Method for designing and implementing a vapor phase hydrogen peroxide decontamination cycle

Abstract

A method for decontaminating a chamber using a VPHP decontamination cycle includes sealing the chamber, circulating a dose of gas through the chamber for a residence time, and aerating the chamber until no more than an acceptable residual amount of gas remains within the chamber. A method for selecting parameters of a VPHP decontamination cycle for the chamber includes conducting multiple experiments testing different amounts of gas and different amounts of time, selecting a dose of gas that results in a minimum amount of gas that maintains full saturation within the chamber for a selected time, and selecting a residence time that is both no more than the selected time and a minimum amount of time for which the residual amount of viable spores after circulating the dose of gas is acceptable.

Description

[Technical field]

[0001] This application relates generally to vapor phase hydrogen peroxide decontamination cycles, and more specifically to the design (eg, parameter selection) and / or implementation of vapor phase hydrogen peroxide decontamination cycles. [Background technology]

[0002] Vapor phase hydrogen peroxide (VPHP) decontamination is a decontamination method that can be used in industries including life sciences, chemical sciences, pharmaceuticals, medicine, electrical engineering, manufacturing, assembly, and other applications by circulating hydrogen peroxide-containing gas in a closed-loop airflow. Applications of VPHP decontamination include, for example, decontamination of chambers, such as rooms, airlocks, clean rooms, isolators, laminar flow benches, biological safety cabinets, access restriction barrier systems, incubators, and decontamination chambers. The equipment used to perform VPHP decontamination cycles is often a stand-alone equipment. VPHP is popular due to, for example, its ability to penetrate a wide variety of materials, its ability to keep the chamber dry and leave no residues behind under decontamination, its low toxicity, its low operating costs, its ability to reduce cross-contamination due to minimal equipment intrusion, and its compatibility with chambers of various geometries.

[0003] One specific application of VPHP decontamination is the decontamination of isolator chambers used in the manufacture of drug products (e.g., the "fill" stage where drug products are filled into vials or other containers). FDA, in its "Guidance for Industry Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice," recommends that isolators achieve a minimum of a 6 log reduction in colony forming unit (CFU) count (or a reduction to 1 ppm). One way to assess whether a VPHP decontamination cycle achieves the desired CFU reduction is by using biological indicators (BIs). BIs can be manufactured to have a specific D value. The D value is the time required to achieve a 1 log (or 90%) reduction in CFU, as follows:

number

[0004] Factors that affect the effectiveness of a VPHP decontamination cycle in achieving FDA recommended levels of CFU reduction include VPHP exposure time (dwell time), VPHP dosage, VPHP circulation, D value of the BI, initial CFU count, location of the BI within the isolator, isolator design, and humidity and temperature within the isolator. In general, parameters of a VPHP decontamination cycle that can be controlled include VPHP exposure time (dwell time), VPHP dosage, VPHP circulation, and humidity and temperature inside the chamber. In some cases, the isolator configuration can also be controlled to some extent.

[0005] CFU reduction is not the only consideration for VPHP decontamination. Another important consideration is the efficiency of the VPHP decontamination cycle. The "efficiency" of a VPHP decontamination cycle can refer to, for example, time efficiency (i.e., how long a VPHP decontamination cycle takes), material efficiency (e.g., gas consumption), and / or human labor efficiency (e.g., number of person-hours required to perform a VPHP decontamination cycle).

[0006] Time efficiency affects the throughput of an isolator, and a poor time efficiency of a VPHP decontamination cycle will result in a long downtime of the isolator, which will in turn result in a reduced filling rate of the isolator. It is worth noting that in many applications, large isolators with high filling throughput are not feasible for a variety of reasons, including cost, transportation logistics, physical space, etc. Therefore, small isolators with lower throughput compared to large isolators are often used. For such small isolators, it can be even more important to avoid further loss of throughput due to a time-consuming and inefficient decontamination cycle. Therefore, careful determination of the parameters of the VPHP decontamination cycle can be critical.

[0007] In conventional VPHP decontamination, the parameters of the VPHP decontamination cycle may be determined using an "overkill" approach, such as using a longer residence time and a higher dosage than necessary to achieve the desired CFU reduction. However, this "overkill" approach is associated with certain disadvantages. For example, applying too little gas may not achieve the desired CFU reduction, while applying too much gas may reduce efficiency (e.g., in terms of time, materials, and possibly human labor) and may cause condensation on surfaces within the chamber. Furthermore, applying too little residence time may not achieve the desired CFU reduction, while applying too much residence time may reduce efficiency (e.g., in terms of time and possibly human labor). The "overkill" approach also requires guesswork (e.g., trial and error), and is therefore inconsistent, operator-dependent, error-prone, and inefficient (e.g., in terms of time, materials, and possibly human labor). Summary of the Invention [Means for solving the problem]

[0008] One aspect of the present disclosure provides a method of decontaminating a chamber using a gas-phase hydrogen peroxide decontamination cycle, the method including: (a) sealing the chamber from an external environment while a viable spore population is in the chamber; (b) circulating a dosage of hydrogen peroxide-containing gas into the chamber for a residence time, the dosage of gas being a minimum amount of gas that maintains complete saturation in the chamber for the residence time within a first tolerance range, and the residence time being a minimum amount of time that the viable spore population is exposed to the dosage of gas to reduce the viable spore population to an acceptable residual amount, within a second tolerance range; and (c) aerating the chamber until gas remaining in the chamber after circulating the dosage of gas into the chamber for the residence time is equal to or less than the acceptable residual amount, wherein the first tolerance range and the second tolerance range are each equal to or less than 20%.

[0009] Another aspect of the present disclosure provides a method of selecting a dosage and residence time of a decontamination cycle in a chamber using a vapor phase hydrogen peroxide decontamination cycle, the method comprising: (a) conducting a plurality of experiments testing a plurality of amounts of hydrogen peroxide-containing gas and a plurality of amount times, where conducting the plurality of experiments includes, for each experiment in the plurality of experiments, circulating an amount of gas among the plurality of amounts of gas into the chamber for an amount of time among the plurality of amounts of gas, monitoring a concentration of the amount of gas in the chamber for the amount of time, and determining a remaining amount of viable spores in the chamber after circulating the amount of gas into the chamber for the amount of time; (b) selecting a dosage amount of gas from the plurality of amounts of gas that results in a minimum amount of gas that maintained full saturation in the chamber for the selected time when circulated through the chamber during the plurality of experiments; and (c) selecting a residence time that is (i) equal to or less than the selected time, and (ii) a minimum amount of the plurality of amounts of time during which the determined remaining amount of viable spores did not exceed an acceptable remaining amount when the dosage amount of gas was circulated through the chamber for the residence time during the plurality of experiments.

[0010] Those skilled in the art will appreciate that the figures described herein are included for illustrative purposes and are not intended to limit the disclosure. The drawings are not necessarily to scale, emphasis instead being placed on illustrating the principles of the disclosure. It should be understood that in some instances, various aspects of the described embodiments may be shown exaggerated or enlarged to facilitate understanding of the described embodiments. In the drawings, like reference characters generally refer to functionally similar and / or structurally similar components throughout the various views. [Brief description of the drawings]

[0011] [Figure 1] 1 illustrates the inside of an exemplary chamber of an isolator. [Diagram 2] 1 is a graph illustrating exemplary hypothetical experimental results of VPHP concentration over time for various dosages of hydrogen peroxide-containing gas. [Diagram 3] 1 is a table illustrating exemplary hypothetical experiment growth results for multiple biological indicators after exposure to a variety of different doses of gas for a variety of different residence times. [Figure 4] FIG. 1 is a flow diagram illustrating an exemplary method for decontamination within a chamber using a vapor phase hydrogen peroxide decontamination cycle. [Diagram 5] FIG. 1 is a flow diagram illustrating an exemplary method for selecting parameters for a chamber interior decontamination cycle using a vapor phase hydrogen peroxide decontamination cycle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present disclosure aims to alleviate problems associated with conventional approaches (e.g., as described in the Background section) by providing one or more improved methods for designing and / or implementing VPHP decontamination cycles. These one or more methods may include determining a residence time and dosage each large enough to achieve a desired CFU reduction without the inefficiencies of conventional VPHP decontamination, and without causing humidity increase and condensation, and in the example of an isolator, potentially compromising product quality.

[0013] Furthermore, in some embodiments, one or more methods of the present disclosure may be partially or fully automated, thereby not only increasing efficiency with respect to human labor, but also eliminating inconsistencies that result from reliance on the technical skills of operators.

[0014] The various concepts introduced above and discussed in more detail below may be implemented in any of numerous ways, and the concepts described are not limited to any particular manner of implementation. Example implementations are provided below for illustrative purposes.

[0015] FIG. 1 illustrates a top view of an exemplary chamber of an isolator 100 that may be decontaminated by the VPHP decontamination techniques described herein. The isolator shown in FIG. 1 may be a stand-alone piece of equipment, such as a Vanrx® SA 25 filling machine, but in other examples, the isolator 100 may be integrated into other equipment. The isolator 100 may be used to fill containers, including vials, syringes, cartridges, tubes, beakers, cups, or any other suitable holding structure, with liquids, solids, gases, or plasma (e.g., drug products). The isolator 100 may be a globeless isolator and / or the isolator 100 may use peristaltic filling.

[0016] In this example, the isolator 100 includes two chambers: a decontamination staging isolator (DSI) chamber 102 and a loading isolator chamber 104. The DSI chamber 102 may be a container preparation area, and the loading isolator chamber 104 may be an area for loading the container. The DSI chamber 102 may include equipment for container picking, preparation, movement, or storage, such as a carousel. The loading isolator chamber 104 may include equipment for loading the container, such as a loading nozzle. In the example shown, the interior volume of the loading isolator chamber 104 is larger than the interior volume of the DSI chamber 102.

[0017] The DSI chamber 102 and the filled isolator chamber 104 have exterior doors 106 and 108, respectively. Each of the exterior doors 106 and 108 can be opened individually to provide access to each of the DSI chamber 102 and the filled isolator chamber 104. Between the DSI chamber 102 and the filled isolator chamber 104 is an interior door 110, which can be opened to allow transfer of containers between the DSI chamber 102 and the filled isolator chamber 104.

[0018] In one example, if one of the exterior doors 106 or 108 is open and the interior door 110 is closed, then the chamber to which the exterior door is open (either the DSI chamber 102 or the filled isolator chamber 104) may be considered contaminated. In another example, if the interior door 110 is open when one of the exterior doors 106 or 108 is opened, then both the DSI chamber 102 and the filled isolator chamber 104 may be considered contaminated. In another example, if both exterior doors 106 and 108 are closed and one of the chambers (either the DSI chamber 102 or the filled isolator chamber 104) is considered contaminated, and the interior door 110 is open, then both the DSI chamber 102 and the filled isolator chamber 104 may be considered contaminated. In another example, if both exterior doors 106 and 108 are open, then both the DSI chamber 102 and the filled isolator chamber 104 may be considered contaminated, regardless of the state of the interior door 110.

[0019] Decontamination of all or a portion of the isolator 100 may be accomplished through any number of decontamination cycles. Three exemplary decontamination cycle types are described herein: (i) full cycle decontamination, (ii) filled isolator decontamination cycle, and (iii) decontamination cycle isolator decontamination cycle.

[0020] A full cycle decontamination may be performed by opening the interior door 110, closing both exterior doors 106 and 108, and circulating a gas containing hydrogen peroxide through both the DSI chamber 102 and the filled isolator chamber 104. Given that both the DSI chamber 102 and the filled isolator chamber 104 were considered contaminated prior to performing the full cycle decontamination, after performing the full cycle decontamination, the filled isolator chamber 104 may be considered decontaminated and the DSI chamber 102 may be considered contaminated. After performing the full cycle decontamination, the seal of the interior door 110 may also be considered decontaminated.

[0021] The fill isolator decontamination cycle may be performed by closing the interior door 110, closing the exterior door 108 of the fill isolator chamber 104, and circulating a gas containing hydrogen peroxide through the fill isolator chamber 104. After performing the fill isolator decontamination cycle, the fill isolator chamber 104 may be considered decontaminated.

[0022] A decontamination preparation isolator decontamination cycle may be performed by closing the interior door 110, closing the exterior door 106 of the DSI chamber 102, and circulating a gas containing hydrogen peroxide through the DSI chamber 102. After performing a decontamination preparation isolator decontamination cycle, the DSI chamber 102 may be considered decontaminated.

[0023] Generally, performing one of the three decontamination cycles listed above involves circulating a dose of hydrogen peroxide-containing gas to the desired isolator chamber or chambers, waiting for a residence time to elapse, and then aerating to remove the gas until the residual gas concentration level is below some threshold amount (e.g., 1 ppm). The isolator 100 may have multiple chambers to be decontaminated. As used herein, the term "chamber chamber" refers to all of the chambers (or chambers) through which the hydrogen peroxide-containing gas is circulated for the purpose of the VPHP decontamination cycle. For example, in a full cycle decontamination, gas is circulated to both the filled isolator chamber 104 and the DSI chamber 102; therefore, in this example, the collective chambers of these two chambers may be referred to as the "chamber chamber". In another example, in a filled isolator decontamination cycle, gas is circulated only to the filled isolator chamber 104; therefore, in this example, only the chamber of the filled isolator chamber 104 may be referred to as the "chamber chamber".

[0024] 2 illustrates a graph 200 illustrating exemplary hypothetical experimental results of VPHP concentration over time for various dosages of hydrogen peroxide-containing gas. In general, the exemplary experimental results included in FIG. 2 may be used in determining the dosage of an exemplary VPHP decontamination cycle.

[0025] The exemplary hypothetical experimental data included in FIG. 2 may correspond to multiple experiments varying the amount of gas containing hydrogen peroxide. FIG. 2 illustrates hypothetical results of an experiment involving testing five amounts of gas (specifically, 10 mL, 8 mL, 6 mL, 4 mL, and 2 mL). It is noted that the gas may include a variety of different concentrations of hydrogen peroxide. For example, the gas may be 10% hydrogen peroxide, 20% hydrogen peroxide, 30% hydrogen peroxide, 40% hydrogen peroxide, 50% hydrogen peroxide, 60% hydrogen peroxide, 70% hydrogen peroxide, 80% hydrogen peroxide, or any other suitable concentration of hydrogen peroxide.

[0026] In Figure 2, the parts per million (ppm) of VPHP are plotted as a function of time for five amounts of gas. Three main time intervals are illustrated in Figure 2. In chronological order, they are: (i) an introduction phase during which gas is introduced into the chamber, (ii) a circulation phase during which gas is circulated throughout the chamber, and (iii) an aeration phase during which gas is removed from the chamber.

[0027] Looking initially at the introduction phase, toward the beginning of the recorded time period (approximately the first 200 seconds in this example), each of the five curves rises sharply from 0 ppm to higher ppm corresponding to gas being introduced into the chamber. The introduction phase can be considered complete once the entire amount of gas has been introduced into the chamber.

[0028] Turning now to the circulation phase (which begins at approximately 200 seconds and ends at approximately 1100 seconds in this example), gas circulates throughout the chamber. The 2 mL, 4 mL, and 6 mL volumes of gas each experience a drop in VPHP ppm over the circulation time interval. However, the 8 mL and 10 mL volumes of gas each exhibit a plateau or "table-top" behavior over the circulation time interval. This table-top behavior suggests that the 8 mL and 10 mL volumes of gas are each sufficient to maintain full saturation in the chamber over the circulation time interval. Full saturation in the chamber corresponds to the highest VPHP ppm that may exist inside the chamber. Introducing more gas beyond the full saturation point will not increase the VPHP ppm inside the chamber, but may instead result in undesirable condensation of gas on surfaces within the chamber.

[0029] Finally, looking at the aeration phase (starting at approximately 1100 seconds in this example), the five curves each have a steep drop reflecting the gas being removed from within the chamber. The aeration phase may be considered complete once the VPHP ppm has dropped below a threshold value (e.g., 1 ppm). It is noteworthy that for each of these five amounts of gas, the higher the amount of gas, the longer it takes for the VPHP ppm to drop below the desired threshold.

[0030] As discussed above, based on the exemplary hypothetical results shown in FIG. 2, both 8 mL and 10 mL of gas are sufficient to maintain full saturation in the chamber over the cycling time interval. However, the 10 mL of gas is more likely to cause condensation (or more condensation) on surfaces in the chamber than the 8 mL of gas. In addition, as seen in FIG. 2, the 8 mL of gas is more quickly aerated and removed from the chamber than the 10 mL of gas. For at least these reasons, in this example, 8 mL is the preferred amount of gas among those tested in these five experiments. Thus, in this example, 8 mL may be selected as the application volume.

[0031] The result of 8mL as the dosage may be unique to this example and may depend, for example, on the chamber interior under decontamination. For example, if the chamber interior is the isolator 100 shown in FIG. 1, the dosage may vary between the three different decontamination cycles described. Taking this example further, the full cycle decontamination may have a larger chamber interior volume compared to the pre-decontamination isolator decontamination cycle. Thus, the dosage required for the full cycle decontamination may be greater than the dosage required for the pre-decontamination isolator decontamination cycle. Also, the difference in chamber volume between the full cycle decontamination and the filled isolator decontamination cycle may not be enough to require different dosages. Thus, the dosage required for the full cycle decontamination may be the same as the dosage required for the filled isolator decontamination cycle.

[0032] 3 illustrates a table 300 of experimental hypothetical growth results for biological indicators after exposure to different amounts of gas for different amounts of time in a chamber. In general, the exemplary experimental results included in FIG. 3 may be used in determining the residence time of a VPHP decontamination cycle.

[0033] In Figure 3, exemplary hypothetical data for multiple experiments is illustrated. The hypothetical data illustrated in Figure 3 may correspond to the same or a different experiment as the hypothetical data illustrated in Figure 2. Regardless of whether the hypothetical data illustrated in Figure 3 corresponds to the same experiment as the hypothetical data illustrated in Figure 2, the hypothetical data illustrated in Figure 3 may correspond to the same isolator as the hypothetical data illustrated in Figure 2 or to a different isolator, either or both of which may be the isolator 100 of Figure 1.

[0034] Generally, for each of these experiments, a respective amount of gas is circulated through a chamber containing the BIs (in these experiments, seven BIs) for a respective amount of time. The gas is then removed from the chamber, and the BIs are then tested to determine if the desired CFU reduction was achieved.

[0035] One exemplary method for determining whether a desired CFU reduction has been achieved is by removing the BI from the chamber after circulating a certain amount of gas for a certain amount of time and incubating the BI in a growth-promoting medium for 7 days. Given that over 1 million CFUs were inoculated, and given that the desired CFU reduction is a 6 log reduction, the absence of growth after 7 days indicates that circulating gas for that amount of time has achieved a 6 log reduction in CFU (a "negative" result). Conversely, the presence of cell growth within the 7 day incubation period indicates that at least one viable organism survived circulating gas for that amount of time (a "positive" result).

[0036] In this example, the seven BIs of FIG. 3 may be in one or more locations within the chamber (e.g., at least some in locations within the chamber that are relatively difficult to decontaminate). The BIs may be inoculated with, for example, viable spores of Geobacillus stearothermophilus, or another suitable type of thermophilic bacteria. The D-values ​​of the BIs may be provided by the manufacturer of the BIs and may be, for example, 0.25 min, 0.5 min, 1 min, 1.5 min, 2 min, 2.5 min, or any other suitable D-value.

[0037] Assuming that the hypothetical data in FIG. 3 corresponds to the same isolator as the hypothetical data in FIG. 2, the application volume may be assumed to be 8 mL, in which case the hypothetical data in FIG. 3 serves primarily to aid in determining residence time.

[0038] For an 8 mL dose, table 300 shows that circulating the gas for 100 seconds results in no growth for all BIs except one (BI#4). 100 seconds is not selected as the residence time because it does not result in no growth for all BIs. On the other hand, 300 seconds and 500 seconds both result in no growth for all seven BIs. Therefore, 300 seconds is the minimum amount of time (among the amounts of time tested) to achieve no growth for all seven BIs. Thus, in this example, 300 seconds may be selected as the residence time.

[0039] It is also noteworthy that the hypothetical data in Figure 3 show that once full saturation over the entire residence time is achieved, further increases in application rate do not result in improved CFU reduction, as observed in that the growth-non-growth behavior over time is the same for 8 mL and 10 mL volumes of gas (assuming that 8 mL achieves full saturation over that amount of time, consistent with the hypothetical results in Figure 2).

[0040] Although table 300 only shows one trial / experiment for each combination of dose and dwell time, it is understood that multiple trials / experiments may be performed. For example, performing each trial / experiment in triplicate helps validate the accuracy of the results. In another example, multiple trials / experiments may be performed, each using BIs with different D values ​​and / or BIs in different locations.

[0041] It is understood that the result of 300 seconds as the residence time may be unique to this example and may depend on a number of factors, such as the size and geometry of the chamber chamber under decontamination, the concentration of gas, the temperature and humidity within the chamber chamber. For example, if the chamber chamber is the isolator 100 shown in FIG. 1, the residence time may vary between the three different decontamination cycles described. Taking this example further, the full cycle decontamination may have a larger chamber chamber volume compared to the pre-decontamination isolator decontamination cycle. Thus, the residence time required for the full cycle decontamination may be longer compared to the residence time required for the pre-decontamination isolator decontamination cycle. Also, the difference in chamber volume between the full cycle decontamination and the filled isolator decontamination cycle may not be sufficient to require a variety of different residence times. Thus, the residence time required for the full cycle decontamination may be the same as the residence time required for the filled isolator decontamination cycle.

[0042] FIG. 4 is a flow diagram illustrating an exemplary method 400 for decontaminating the interior of a chamber using a vapor phase hydrogen peroxide decontamination cycle.

[0043] In the illustrated method 400, the chamber is initially sealed from the outside environment while a viable spore population is present within the chamber (block 402). The viable spore population may be contained within one or more BIs, which may be located at one or more locations within the chamber. The viable spore population may be a population of bacteria, such as a thermophilic bacterium (e.g., Geobacillus stearothermophilus). In some embodiments, the viable spore population comprises between 1 million and 5 million colony forming units. The "external environment" may be anywhere outside the chamber. For example, if the chamber is a filled isolator chamber 104 of FIG. 1, the external environment may include the DSI chamber 102, the laboratory environment in which the isolator is located, etc. A chamber may be considered sealed if it is "airtight" to the outside environment (e.g., does not allow air, gases including hydrogen peroxide, or any other gases to flow between the chamber and the outside environment). The volume within the chamber may be 50 cubic meters, 25 cubic meters, 10 cubic meters, 5 cubic meters, 1 cubic meter, or any other suitable chamber volume. Sealing the chamber from the outside environment as in block 402 may be performed by at least one of one or more processors providing instructions to the hardware or by a human. For example, a VPHP decontamination process may begin when a human inputs an instruction (e.g., pressing a virtual button on a graphical user interface generated by the one or more processors), in response to which one or more actuators may be actuated by the one or more processors to seal the chamber.

[0044] Next, the illustrated method 400 circulates a dose of hydrogen peroxide-containing gas into the chamber for a residence time, where the dose of gas is within a first tolerance range, a minimum amount of gas that maintains full saturation in the chamber for the residence time when circulated therein, and the residence time is within a second tolerance range, a minimum amount of time that the viable spore population is exposed to the dose of gas to reduce the viable spore population to an acceptable residual amount (block 404). In some embodiments, a vacuum is created in the chamber before circulating the gas into the chamber. The first and second tolerance ranges can each be, for example, 30%, 20%, 15%, 10%, 5%, 3%, 1%, 0.5% or less, or any other suitable tolerance. The tolerance percentage may be measured either relative to a determined value (i.e., determined dosage and determined residence time) or relative to a theoretical optimum value (i.e., optimum dosage and optimum residence time). The chamber may be a decontamination-ready isolator chamber (e.g., decontamination-ready isolator 102 of FIG. 1) and / or a filled isolator chamber (e.g., filled isolator chamber 104 of FIG. 1) of an isolator (e.g., isolator 100 of FIG. 1). The gas may be 10% hydrogen peroxide, 20% hydrogen peroxide, 30% hydrogen peroxide, 40% hydrogen peroxide, 50% hydrogen peroxide, 60% hydrogen peroxide, 70% hydrogen peroxide, 80% hydrogen peroxide, or any other suitable hydrogen peroxide concentration. The dosage may be 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 15 mL, 20 mL, 25 mL, or any other suitable dosage of gas. The residence time may be 10 seconds, 30 seconds, 60 seconds, 100 seconds, 200 seconds, 300 seconds, 400 seconds, 500 seconds, 750 seconds, 1000 seconds, or any other suitable residence time. The residence time may be 250-350 seconds, 300-500 seconds, or any other suitable range. In a more specific example, the gas may be hydrogen peroxide at a concentration of 45%-55%, and the dosage of gas may contain 6-10 mL of gas. In another example, the gas may be hydrogen peroxide at a concentration of 45%-55%, and the dosage of gas may contain 4-8 mL. In another example, the gas may be hydrogen peroxide at a concentration of 25%-75%.The residence time may be 1-2 times, 2-3 times, 3-4 times, 5-6 times, 6-7 times, 7-8 times, 8-9 times, or 9-10 times the manufacturer specified D value for the viable spore population, or any other suitable multiple compared to the specified D value. The acceptable remaining amount of viable spore population may be 100 ppm, 10 ppm, 2 ppm, 1 ppm, or any other suitable amount. Circulating the dose of gas through the chamber for the residence time as in block 404 may be performed by at least one of one or more processors controlling hardware with commands or control signals, or by a human. For example, a human may input the dose and residence time (e.g., by entering numbers on a graphical user interface generated by one or more processors), or a pump, fan, or other device driven by one or more processors may release and / or circulate the dose of gas through the chamber for the residence time.

[0045] Finally, in the illustrated method 400, the chamber is aerated (block 406) until the gas remaining in the chamber is equal to or less than the allowable residual amount. The allowable residual amount of gas may be 100 ppm, 10 ppm, 2 ppm, 1 ppm, or any other allowable amount of gas. The allowable residual amount of gas may be relative to air. For example, if the allowable residual amount of gas is 1 ppm, it may mean that there is one part of gas for every one million parts of air in the chamber. Aeration of the chamber as in block 406 may be performed by at least one of the one or more processors instructing the hardware or by a human. For example, a human may input the allowable residual amount of gas (e.g., by entering a number on a graphical user interface generated by the one or more processors), and a pump or other device driven by the one or more processors may aerate the chamber until the gas remaining in the chamber is equal to or less than the allowable residual amount.

[0046] Upon completion of method 400, the chamber interior may be considered decontaminated. For the example isolator 100 of FIG. 1, if method 400 is performed according to a full system decontamination, the filled isolator chamber 104 and the seal of the interior door 110 may be considered decontaminated. If method 400 is performed according to a filled isolator decontamination cycle, the filled isolator chamber 104 of FIG. 1 may be considered decontaminated. If method 400 is performed according to a decontamination cycle isolator decontamination cycle, the DSI chamber 102 of FIG. 1 may be considered decontaminated.

[0047] Method 400 may be performed entirely by a human operator in some embodiments. Alternatively, method 400 may be performed entirely by automation, such as by one or more processors (e.g., a CPU and / or a GPU) executing instructions stored in one or more non-transitory computer-readable storage media (e.g., volatile or non-volatile memory, read-only memory, random access memory, flash memory, electronically erasable program read-only memory, and / or one or more other types of memory). In yet other embodiments, method 400 is performed in part by a human operator and in part by one or more processors executing instructions.

[0048] 5 is a flow diagram illustrating an example method 500 of selecting parameters for a decontamination cycle in a chamber using a vapor phase hydrogen peroxide decontamination cycle. Specifically, the parameters include at least a dosage and a residence time for a VPHP decontamination cycle.

[0049] In the illustrated method 500, multiple experiments are performed testing multiple amounts of hydrogen peroxide-containing gas and multiple amounts of time (Block 502). For example, there may be five different amounts of gas tested and five different amounts of time tested, resulting in a total of 25 experiments assuming each experiment is performed once, or a total of 75 experiments if each experiment is performed in triplicate.

[0050] For each experiment in the plurality of experiments, a quantity of gas (i.e., one of the plurality of quantities of gas) is circulated within the chamber for one of the plurality of quantities of time (Block 502a). For each experiment in the plurality of experiments, a concentration of the quantity of gas within the chamber is monitored for the quantity of time (Block 502b). The concentration of the quantity of gas within the chamber may be monitored continuously or discretely using a suitable measurement device (e.g., a refractometer). After circulating the quantity of gas within the chamber for the quantity of time for each experiment in the plurality of experiments, a remaining amount of viable spores within the chamber is determined (Block 502c). Determining the remaining amount of viable spores within the chamber may be accomplished in a number of ways. One exemplary method for determining the remaining amount of viable spores within the chamber includes removing a BI containing a viable spore population and incubating the BI in a growth-promoting medium for 7 days. Assuming that the BI was inoculated with a viable spore population containing more than 1 million CFUs, a lack of growth after 7 days indicates that less than 1 ppm of viable spore population remains. Any cell growth within the 7 day incubation period indicates that a viable spore population of greater than 1 ppm remains.

[0051] The illustrated method 500 then selects from among the multiple amounts of gas that is the smallest amount of gas that maintained full saturation in the chamber for a selected time when circulated through the chamber during multiple experiments (block 504). Full saturation may be identified by the appearance of a plateau or "table top" as shown in FIG. 2. In one embodiment, the selected time must be an amount of time equal to or greater than the residence time. In this embodiment, the residence time may not yet be known at the time the selected time is determined, and the selected time may need to be selected long enough to be equal to or greater than what the residence time is expected to be. For example, the selected time may be selected based on the D value of the viable spore population.

[0052] Finally, the illustrated method 500 selects a residence time (block 506) such that the residence time is (i) equal to or less than the selected time, and (ii) the smallest amount of time among the plurality of amounts during which the determined remaining amount of viable spores did not exceed an acceptable remaining amount when the bolus of gas was circulated in the chamber for the residence time while performing the plurality of experiments. In one embodiment, the residence time must be equal to or less than the selected time. If the residence time is longer than the selected time, it may not be possible to be certain that full saturation in the chamber will be maintained for the residence time. Thus, it may be necessary to repeat (possibly iteratively) at least a portion of the plurality of experiments using a longer selected time. The gas may be 10% hydrogen peroxide, 20% hydrogen peroxide, 30% hydrogen peroxide, 40% hydrogen peroxide, 50% hydrogen peroxide, 60% hydrogen peroxide, 70% hydrogen peroxide, 80% hydrogen peroxide, or any other suitable hydrogen peroxide concentration. The dosage may be 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 15 mL, 20 mL, 25 mL, or any other suitable dosage of gas. The residence time may be 10 seconds, 30 seconds, 60 seconds, 100 seconds, 200 seconds, 300 seconds, 400 seconds, 500 seconds, 750 seconds, 1000 seconds, or any other suitable residence time. The residence time may be 250-350 seconds, 300-500 seconds, or any other suitable range. In a more specific example, the gas may be hydrogen peroxide at a concentration of 45%-55%, and the dosage of gas may contain 6-10 mL of gas. In another example, the gas may be hydrogen peroxide at a concentration of 45%-55%, and the dosage of gas may contain 4-8 mL. In another example, the gas may be hydrogen peroxide at a concentration of 25%-75%. The residence time can be 1-2 times, 2-3 times, 3-4 times, 5-6 times, 6-7 times, 7-8 times, 8-9 times, or 9-10 times the manufacturer specified D value for the viable spore population, or any other suitable multiple of the specified D value. The acceptable residual amount of viable spore population can be 100 ppm, 10 ppm, 2 ppm, 1 ppm, or any other suitable amount.

[0053] In some embodiments, the method 500 also includes, after block 506, performing a VPHP decontamination using a selected dosage and dwell time (eg, as per the method 400 illustrated in FIG. 4).

[0054] Method 500 may be performed entirely by a human operator in some embodiments. Alternatively, method 500 may be performed entirely by automation, e.g., by one or more processors (e.g., a CPU and / or a GPU) executing instructions stored in one or more non-transitory computer-readable storage media (e.g., volatile or non-volatile memory, read-only memory, random access memory, flash memory, electronically erasable program read-only memory, and / or one or more other types of memory). In yet other embodiments, method 500 is performed in part by a human operator and in part by one or more processors executing instructions. For example, an experiment may begin when a person inputs an instruction (e.g., pressing a virtual button on a graphical user interface generated by one or more processors), in response to which one or more actuators, pumps, fans, or other devices may be activated by one or more processors to perform the experiment.

[0055] Some figures described herein illustrate example block diagrams having one or more functional components. It will be understood that such block diagrams are for illustrative purposes, and that the devices described and illustrated may have additional, fewer, or alternative components than those described. Additionally, in various embodiments, the components (and the functionality provided by each component) may be combined with, or otherwise integrated as part of, any suitable component.

[0056] Some embodiments of the present disclosure relate to non-transitory computer-readable storage media having instructions / computer-readable storage media for performing various computer-implemented operations. The term "instructions / computer-readable storage media" is used herein to include any medium capable of storing or encoding a sequence of instructions or computer code for performing the operations, methodologies, and techniques described herein. The media and computer code may be specially designed and constructed for the purposes of the embodiments of the present disclosure, or they may be of a type known and available to those skilled in the computer software arts. Examples of computer-readable storage media include, but are not limited to, magnetic media such as hard disks, floppy disks, and magnetic tapes, optical media such as CD-ROMs and holographic devices, magneto-optical media such as optical disks, and hardware devices specially configured to store and execute program code, such as ASICs, programmable logic devices ("PLDs"), and ROM and RAM devices.

[0057] Examples of computer code include machine code, such as that produced by a compiler, and files containing advanced code executed by a computer using an interpreter or compiler. For example, an embodiment of the present disclosure may be implemented using Java, C++, or other object-oriented programming languages ​​and development tools. Further examples of computer code include encryption and compression code. Moreover, an embodiment of the present disclosure may be downloaded as a computer program product, which may be transferred from a remote computer (e.g., a server computer) to a requesting computer (e.g., a client computer or another server computer) over a transmission channel. Other embodiments of the present disclosure may be implemented in hardwired circuitry in place of, or in combination with, machine-executable software instructions.

[0058] As used herein, the singular terms "a," "an," and "the" can include plural referents unless the context clearly dictates otherwise.

[0059] As used herein, the terms "approximately," "substantially," "substantial," "about," and "about" are used to describe and take into account slight variations. When used in conjunction with an event or circumstance, these terms can refer to the exact occurrence of the event or circumstance as well as the occurrence of the event or circumstance to a very close approximation. For example, when used in conjunction with a numerical value, these terms can refer to a range of variation that is within ±10% of the numerical value, e.g., within ±5%, within ±4%, within ±3%, within ±2%, within ±1%, within ±0.5%, within ±0.1%, or within ±0.05%. For example, two numerical values ​​can be considered to be "substantially" the same if the difference between their values ​​is within ±10% of the mean value of the values, e.g., within ±5%, within ±4%, within ±3%, within ±2%, within ±1%, within ±0.5%, within ±0.1%, or within ±0.05%.

[0060] In addition, amounts, ratios, and other numerical values ​​are sometimes presented herein in a range format. It should be understood that such range format is used for convenience and brevity, and while it includes numerical values ​​explicitly set forth as range limits, it should be understood that the flexibility of including all individual numerical values ​​or subranges subsumed within the range is also included as if each numerical value and subrange were explicitly set forth.

[0061] Although the present disclosure has been described and illustrated with reference to specific embodiments thereof, the disclosure is not limited by such descriptions and illustrations. It should be understood by those skilled in the art that various modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the present disclosure as defined by the appended claims. The illustrative figures are not necessarily drawn to scale. There may be differences between the artistic depictions in the present disclosure and the actual devices due to manufacturing processes, tolerances and / or other reasons. There may be other embodiments of the present disclosure that are not specifically described. The specification (except for the claims) and the drawings should be regarded as illustrative rather than restrictive. Modifications may be made to adapt the particular circumstances, materials, compositions of matter, techniques, or methods to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto. Although the techniques disclosed herein are described with reference to certain operations performed in a particular order, it will be understood that the operations may be combined, sub-divided, or rearranged to form equivalent techniques without departing from the teachings of the present disclosure. Thus, unless specifically indicated herein, the order and organization of operations is not a limitation of the present disclosure.

Claims

1. 1. A method for decontaminating a chamber interior using a vapor phase hydrogen peroxide decontamination cycle, comprising: sealing the chamber from the external environment while the viable spore population is within the chamber; circulating a dose of hydrogen peroxide-containing gas through the chamber for a residence time; the applied amount of the gas is a minimum amount of the gas that, within a first tolerance, when circulated through the chamber, maintains full saturation within the chamber for the residence time; and the residence time being a minimum amount of time the viable spore population is exposed to the dose of the gas to reduce the viable spore population to an acceptable residual amount, within a second tolerance range; and aerating the chamber after circulating the dose of gas through the chamber for the residence time until no more than an acceptable residual amount of the gas remains within the chamber. In a method comprising: The method, wherein the first tolerance range and the second tolerance range are each 20% or less.

2. The method of claim 1 , wherein the first tolerance range and the second tolerance range are each less than or equal to 10%.

3. The method of claim 1 , wherein the chamber interior comprises the interior of a chamber of an isolator.

4. The gas phase decontamination cycle comprises: a full system decontamination cycle, and the chamber interior includes a decontamination preparation isolator chamber and a fill isolator chamber; or a filled isolator decontamination cycle, and wherein the chamber interior comprises a filled isolator chamber interior, and optionally 4. The method of claim 3, wherein the gas is 45% to 55% hydrogen peroxide and the dose of gas comprises 6 to 10 milliliters of the 45% to 55% hydrogen peroxide.

5. 4. The method of claim 3, wherein the residence time is from 300 to 500 seconds.

6. the vapor-phase decontamination cycle is a decontamination preparation isolator decontamination cycle; the chamber interior comprises a decontamination preparation isolator chamber interior, and optionally 4. The method of claim 3, wherein the gas is 45% to 55% concentrated hydrogen peroxide, and the dose of the gas is 4 to 8 milliliters of the 45% to 55% concentrated hydrogen peroxide.

7. 7. The method of claim 6, wherein the residence time is from 250 to 350 seconds.

8. 8. The method of any one of claims 1 to 7, wherein the acceptable remaining amount of the viable spore population is selected from the group consisting of 1 part per million of the viable spore population, 2 parts per million of the viable spore population, and 10 parts per million of the viable spore population.

9. 8. The method of any one of claims 1 to 7, wherein the residence time is 5 to 7 times the designated D value of the viable spore population.

10. 1. A method for selecting a decontamination cycle dosage and residence time within a chamber using a vapor phase hydrogen peroxide decontamination cycle, comprising: conducting a plurality of experiments testing a plurality of amounts of hydrogen peroxide-containing gas and a plurality of amounts of time, wherein conducting the plurality of experiments includes, for each experiment in the plurality of experiments: circulating a quantity of the gas within the chamber for a period of time among the plurality of periods of time; monitoring the concentration of the amount of gas in the chamber for the amount of time; and determining the remaining amount of viable spores in the chamber after circulating the amount of gas through the chamber for the amount of time; containing; selecting the dose of gas from among the plurality of amounts of gas that is the smallest amount of gas that, when circulated through the chamber during the plurality of experiments, maintained full saturation within the chamber for a selected time; and selecting the residence time such that (i) the residence time is equal to or less than the selected time, and (ii) the residence time is the smallest amount of time among the plurality of amounts during which the determined residual amount of viable spores does not exceed an acceptable residual amount when the selected dose of gas is circulated through the chamber for the residence time during the plurality of experiments. A method comprising:

11. The method of claim 10 , wherein the chamber interior comprises the interior of an isolator chamber.

12. The gas phase decontamination cycle comprises: a full system decontamination cycle, and the chamber interior includes a decontamination preparation isolator chamber and a fill isolator chamber; or a filled isolator decontamination cycle, and wherein the chamber interior comprises a filled isolator chamber interior, and optionally 12. The method of claim 11, wherein the gas is 45% to 55% hydrogen peroxide and the dose of gas comprises 6 to 10 milliliters of the 45% to 55% hydrogen peroxide.

13. 13. The method of claim 12, wherein the residence time is from 300 to 500 seconds.

14. the gas-phase decontamination cycle is a decontamination preparation isolator decontamination cycle, and the chamber interior comprises the interior of a decontamination preparation isolator chamber; the gas is 45% to 55% hydrogen peroxide, and the dose of the gas is 4 to 8 milliliters of the 45% to 55% hydrogen peroxide; and optionally The method of claim 11, wherein the residence time is from 250 to 350 seconds.

15. 15. The method of any one of claims 10 to 14, further comprising decontaminating the interior of the chamber using the vapor phase hydrogen peroxide decontamination cycle at the selected dosage and the selected residence time.

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