CI Label each document with the equipment ID, load description, date, test run number and cycle start/end time. If you fail to generate good documentation while conducting the validation test runs, you will not be able to analyse the data when putting together the report. Inadequate or poor quality data to support the validation process will not survive the scrutiny of an auditor.Tip: Be cautious about the acceptance criteria you employ to verify the accuracy of thermocouples. If the criterion is too tight (e.g., all thermocouples must meet the acceptance criteria), you may lose a lot of runs if one or two thermocouples cease functioning or are outside the temperature tolerance after the runs.Consideration 8 The frequency of thermocouple accuracy verificationIf you are performing a large number of test runs (e.g., over the course of several weeks), you need to think about the points at which you will verify the thermocouples' accuracy. This could be done after every run and/or at the end of the entire testing period. If you wait until the end of the testing period, you run the risk that all of the runs are of no value due to their failure to meet the verification acceptance criteria. Verifying after every run, however, adds considerably to the length of time required to complete the testing. Performing the verification every three runs or every few days is a reasonable compromise.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 9 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveAs noted in Consideration 6, the acceptance criterion you employ to verify the thermocouples' accuracy should allow at least one or two thermocouples to fail.Consideration 9 Having adequate time and access to the autoclave to complete the validationIt’s easy to under estimate the length of time it takes to validate an autoclave, and how much access you need to it during the process. For example, it can take up to four hours to set up your run, i.e., prepare the load, place probes, BIs and CIs into the load, etc. If Production needs to use the autoclave and you need to remove your probes, BIs and CIs, then you need to start all over again, effectively losing a day. Work with the Production department when planning the Validation project to ensure that you have adequate access to the autoclave. Another approach is to combine Phase II and III (Heat Distribution) with Phase IV (Heat Penetration) studies to save time. Combining these three phases could reduce the time it takes to complete th however, you need to consider the following when doing this: 1. You will need to place probes into the chamber and into load items at the same time. Can you fit all the probes through the autoclave's inlet? If not, then you need to either validate each phase separately, or reduce the number of probes. 2. Combining these three phases greatly increases your preparation time. If you are working on a tight schedule (e.g., on a construction site where you need to evacuate at a certain time), you may not have time to complete the study. If this happens, then it may take more time to perform the work than if you had done each phase separately. 3. If you are under time pressure, there is a greater chance that you will miss something or make a mistake. 4. There are more data to consider. If you check only a few critical requirements before proceeding to the next study, you may miss something that did not meet an acceptance criterion. This may mean that all subsequent studies are at risk, because the data cannot be verified. For example, a probe may be falsely reading too high. 5. Allow enough time for the report to be completed. If you are validating a new autoclave, then you need to allow enough time for: (i) (ii) (iii) (iv) (v) writing a validation plan writing the commissioning and IQ protocols preparing the OQ/PQ protocols performing OQ/PQ studies writing the OQ/PQ reports, preparing folders, etc.If you are performing a large number of test runs (e.g., over the course of several weeks), then you need to ensure that enough time has been allocated to prepare the folders and write the reports. Allow one day to do a run and another day to analyse the data, i.e., two days per study. Also allow time to write protocols and reports, and to have them reviewed and approved by other people (if appropriate). If you are developing the validation cycles, then this will also take time.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 10 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveConsideration 10 Have the right procedural controls in place to ensure ongoing consistency and correct operationCongratulations, you have just finished validating a new autoclave for a number of different cycles and load configurations. Now, what controls need to be in place to ensure that the validated loads are used consistently? ? A Standard Operating Procedure (SOP) for the new autoclave should be prepared. It must include clear guidelines for each of the validated cycles, including diagrams of the load configurations. Test the procedure's clarity by asking a typical operator to follow the instructions with a dummy load. Each operator who uses the autoclave should be trained and tested on the SOP. Logbooks should be in place for each cycle. Use a risk-based approach to determine the troubleshooting guidelines to include in the SOP. The manufacturer’s documentation and website may detail things that commonly go wrong. An ongoing requalification program for the autoclave and the loads is required. The frequency can be 6, 12 or 24 months.? ? ??GlossaryTerm Biological Indicator (BI) Meaning Spore strips or vials with a verified microbial count that are placed within the load to challenge the autoclave's performance Commercially available indicators that indicate exposure to steam Articles are free of microbial contaminants but are not suitable for use in a Grade A sterile area. This is the number of minutes required to kill a specified number of microorganisms with a Z-value of 10 °C at a temperature of 121.1 °C. The items placed into the autoclave to be sterilised A 12-log reduction in the number of microorganisms with an SAL of 10-6 Sterility Assurance Level. An SAL of 10-6 is a one in one million probability of a single viable microorganism being present. The temperature at which sterilisation occurs. This is the temperature the autoclave is held at for a specified period of time to reach the required sterilisation level. The destruction of all living microorganisms such as pathogenic or saprophytic bacteria, vegetative formsChemical Indicator (CI) decontamination F0 valueload overkill SALSET temperaturesterilisation?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 11 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveTermMeaning and spores. Articles that have been sterilised can be used for aseptic purposes in all areas, including areas classified as Grade A sterile areas.thermocoupleA temperature measuring device?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 12 of 13 Version -01White Paper Top 10 considerations when validating an autoclaveAbout PharmOutPharmOut is a professional consultancy offering product registration, engineering, validation and regulatory compliance solutions to the Medical Device, Pharmaceutical and Veterinary drug manufacturing industry from concept development, feasibility studies, scale up, engineering design, project management to the final product regulatory approval and GMP compliance certification.How PharmOut can helpWe offer the following range of services:ISO, GMP & APVMA compliance consultingPolicies, SOP, and Forms. We can also help you obtain approval from the following international regulatory authorities (APVMA, FDA, MHRA, and TGA).EngineeringOur experienced industry engineers can develop concept and detailed designs, around your production process ensuring full GMP compliance by careful project management and verification (validation) to ensure that the exacting GEP standards are met.GMP ComplianceWe can visit your site before or after a FDA or TGA GMP audit to assess and improve your quality management systems and/or validation documentation, business processes and physical operations.Quality Management SystemsWe can help you create a Quality Management System from scratch, or bring your current system into compliance.Technical Document WritingWe can help you write procedures and work instructions that your staff will actually use and can follow.ISO & GMP consultingWe can provide practical recommendations and advice on the implementation of ISO 9001 for Pharmaceuticals or ISO 13485 for Medical Device Quality Management Systems, Policies, SOP, and Forms. We can also help you obtain approval from the following international regulatory authorities (FDA, MHRA, and TGA). This includes Part 11 and Annex 11 compliance to FDA and TGA requirements.TrainingWe run on-site or in-the-city classroom training on GLP, GMP compliance, validation and documentation writing. We also develop e-learning modules on topics such as Good Record Keeping that you can use for your ongoing training needs.ValidationOur validation engineers / specialists can write validation plans, specifications and qualification protocols for i.e. cleaning validation, equipment validation, computers systems validation, analytical method validation or process validation.?2013 PharmOut. This document has been prepared solely for the use of PharmOut and its clients. Copying is prohibited. www.pharmout.net Page 13 of 13 Version -01White Paper Top 10 considerations when validating an autoclave白皮书高压灭菌器验证的 10 大注意事项高压灭菌器的验证是一项艰巨而耗时的任务。本白皮书详细描述了验证项目的技巧和 窍门，如何选择验证运行中的负荷配置。? 2011 PharmOut Pty LtdPage 1 of 10Version - 01White Paper Top 10 considerations when validating an autoclave注意事项 1 选择正确的灭菌周期 有三种基本类型的灭菌周期。根据待灭菌物质的类型选择一个正确的。 耐热品（真空） 适用于那些易于灭菌的物质，因为除气和蒸汽渗透对这些物质是高度有效的。 例如：敞开玻璃器皿及大口径的管道 典型的耐热品灭菌循环在引入蒸汽前已接近一个真空度达到预期的灭菌温度。 包裹品（真空） 用于灭菌困难的物质，因为和耐热品比起来除气和蒸汽渗透更难实现。 例如，有盖子的空瓶（玻璃或塑料） ，洁净服，长软管/管子，抽气过滤器，进/出口 小的便携式容器。 一个典型的包裹品灭菌循环在灭菌前接近大于等于 3 个真空度。灭菌后的真空度接近 负载的蒸汽。 液体（非真空） 一般含有液体的物品不能有大的真空度或液体会溢出。针对液体来说高压灭菌锅循环 是在没有真空度的情况下加热和冷却。蒸汽进入膛顶部替代空气，空气推入膛的底部 并排出。? 2011 PharmOut Pty LtdPage 2 of 10Version - 01White Paper Top 10 considerations when validating an autoclave? 2011 PharmOut Pty LtdPage 3 of 10Version - 01White Paper Top 10 considerations when validating an autoclave注意事项 2 使用那一种负载配置 选择固定的负载还是可变的负载时要考虑一个变量。在验证和业务灵活性之间有一个 权衡- 加载高压灭菌器时你是否要验证负载的范围以增加生产的灵活性？下面是一 些典型负载配置需要考虑： 固定负载/固定位置配置指任何负载待灭菌物质在膛内放置的位置和运行状态完全一 样。在标准作业流程（SOP）中应有负载配置的图表，因此操作者可以在脑海中再现 每一个运行过程的负载。 这种情况要求最少的验证运行 （3） ， 但负载配置没有灵活性。 固定负载/可变位置的配置指负载在高压灭菌器内的位置是可变的。在 SOP 中只需一 个负载列表。在测试运行过程中，验证运行时通过旋转负荷的不同位置，表现出位置 等价性。如果经过 3 个验证运行证明了位置的等价性那就可以停止。固定负载/变位 置的配置给操作者操作高压灭菌器时带来灵活性。针对不同类型大负荷的情况这样可 以节省时间。 可变负载配置指不同的组合物品和/或多个项目可以定置在膛内。验证运行时必须表 明此循环周期可以满足最大和最小两个负载配置。最小负载测试高压灭菌器膛内一个 项目，该项目必须能表明其是最难灭菌的一个项目。 注意事项 3 选择合适的液体循环控制 灭菌液体时决定选择使用的控件取决于待灭菌的负荷是否能通过验收标准。 需要不止一个液体控件以证明不同类型的瓶子和液体能满足灭菌要求。选择液体循环 控制时需考虑以下因素： ? ? ? 瓶子的大小和填充量-瓶子越大其体积越大，就越难灭菌。 玻璃的厚度，厚玻璃比薄玻璃难灭菌 液体的粘度 C 粘度越大传热越慢，就越难灭菌。观念上认为液体控制是最难灭菌的（最坏情况） ，设在膛内最冷的地方（较低水平靠 近前门或在排水管的正上方） 。 不要对不同组分的负载尝试控制，如果液体控制需要很长时间还达不到灭菌温度，则 负载介质中的蛋白质将会变性 （这可能已经超出了控制的时候达到杀菌所需的温度） 。 如有疑问，应进行初步研究，采用不同的液体控制以得到负载加热时间和 F0 值的信 息。 根据相似粘度，瓶子大小和填充量大小分组，不同类型的液体和瓶子所需验证运行的 次数可减少。每个液体控制将有一个与配置相关的最大和最小负载。 使用程序控制，以确保液体、瓶子体积、填充量和在膛内的位置等参数的选择在验证 运行和后续运行过程中保持一致。 负载配置和控制选择实例： 假设一个实验室准备在下列配置下对 4 中不同介质在 3 个不同大小的瓶子进行试验：? 2011 PharmOut Pty Ltd Page 4 of 10 Version - 01White Paper Top 10 considerations when validating an autoclave表 1、高压灭菌器内介质类型和瓶子大小 介质 最大/最小负载 100ml 瓶子 介质 A 固定 50 最大 160 介质 A 50ml 装量 最小 40 最大 144 介质 B 空白 最小 9 最大 144 介质 C 空白 最小 9 最大 144 介质 D 空白 最小 9500ml 瓶子 400ml 装量 空白 400ml 和 500ml 装量 400ml 和 500ml 装量 400ml 和 500ml 装量600ml 瓶子 空白（不可用） 空白 500ml 和 600ml 装量 空白 空白介质 A 是最粘稠的，放在两个不同大小的瓶子里 500ml（高压灭菌器中的负载固定为 50 瓶）和 100ml（高压灭菌器中可变负载 40-160 瓶） 。这意味着，控制 1 是 500ml 瓶子中装有固定负载介质 A400ml(3 个研究)，控制 2 是一个 100ml 瓶子中装有可变负 载介质 A50ml（6 中情况，3 个最大负载和 3 个最小负载） 。 剩余所有的介质有类似的粘度，并在相似的瓶子里填充体积从 400-600ml 不等。这意 味着控制 3 是 600ml 瓶子里装有可变负载介质 B600ml 分 3 不同浓度，即 6 中情况： 使用 600ml 瓶子分为 3 × 144（最大）和 3 × 9（最小）两种。 注： 每个验证负载包括介质的类型， 有固定的热电偶、 生物指标 （BI） 和化学指标 （CI） 。 其余负载是放在相同瓶子内所需的水。 注意事项 4 确定哪些负载项是最难灭菌的和哪些位置最能代表灭菌的最差情况 大负载、不同类型的介质有一个很大范围的检测项目，种类繁多的检测项目在不同的 检测点上方法是接近无穷大。在不影响灭菌能力和破坏项目（关注贵重物品）的情况 下，得到项目的热电偶和指标（BI 与 CI）也是非常困难的。 我们必须在逐案的基础上评估每个项目，确定如何使项目的挑战性最好。通常，项目 必须密封，以某种方式返回到一种状态，此状态相当于蒸汽渗透。 举例： 问：一个直径均一的软管内哪一点最难灭菌？ 答：在软管长度的中心。 问：如何将一个 3 米长的热电偶插入 20 米的软管中间？ 答：在软管中刻一插槽，热电偶沿着插槽插入软管，确保用硅将插槽密封，如果你没 有密封，则不能挑战软管。或者，将两个 10 米的软管（如果可行）插入热电偶后用 连接器将其连接，用这种方法则不用破坏 20 米长的管子 问：瓶子、锥形瓶和柱形瓶最坏位置是哪儿？ 答：在靠近底部的中间（但不接触底面） 。 问：如何保持热电偶在一个密封瓶子里的位置？ 选择一个内径与热电偶探头差别足够小的硅橡胶管件套住它以确保不能滑落。在瓶盖 上钻一个和管子外径一样大的孔。通过孔将管子插入瓶中。将探头推入管子中，推动 探头直至到达瓶子中所需位置。确保它不要触碰瓶壁。对于橡胶瓶塞的瓶子，在筛子? 2011 PharmOut Pty Ltd Page 5 of 10 Version - 01White Paper Top 10 considerations when validating an autoclave中间钻一个小孔，足以使热电偶通过。 注意事项 5 热电偶温度传感器比较复杂，而且并非总是提供准确的数据 下列重点介绍一些使用热电偶传感器时的注意事项： ? 当导线的外层塑料保护膜被切割并且有空气或蒸汽通过，就会发生一些蒸汽损 耗（泄漏），可能会导致泄漏测试失败。 ? 验证热电偶装置是涂凝析油并且削掉外部保护层，以确保任何流体释放。如 ? 冷凝水通过电线传递到电子，热电偶将被销毁。 ? 很难验证热电偶，它对灭菌能力影响很大（高额的投资）。 ? 当进料或出料时导线可能被高压灭菌器的轮子卡住（并损坏） ? 将导线装在密封瓶里并且不碰到内壁是很难做到的，并且降低瓶子的无菌程 ? 你可能会受限于高温灭菌器进口的导线数量。 ? 尽管前/后校准核查符合规格，某些热电偶电阻位置的改变，也可产生不准确 的和/或不可靠的数据。 案例研究 这个例子是一箱装九个热电偶。他们均匀分布在顶部，中部和底部和前、中、后部。 均在箱内，遵循第二阶段热分布的要求。 该研究采用箱内热电偶传感器在 121.1 ° C 周期 40 分钟 。 箱内最大压 2.16bar （在 任何时间）相当于 122.7 ° C。一个探头（顶部前左）温度连续达成 123.3 ° C 和 123.5 ° C。所有其他探头在规定限额温度 120.1 ° C +2 ° C/-1 ° C，122.4 ° C 至 122.7 ° C 之间 温度差始于加热阶段，甚至在消毒灭菌和真空冷却阶段仍然存在。该设备工程师和制 造商一致认为，在这个点的温度读数是不准确和不可靠的。热电偶读数与蒸汽压力指 示数和其他热电偶读数不一致。因此，在这一点没有任何有用的数据。注意事项 6 确定验收标准 ? 一个例子： 当您运行验证研究时，您只认识到能不能达到验收标准。但是，是不是真的需 要摆在首位？ 重要的是要了解灭菌柜的周期及其参数。 例如， 对于消毒或去污是负载热敏感， 还是可以遵循矫枉过正循环？它是一种渗透负载（硬/包装货物），或者是一 种液体呢？ 大多数验证部门有标准操作程序（SOP）详细说明灭菌工艺验证的要求。列出 所有验收标准的完整清单。 灭菌柜不同阶段的循环周期存在不同的遵循标准： 第一阶段 - 热分布（空室） 第二阶段 - 热分布（装载） 第三阶段 - 热分布（装载）内部冷点测定 第四阶段 - 热渗透 第三阶段和第四阶段可能存在不同的要求，如果你是灭菌液体（非真空）与渗Page 6 of 10 Version - 01? 2011 PharmOut Pty LtdWhite Paper Top 10 considerations when validating an autoclave? ? ? ? ? ? ? ? ?透（真空）的情况，灭菌结束 F0&15（只有液体）。 典型的验收标准如下： 灭菌结束所有渗透周期需要在 SAL 10-6（无菌保证值《10-6）。所有渗透至少遵 循一次后真空循环，消除灭菌箱内蒸汽（阶段三及四）。 所有液体循环周期每分钟 SAL 10-6，每分钟 F0 & 15，因为它们不使用真空，并自 然冷却 （阶段三及四）。 在整个消毒阶段所有的温度都在 3 ° C 变化的范围内（例如阶段第二，三及四） 121.1 ° C -1℃/ 2 ° C 在整个灭菌阶段，灭菌柜温度都在柜内平均温度 1.0 °，（阶段二）。 蒸汽的温度相当于其蒸气压（阶段 II，III 及 IV）。 定时测量控制在准确度± 1％。? 记录验证前和验证后的数据确保温度测量系统的准确度在± 0.5℃ 装载物在周期结束时干燥（只有渗透周期）。 所有灭菌器的生物指标为负，有效的控制潜伏期内（第四期）。注意事项 7 充分验证运行测试记录 测试过程中做验证运行记录文件要知道那些是需要被记录的以及如何陈述它。这个文 件必须是明确的，文件是公开透明的，且必须符合 GMP 要求。它必须是完整的，并且 必须包括以下项目： ? 显示器显示灭菌柜内物料的位置 ? 各热电偶数目和精确位置，每个里面都有生物指示和化学指示 ? 从数据记录仪打印输出 ? 从灭菌器打印或输出图表 ? 灭菌周期起始和结束（每个数据的记录时间） ? 高压灭菌柜控制器和温度验证监测装置的时间差异 ? 每个生物指示和化学指示的结果 每个设备 ID 都有负载说明，日期，运行次数和行周期的开始/结束时间的文件。 当进行运行测试验证，如果你没有记录好文件，一起拿来做报告时，你将无法进行数 据分析。用不足或质量差的数据来支持验证过程将无法通过审计。 注意核实热电偶的精确度验证标准，如果标准过高（如所有的热电偶必须达到验证标 准），如果有一或两个热电偶停止运行，其他的也可能停止运行或运行后超出温度限 制 注意事项 8 热电偶性能验证的频率 如果您很多次进行运行测试（在几个星期内），你需要考虑热电偶的准确度。可以在 每次运行和/或在整个测试周期结束后完成。如果你一直等到测试周期结束后，所有 运行的风险的评估没有任何价值，因为它们不符合验证标准。但是，在每次运行后做 验证，大大增加了所需的时间来完成测试。每运行三次或每隔数天进行验证是比较合 理的。 正如注意事项 6 指出，验证热电偶的准确度，应让至少一个或两个热电偶失效。? 2011 PharmOut Pty Ltd Page 7 of 10 Version - 01White Paper Top 10 considerations when validating an autoclave注意事项 9 有足够的时间完成高温灭菌器的验证 人们很容易低估验证高温灭菌器的时间，在整个验证过程中你需要做些什么。 例如，它可能需要设置长达四个小时来运行，也就是说，准备装载，放置探头，BLS 和 CIS 导入负载等， 如果生产需要使用高压灭菌器， 你需要去掉您的探针， BLS 和 CIS， 然后重新开始，有效地运行一天。进行验证时配合生产部门的工作，以确保您可充分 将装入高温灭菌器。 另一种方法是结合第二、第三阶段（热分布）与第四阶段（热渗透），以节省时间。 结合这三个阶段可以减少完成验证的时间，不过，这样做您需要考虑以下几点： 1 您需要同一时间将探头放入箱内和负载物上。通过高压灭菌器内层锅你能安装所有 的探头吗？如果不能，那么你需要单独验证每个阶段，或降低探头的次数。 2 结合这三个阶段大大增加你的准备时间。如果你的时间比较紧，你可能没有时间完 成这项研究。如果发生这种情况，那么它需要完成的时间比单独做每个阶段的时间要 长。 3 如果你的时间比较紧，将很容易遗忘一些东西或者犯错误。 4 还有更多的数据需要考虑。进行下一个研究前，如果你只检查了几个关键点，您可 能会疏忽一些不符合验证标准的,这可能意味着所有后来的研究处于风险，因为数据 无法得到证实。例如，一个探头读数可能过高。 5 充足的时间完成报告。 如果你是对新的高压灭菌器进行验证，那么你需要足够的时间： （一）书面验证计划 （二）书面委托协议和 IQ （三）准备 OQ / PQ （四）开展 OQ / PQ 的研究 （五）书写 OQ / PQ 的报告，准备文件夹等 如果您正在进行数次运行测试（在几个星期内），那么你需要确保有足够的时间准备 下发文件和写报告。允许运行一天，再用一天来分析数据，也就是说，有两个研究日。 留下充足的时间写协议和报告， 并有充足的时间核查且可通过其他人批准 （如适用） 。 如果您正在摸索验证周期，那么这也将需要时间 注意事项 10 制定正确的程序进行控制，以确保操作一致性和正确性 恭喜你，你刚刚完成了一个新的高压灭菌器配置不同周期和负载物的验证。现在，需 要那些控制，确保装载验证统一使用？ ? ? ? 准备新高温灭菌器的标准操作程序（SOP）。对每个验证周期必须有明确的指 引，包括负载的配置图，专业操作者按照说明测试。 对每个使用高压灭菌器操作者进行培训和 SOP 考试。 每个运行周期都应准备记录本。Page 8 of 10 Version - 01? 2011 PharmOut Pty LtdWhite Paper Top 10 considerations when validating an autoclave? ?采用基于风险评估的方法制定故障检测指南，包含在 SOP 里。制造商的文件和 网站可详述通常出现的故障。 对于高压灭菌器和装载量来说，连续鉴定程序是必需的，频率可为 6，12 或 24 个月。词汇 术语 生物指标（BI） 芽孢指标和检验微生物数量的小瓶放在装载物里高压灭菌柜的性能 化学指标（CI） 商业可利用性指标，指示蒸汽的暴露量 净化 物品没有微生物污染物，但并不适合在 A 级洁净区使用。 F0 值 F0 值为一定灭菌温度（T）下产生的灭菌效果与 121℃，Z 值 为 10℃所产生的灭菌效果相同时所相当的时间相同 装载物 装入高压灭菌柜是进行灭菌的 杀伤力 SAL 10-6 微生物的数量减少到 10-12 SAL 产品经灭菌/除菌后微生物残存的概率,规定一个 10-6 SAL 有百 万分之一的微生物残存。 设定温度 在该温度下灭菌。这是高压灭菌柜达到灭菌要求的灭菌温度。 灭菌 杀死所有活的微生物，如致病性或腐生菌，无性孢子。 灭菌后的物品可用于所有领域，包括 A 级洁净区。 热电偶 温度测量装置? 2011 PharmOut Pty LtdPage 9 of 10Version - 01White Paper Top 10 considerations when validating an autoclave关于珐奥药品器械咨询顾问有限公司珐奥药品器械咨询顾问有限公司是对药品，医疗设备，兽药工业的咨询顾问公司。 珐奥药品器械咨询顾问有限公司专门从事 GMP 认证，验证，不断改进的咨询和培训。珐奥药品器械咨询顾问有限公司怎样帮助您审计准备和差距分析: 我们拥有经验丰富的顾问包括前 TGA 和 PIC/S 的审计官，能够执行 TGA, PICS 和美国 FDA 对设施 GMP 要求的审计准备和 GMP 的差距分析。 审计报告的回应:如果缺陷在药政法规审计时发现， 我们可以提供纠正缺陷和准备审计报告回 应的帮助 协助国际药政监管事务: 我们可以帮助您准备下列国际监管机构- TGA, EMA 和美国 FDA 药品 注册申请并帮助您获得批准。 质量管理体系: 我们有经验丰富的质量管理体系设计顾问，可以适应您的业务或重新设计符 合相关标准的现有质量管理体系。 技术文件编写: 我们可以帮您写的操作规程和工作指示，您的员工能直接使用并易于遵循。 ISO及GMP的咨询: 我们可以提供有关药品的ISO 9001或医疗器械的ISO 13485质量管理系统， 政策 和形式的实际建议和意见。 我们还可以帮助您获得下列国际（美国 FDA，英国 MHRA，和 TGA）监管当局的批准。这包括 第 11 部分和附件 11FDA 和 TGA 要求的认证。 培训: 我们提供 GAMP/GLP/GMP 和审计的培训服务， 可以专门制定这些培训以满足您的业务需 求.www.pharmout.cn? 2011 PharmOut Pty LtdPage 10 of 10Version - 01
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二、验证目的:通过对设备的热分布试验和热穿透试验,证实该蒸汽灭菌柜的运行能...(注意不要将探头插入待灭菌材料中,而应在它的周围) 4.4.3 按《LZZ-1.2 ...立式压力蒸汽灭菌器验证。1 主题内容 本标准规定了立式压力蒸汽灭菌器的确认方案...7.2.4.4 结果判定 若被检培养基上的菌落平均数不小于对照培养基上的菌落...哈尔滨红豆杉生物制药有限公司验证文件文 件名称 1 1.1 引言 概述 出厂日期: 纯蒸汽灭菌柜验证报告 文件编号 第 3 页共 10 页 生产厂家:张家港市环宇制药设备...4、验证内容: 4.1 XG1?DWF-1.5 B 型脉动真空蒸汽...(1)对照蒸汽灭菌柜设计规范、GMP 要求以及供应商...注意热电偶焊接的尖端不能与灭菌腔的金属表面 接触,...8 - 2 - XX 生物制药有限公司 GMP 验证文件 型立式压力蒸汽灭菌器验证方案 型立式压力蒸汽灭菌器验证方案方案编号: 一、 验证概述和目的(一)验证概述: LS-...立式压力蒸汽灭菌器验证 验证编号: 设备编号: 年 6 月 目一、文件...用灭菌锅灭菌的培养基中每次取 10 瓶(注意分别从灭菌器中不同位置)分别做实验...高压蒸汽灭菌器的使用方法与注意事项_自然科学_专业资料。高压蒸汽灭菌锅 高压蒸汽灭菌锅的使用方法与注意事项 一、高压蒸汽灭菌锅的使用方法 (1)在外层锅内加适量...蒸汽灭菌柜的验证指南,以及蒸汽灭菌工 艺及验证的...安全注意事项;修理手册(包括可更换的部件一览表) ;...保存和使用生物指 示剂,并通过阳性对照试验来确认其...4.2 验证灭菌柜位置:质检室灭菌间 5 职责 姓名 xxxx xxxx xxxx xxxx xxxx xxxx 6 生物指示剂 品名:四环牌 ME-压力蒸汽灭菌生物指示剂 规格:该生物指示剂为 ...水浴式灭菌柜验证方案 编号: 起草人: 年 月 审核人: 年 月 批准人: 年 月 日 目 录 1、验证目的 2、验证小组职责与分工 3、灭菌器概述 4、文件 5、...
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